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Review article
a r t i c l e i n f o a b s t r a c t
Article history: In spite of the development of a large number of novel anticancer drugs over the years, Cancer remains as
Received 31 May 2017 a prominent cause of death, worldwide. Numerous drugs that are currently in clinical practice have
Received in revised form developed multidrug resistance along with fatal side effects. Therefore, the utilization of single-target
13 July 2017
therapy is incapable of providing an effective control on the malignant process. Molecular hybridiza-
Accepted 18 July 2017
Available online 20 July 2017
tion, involving a combination of two or more pharmacophores of bioactive scaffolds to generate a single
molecular architecture with improved affinity and activity, in comparison to their parent molecules, has
emerged as a promising strategy in recent drug discovery research. Hybrid anticancer drugs are of great
Keywords:
Cancer
therapeutic interests since they can potentially overcome most of the pharmacokinetic drawbacks
Anticancer hybrids encountered with conventional anticancer drugs. Strategically, the design of anticancer drugs involved
Structure-activity relationship the blending or linking of an anticancer drug with another anticancer drug or a carrier molecule which
Mechanism of action can efficiently target cancer cells with improved biological potential. Major advantages of hybrid anti-
cancer drugs involved increased specificity, better patient compliance, and lower side effects along with
reduction in chemo-resistance. The successful utilization of this technique in design and synthesis of
novel anticancer hybrids has been well illustrated and documented in the literature. The purpose of the
present review article will be to provide an emphasis on the recent developments (2015e16) in anti-
cancer hybrids with insights into their structure-activity relationship (SAR) and mechanism of action.
© 2017 Elsevier Masson SAS. All rights reserved.
Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180
2. Anticancer molecular hybrids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180
2.1. Curcumin based hybrids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180
2.2. Benzimidazole based hybrids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181
2.3. Pyrimidine based hybrids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183
2.4. Coumarin based hybrids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187
2.5. Pyrazole based hybrids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 190
2.6. Quinoline based hybrids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193
2.7. Quinone based hybrids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193
2.8. Quinazoline based hybrids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194
2.9. Pyridine based hybrids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195
2.10. Triazole based hybrids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199
2.11. Isatin based hybrids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201
2.11.1. Chalcone based hybrids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203
2.12. Imidazole based hybrid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204
2.13. Selenium/sulfur based hybrids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204
* Corresponding author.
** Corresponding author.
E-mail addresses: singhp4@ukzn.ac.za (P. Singh), vipan_org@yahoo.com
(V. Kumar).
http://dx.doi.org/10.1016/j.ejmech.2017.07.033
0223-5234/© 2017 Elsevier Masson SAS. All rights reserved.
180 N. Kerru et al. / European Journal of Medicinal Chemistry 142 (2017) 179e212
Quinolone
O OH O OH
R H3C
N O OH N O OH
R1 1 O O
1a Curcumin
R = -H, -Cl, -F, -OCH3, -CH3
R1 = -H, allyl, propargly, benzyl
Fig. 2. Curcumin-quinolone hybrids (1) with the potent anti-cancer compound 1a.
O O
H3CO Isatin
H3CO OCH3
X
R
O O OCH3
Curcumin OCH3
N N
N N N N N N
O O
O 2 2a
O
R = H, Cl, Br
H3CO
X=
H3CO OCH3 OCH3 OCH3
OCzH3 OCH3 OCH3
1 2 3 4 5 6 7
O S
Br NO2
Cl Br NO2
8 9 10 11 12 13 14
Fig. 4. Curcumin-imidazol hybrids (3) with the potent antiproliferative hybrid 3a.
Fig. 5. Curcumin-benzimidazol hybrids (4) with the potent anti-proliferative hybrids 4a-b.
potential. Benzimidazole exhibits its structural resemblance with and TGI levels, respectively. The presence of a 4-chloro substituent
purines, because of which it can easily interact with various bio- at the phenyl ring on benzimidazole enhanced the anticancer ac-
molecules. Recent reports have shown the anti-cancer potential of tivity compared to the methyl, methoxy, or the hydroxyl groups.
substituted benzimidazoles while its hybrids with other heterocy- Further, in vitro interactions between 6a and human serum albumin
clic moieties have displayed improved anticancer activities [22]. (HSA) revealed the importance of hydrogen bonding and Vander
Singla et al. reported the synthesis and anticancer evaluation of Waals interactions in their interface. Further investigation revealed
benzimidazole-triazine hybrids (5, Fig. 6) against NCI-60 cell panel that the hybrid 6a induced cell cycle arrest at G0/G1 phase.
including nine tumour cell lines [23]. Among the evaluated hybrids, Sharma et al. [25] reported the synthesis and anticancer eval-
three compounds viz. 5a, 5b and 5c displayed prominent cell uation of benzimidazole-purine hybrids (7, Fig. 8) against the NCI-
growth inhibition at a concentration of 105 M against variety of 60 cell panel at a single dose of 10 mM concentration. The repre-
cancer cell lines. These compounds were further chosen for sentative compound 7a exhibited considerable inhibition towards
screening against a panel of 60 different tumour cell lines at 5-dose ovarian cancer, CNS cancer and colon cancer cell lines with GI50
concentration range viz. 104, 105, 106, 107 and 108 M. Hybrid values of 1.34, 2.00 and 3.16 mM, respectively. Also, compound 7a
5a showed good antitumor activity with growth inhibition (GI50) (MG-MID GI50 ¼ 18.12 mM) presented 1.25 fold greater activity than
values in the range of 3.56e19.0 mM against nine tumour subpanels 5-fluorouracil (5-FU), and was selective (IC50 ¼ 0.01 mM) towards
with the mean graph mid-point (MG-MID) GI50 value of 9.79 mM. Aurora-A kinase inhibition. Subsequently, QSAR model was devel-
Further, dihydrofolate reductase (DHFR) inhibition assay of the oped with good predictive ability for the affinity of this series of
promising hybrids 5a, 5b and 5c was performed to investigate their Aurora A kinase inhibitors with physicochemical descriptors. Mo-
mechanism of action. Hybrids 5a and 5c revealed excellent inhi- lecular docking studies explored the favourable binding of 7a with
bition potential while compound 5b was found to be ineffective the active site residues (His644, Asp622, Ser625 and Arg626) of
towards DHFR assay. The presence of -chloro substituent at the C-6 Aurora-A.
position of triazine significantly improved the inhibitory activity. Singla and co-workers reported the synthesis and anticancer
Benzimidazole-chalcone hybrids (6, Fig. 7) synthesized by studies of benzimidazole-triazine hybrids (8 and 9; Fig. 9) against
Kalalbandi and co-workers exhibited good to moderate anticancer the NCI-60 cell panel [26]. Four hybrids, 8a, 9a, 9b and 9c exhibited
activity against the NCI-60 cell panel [24]. Compound 6a, the pro- remarkable activity against leukemia cancer cell lines (SR) with GI50
totype of the series, displayed good antitumor activity (GI50 values of 731, 125, 539 and 31 nM, respectively. Moreover, these
values ¼ 0.38e3.13 mM) against nine tumour subpanel cell lines compounds also showed promising activity against renal cancer
(leukemia, non-small cell lung cancer, colon cancer, CNS cancer, cell lines RXF393 (GI50 < 750 nM). The presence of an aryl moiety
melanoma, ovarian cancer, renal cancer, prostate cancer and breast on the triazine ring positively influenced the anticancer activity of
cancer) with selectivity ratios of 0.79e1.53 and 0.47e1.69 at GI50 the hybrids. The strong binding affinity of hybrids with the bovine
N. Kerru et al. / European Journal of Medicinal Chemistry 142 (2017) 179e212 183
Benzimidazol
R
N N
CH3 CH3
HN N HN N
N N N N
R2R1N N N N N N Purine
H H
7
7a
R = Allyl, butyl
NR1R2 = morpholin-4-yl, piperidin-1-yl, pyrrolidin-1-yl, 4-methylpiperazin-1-yl, morpholin-4-yl,
piperidin-1-yl, pyrrolidin-1-yl, 4-methylpiperazin-1-yl, morpholin-4-yl, piperidin-1-yl,
pyrrolidin-1-yl, 4-methylpiperazin-1-yl, morpholin-4-yl, piperidin-1-yl, pyrrolidin-1-yl,
4-methylpiperazin-1-yl
Fig. 8. Benzimidazole-purine hybrids (7) with the potent compound 7a.
Fig. 9. Benzimidazole-triazine hybrids (8e9) with the potent compounds 8a, 9a-c.
N. Kerru et al. / European Journal of Medicinal Chemistry 142 (2017) 179e212 185
Fig. 10. Benzimidazole-pyrazole hybrids (10) with the potent compounds 10a-c.
H3C
R1
NH NH
CN CN
N N
OCH3
N S N S N
R2 N
HN N N HN N N
HN HN OCH3
O OH
N O N Pyrimidine OCH3
O
12 Triazole
12a
R1 = p-CH3, p-CH3, m-CF3, p-CH(CH3)2, p-
OCH3, o-OCH3, m-CF3, p-CH(CH3)2
R2 = 4-Isopropylphenyl , 3,4,5-
Trimethoxylphenyl, 3,4,5-Trimethoxylphenyl,
p-CH3, 4-Methylphenyl, 4-Methylphenyl
4-Bromophenyl, p-Br
CH3 CH3
H3C H3C
NH NH
CN CN
N N
OCH3
N S N N S N
HN N N HN N N
HN OCH3 HN Br
OH OH
N O OCH3 N O
12a 12a
N Pyrazole
H
N N
N N O
N HN
H 13a
N N Pyrimidine
R
N N O
HN N
R = H, Cl
13 R4 H
N N
R4 = cyclohexyl, 3-Cl-phenyl, 4-Cl-3-CF3-phenyl,
2-Cl-phenyl N N O
HN
13b
Cl
Fig. 13. Pyrimidine-pyrazolo hybrids (13) with the potent compound 13a.
N. Kerru et al. / European Journal of Medicinal Chemistry 142 (2017) 179e212 187
N H
H N N
R N
S N
14
R = 2-Cl, 3-Cl, 4-Cl, 2-BnO- 3-BnO, 4-BnO, 4-F, 4-Br, 4-BnCH2O, 4-Bn(CH2)2O, 4-Bn(CH2)3O
Pyrimidine
Thiazole N H H
H N N H N
N N N N
Bn
Bn S N S N
O O
14a 14b
Fig. 14. Diaminopyrimidine-thiazole hybrids (14) with the potent compounds 14a-b.
N
N N
O
N
N
S
HN
N N R
15
R = 4-FC6H4, 2,4-FC6H3, 3-CF3C6H4, (3-Cl-4-FC6H3), Cyclopropane, Cyclohexane, CH2-4-OCF3C6H4,
4-SCF3C6H4, 5(CF3)-1,3,4-thiadiazole, 4-F-benzothiazole, morpholine
Benzothiazol
N N
N N Pyrimidine N N
O O OCF3
N F N
N N
S S
N HN HN
N N N
15a
F 15b
N N
N N N N
O O
N F N
N N
S S S
HN HN
N N 15d N N CF3
15c SCF3 N N
the synthesized hybrids. Compound 16a emerged as the most 2.4. Coumarin based hybrids
potent compound of the series with IC50 of 7.68 and 6.51 mM against
Saos-2 and MCF-7 cell lines respectively. Further, gene expression Coumarin is considered as a privileged framework because of its
was investigated through microarray examination on MCF-7 cell abundance in naturally occurring products with diverse pharma-
lines. SAR studies suggested the role of side groups and their cological profiles such as lipid lowering agents, radical scavangers,
orientation on the increased anticancer activity. Molecular docking HIV integrase inhibitors as well as anti-invasive compounds
studies also supported the strong affinity of these hybrids to bind because of the inhibition of matrix metalloproteases (MMPs) [36].
and block Hsp90 protein.
188 N. Kerru et al. / European Journal of Medicinal Chemistry 142 (2017) 179e212
Pyrimidine Br
O O O O
R
N N N N N N
H H H H
O N Ph O N Ph
16 16a Acyl-urea
R= H3C H3CO F
CH3
O
Cl Br
H2N
Fig. 16. Pyrimidinyl acyl-urea hybrids (16) with the potent compound 16a.
O O
O O
O
N
R N
H R
17 18
R = H, Cl, Br, OH
Coumarin
Indole O
O Br O
OH
O
N
N O H
H
O 18a Br
19
Fig. 17. Indole-coumarin hybrids (17, 18 and 19) with the potent cytotoxic compound 18a.
Coumarin derivatives target a number of pathways in cancer such cycle arrest in the G2/M phase.
as kinase inhibition, cell cycle arrest, angiogenesis inhibition, heat Galayev et al. performed the conjugation of 7-hydroxy-8-
shock protein (HSP90) inhibition, telomerase inhibition, antimitotic methyl-coumarins (20, Fig. 18) with a variety of pharmacophores
activity, carbonic anhydrase inhibition, monocarboxylate trans- viz. pyrimidine, indole, pyran, pyrazole, tetrazolo [1,5-a]pyrimidine,
porters inhibition, aromatase inhibition and sulfatase inhibition 2-oxo-1,2-dihydropyridine, dihydropyrazolo [3,4-b]pyridine and
[37]. pyrimido [1,2-a]benzimidazole, and tested their cytotoxicity
Three series of coumarin-indole hybrids (17e19, Fig. 17) were against the NCI-60 cell panel [39]. Anticancer screening data
synthesized and tested for their in vitro cytotoxicity against human revealed the influence of nature of substituent present at C-6 po-
breast adenocarcinoma (MCF-7) and normal cell lines using MTT sition of indole ring as well as at C-3 and C-4 position of coumarin
assay and compared with that of the standard drug, vincristine [38]. on the anticancer activity. SAR studies recognized indole-coumarin
Halogen-substituted hybrids showed good in vitro cytotoxic activity hybrid 20a, with fluoro substituent at C-6 position of indole ring,
against MCF-7 (breast cancer) cells as compared to their un- having high anti-mitotic activity against leukemia (GI50 ¼ 3.08 mM)
substituted or hydroxy-substituted analogues. SAR studies of syn- and melanoma (TGI ¼ 9.71 mM) cancer cell lines. The same com-
thesized indole-coumarin hybrids revealed enhancement in anti- pound exhibited highest correlation among synthesized com-
tumour potency with the introduction of a bromine substituent pounds, at GI50 level with glycopeptide antitumor antibiotic
on coumarin, which could be attributed to the increase in lip- Bleomycin [PCC (Pearson correlation coefficients) ¼ 0.595] and dual
ophilicity that favours the passage through bio-membranes. Com- inhibition of topoisomerase I and II, Aclacinomycin A (PCC ¼ 0.636).
pound 18a, with high lipophilicity and good ability to form Three series of coumarin-pyrazoline hybrids (21e23, Fig. 19)
hydrogen bonds, was recognized as the most potent analogue were synthesized and tested for their anti-proliferative activity
(IC50 ¼ 7.4 mM) among the series. In silico docking revealed against carcinoma hepato-cellular (HepG2) cell line [40]. Substi-
favourable binding of potent hybrids with the Bcl2. Also, flow tution pattern on pyrazoline ring influenced the anti-proliferative
cytometric cell cycle analysis of 18a revealed apoptosis due to cell activity. Hybrids with lipophilic moieties and without N-1
N. Kerru et al. / European Journal of Medicinal Chemistry 142 (2017) 179e212 189
CH3 CH3
Indole
HO O O HO O O
R1
NH R2 NH CH3
R3
20 20a Coumarin
F
R1 = H, CH3, (CH2)3, CH2)4
R2 = CH3, (CH2)3, CH2)4, (CH2)2CH3, CH2)3CH3
R3 = H, 6-F, 7-CH3, 5-Br
Fig. 18. Coumarin-indole hybrids (20) with the potent anticancer compound 20a.
Fig. 19. Coumarin-pyrazoline hybrids (21e23) with the potent compounds 21a, 22a and 23a.
substituent on the pyrazoline ring showed appreciable activity. The for their in vitro antitumor activity against the NCI 60-cell panel
potent compounds viz. 21a, 22a and 23a with IC50 values of 10, 15 [41]. SAR of anti-cancer activity data revealed that the nature of
and 18 nM, respectively showed reasonable reduction in telome- substituent present at C-3 and C-6 position of imidazo[1,2-a]pyr-
rase activity (61.7e78%). Furthermore, most potent hybrid, 21a azine influenced the biological potency. The symmetrical diarylated
screened for apoptosis induction displayed apoptosis in a dose hybrids 24a-b showed potent anticancer activity towards most of
dependent manner. the cancer cell lines along with good lipophilicity and drug
Novel imidazo [1,2-a]pyrazine-coumarin hybrids (24, Fig. 20) bioavailability. Compounds, 24a and 24b displayed excellent anti-
were synthesized via Suzuki-Miyaura cross coupling and screened cancer activity with GI values of 90% against renal (A-498) and 93%
190 N. Kerru et al. / European Journal of Medicinal Chemistry 142 (2017) 179e212
Fig. 20. Coumarin-pyrazine hybrids (24) with the potent compounds 24a-b.
Fig. 21. Coumarin-triazole hybrids (25) with the potent compounds 25a.
against breast (MDA-MB-231/ATCC) cancer cell lines. The most benzimidazoles and indole rings on the main core improved the
potent hybrid, 24b exhibited 17% toxicity at a concentration of anticancer activity. Hybrid 25a, induced cell death via triggering
100 mM to normal human embryonic kidney cells (Hek293) in the early apoptosis. Significantly, anticancer properties of hybrid 25a in
MTT assay. Molecular docking studies were in good agreement with HepG2 cells could be linked with its inhibition of 5-lipoxygenase
inhibitory potential of hybrid, 24a. (5-LO).
The coumarin-triazole hybrids (25, Fig. 21), synthesized by
Kraljevic and co-workers using Cu-catalyzed azide-alkyne cyclo- 2.5. Pyrazole based hybrids
addition strategy, emerged as prospective anti-proliferating hy-
brids against A-549 (lung) and HeLa (cervical) carcinoma cell lines Abd El-Karim and co-workers [43] explored the synthesis of
with IC50 < 30 mM [42]. 7-methylcoumarin-1H-1,2,3-triazole-2- novel pyazole-benzofuran hybrids (26, Fig. 22) and their in vitro
ethyl-benzimidazole 25a displayed highest cytotoxicity among anticancer evaluation against the NCI 60-cell panel on a single dose
synthesized hybrids with IC50 value of 0.90 mM against HepG2 concentration (105 M). The analogues with 3-furano-isoxazole
(hepatocellular) cell line, and a selectivity index of 50, but some- and 3-furano-N-acetylpyrazoline rings resulted in hybrids with
what toxic to normal fibroblasts WI38 and 3T3 (IC50 ¼ 45.33 mM). broad spectrum anticancer activities. The most potent hybrid 26a
The introduction of fused heterocycles such as benzothiazole, with GI50 ranging between 1.00 and 2.71 mM displayed a
N. Kerru et al. / European Journal of Medicinal Chemistry 142 (2017) 179e212 191
Pyrazole
R N O
N N O
N H N
O N N
O N N
26
Benzofuran 26a
Fig. 22. Pyrazole-benzofuran hybrids (26) with the potent anticancer hybrid 26a.
noteworthy growth inhibitory activity pattern against leukemia better inhibitory effects on mushroom tyrosinase than the positive
(CCRF-CEM, MOLT-4), breast cancer (HS 578T, T-47D), lung cancer control. Among these, compound 27a exhibited promising anti-
(HOP-92), CNS cancer (SNB-75), ovarian cancer (IGROV1), colon cancer activity (IC50 ¼ 0.9e2.2 mM) towards all tested cell lines,
cancer (HCC-2998), melanoma (SK-MEL-2) and renal cancer whereas hybrid 28a (IC50 ¼ 4.72 mM) displayed three folds greater
(786e0, RXF 393). Furthermore, 26a proved to be a good inhibitor tyrosinase inhibition than kojic acid (IC50 ¼ 12.42 mM). SAR analysis
of c-Src at10 mM. Molecular docking studies of synthesized hybrids disclosed the importance of pyrazoline in the anticancer activity as
were performed with binding site of Src kinase with 26a displaying its absence decreased the activity significantly against all tested
excellent fitting with these binding sites. Additionally, hybrid 26a cancer cell lines. To investigate the interactions of these compounds
fulfilled Lipinski's rule of five along with ADME profile making it a with tyrosinase enzyme, molecular modelling studies were per-
promising scaffold for future amendments. formed, the results of which agreed well with the in vitro tumour
Qin et al. tested the inhibitory effects of pyrazoline-benzofuran cell inhibitory activity.
hybrids (27 and 28, Fig. 23) on the diphenolase activity of mush- A series of pyrazole-triazole hybrids (29, Fig. 24) were synthe-
room tyrosinase along with their anti-proliferation studies against sized by Reddy and co-workers displayed remarkable cell growth
a panel of cancer cell lines [44]. Four compounds exhibited the inhibition against four human tumour cell lines viz. HT-29 (colon),
R N S Benzofuran
N
NH2 Pyrazole
O
R4 R1 N
S
N
R2
NH2
R3
27
O
27a
N
R=
O ,
O
R1 = H, OCH3
R2 = H, OCH3; R3 = N(CH3)2, H, OCH3
R4 = H, OCH3
R N O O
N N
HN Cl O
N
R4 R1 HN
Cl
R2
R3 28a
N
28
Fig. 23. Pyrazole-benzofuran hybrids (27 and 28) with the potent anticancer hybrids 27a, 28a.
192 N. Kerru et al. / European Journal of Medicinal Chemistry 142 (2017) 179e212
R Triazole
F
O
N O OCH3
N N
R1 N
N OCH3
N N
N N
N
29 Pyrazole
29a
Cl
H3CO
O OCH3
N O OCH3
N N
OCH3 N
N OCH3
N
N
N N
N
29b 29c
PC-3 (prostate), A549 (lung) and U87MG (glioblastoma), as exem- functionalized pyrazoles (30). The anti-proliferative evaluation of
plified by 29a-c which showed superior cytotoxic activity the synthesized compounds against Bcap-37, MGC-803 and SGC-
(IC50 ¼ 0.86e3.72 mM) to the reference drug (5-FU) [45]. Flow 7901 cell lines disclosed four potential anticancer compounds with
cytometry analysis indicated that these compounds induced cell IC50 < 7.5 mM for the MGC-803 cell line. The representative com-
cycle arrest at the G1 phase. For U87MG cells, the synthesized hy- pound 30a displayed superior activity to 5-FU, and showed the
brids induced apoptosis via mitochondrial pathway through up- following toxicity order: MGC-803 (IC50 ¼ 3.01 mM) > SGC-7901
regulation of pro-apoptotic (Bax) and down-regulation of anti- (IC50 ¼ 8.30 mM) > Bcap-37 (IC50 ¼ 10.50 mM). Interestingly,
apoptotic (Bcl-2) genes. incorporation of a pyrimidine ring in this class of compounds
Novel pyrazole-pyrimidine hybrids (31, Fig. 25) were developed decreased their anti-proliferative activity. The most potent
by Shi et al. [46] using a base induced cyclization reaction of the pyrazole-pyrimidine analogue (31b) with an IC50 value of 7.14 mM
Pyrazole
O Pyrimidine O
O N N N
HN O HN N
N N N N
R N O O
H R N N N
NH2 H
O NH2 31a
30a O
30 31
O
O O
R = O
O O
O O O O
Fig. 25. Functionalized pyrazole (30) and Pyrazoloepyrimidine hybrids (31) with potent compounds 30a and 31a.
N. Kerru et al. / European Journal of Medicinal Chemistry 142 (2017) 179e212 193
displayed lower activity than 5-FU. Flow cytometric analysis of 30a improvement in the cytotoxicity of both compounds was observed
on MGC-803 cell lines showed cell arrest in S phase. The docking with respect to the parent phenol 32, which could be attributed to
studies of 30a into the active site containing ASP 254 simulated better cellular uptake and subsequent metabolism.
binding of compound into catalytic subunit of tolmerase (TERT). Tang et al. described the synthesis and screening of another
series of 6-aryl-indenoisoquinolone hybrids (35, Fig. 28) as dual
inhibitors of oestrogen receptor ERa and vascular endothelial
2.6. Quinoline based hybrids
growth factor receptor-2(VEGFR-2) [49]. Most hybrids exhibited
good inhibitory activities towards ERa with exceptional anti-
Quinoline-stilbene hybrids (32, Fig. 26) developed by Srivastava
proliferative activities against human endometrial cancer cell line
et al. were evaluated for their anti-proliferative activity against
(Ishikawa), human breast cancer cell lines (MDA-MB-231 and MCF-
various cancer cell lines [47]. Among twenty five synthesized
7) while some of them exhibited potent VEGFR-2 inhibitory activ-
compounds, three cis-compounds (32a-c) exhibited potent anti-
ity. SAR indicated reduction in anti-proliferative activity with in-
proliferative activity with IC50 less than 4 mM being two folds
crease in length of side chain against MCF-7 and MDA-MB-231 cell
more selective against cancer cells as compared to non-cancerous
lines. Compound 35a exhibited the strongest inhibition for both
cells. The trans-hybrid 32d, showed amazingly high activity
targets, and was able to inhibit the activation of VEGFR-2 and
against MDA-MB 468 breast cancer cells (IC50 ¼ 0.12 mM). Data from
signaling transduction in the Raf-1/MAPK/ERK pathway in MCF-
flow cytometry and immune fluorescence microscopy confirmed
7 cells.
that 32d resulted in significant DNA damage with the consequential
cell cycle arrest in the S-phase and eventual apoptosis. The cis-
compound, 32a with an IC50 of 6.01 mM against MCF-7 caused 2.7. Quinone based hybrids
prolonged cell cycle arrest at the spindle checkpoint step, which
ultimately resulted in cell death via apoptosis. In silico molecular The conjugation of anthraquinone and chalcone pharmaco-
modelling studies were in agreement with experimental data and phores (36, Fig. 29) was reported by Markovi and co-workers [50].
predicted that the compound 32a binds in the same cavity where Three hybrids 36a-c with encouraging anticancer activity
podophyllotoxin binds. (IC50 ¼ 2.73e2.36 mM) equivalent to cisplatin against HeLa (cervix
The cytotoxic evaluation of indeno-isoquinoline hybrids (34, cancer) cells and low cytotoxicity for MRC-5 (non-cancerous) cell
Fig. 27) resulted in several potent derivatives with GI50 line was identified. These hybrids showed selective cytotoxic effect
values < 10 nM against a variety of human cancer cell lines [48]. especially on HeLa cells promoting accumulation of cells in the S
Compounds 34a and 33b with GI50 values < 0.01 mM showed and G2/M phase and kills cancerous cells by inducing caspase-
promising activity against MCF-7 (breast), DU-145 (prostate), dependent apoptosis. From SAR point of view, the hybrids with
SN12C (renal) and SF-539 (CNS) cancer cell lines. A noteworthy the two enone units displayed higher anticancer activity than those
R2
R3 R1 R1 = H, CF3
R2 = H, CF3
R4 R3 = H, F, CF3
R4 = H, CF3
R5
R5 = H, OCH3, -OCH2O-
R6 = H, Cl
R6 N Cl
32
H3CO H3CO
N Cl
N Cl N Cl N Cl 32d
32a Quinoline 32b 32b
Fig. 27. Indenoisoquinoline prodrugs (34) with the two potent antiproliferative hybrids 34a-b.
Fig. 28. 6-Aryl-indenoisoquinolone hybrids (35) with the potent anti-breast cancer hybrid 35a.
with a single enone unit without any noticeable influence of the on the quinazoline ring and methoxy or chlorine functionalities on
nature and position of the substituents. the isatin moiety enhanced the anticancer activity whereas com-
Jiang and co-workers generated a new series of tricyclic pound with thiophene functionality at quinazoline ring proved to
quinone-based hybrids (37, Fig. 30) by coupling its nucleus with be less potent.
pyran and lactone moieties, and tested their anticancer activity Qiao et al. explored the anticancer potential of novel quinazo-
against various cancer cell lines [51]. Most of the synthesized hy- line-1,3,4-oxadiazole hybrids (40, Fig. 32) against A549 (lung),
brids exhibited significant anticancer activity, as exemplified by 36a MCF-7 (breast) and HeLa (cervix) cancer cell lines [45,53]. Hybrids
with IC50 ¼ 0.66 mg/mL against KB cells which is comparable with bearing substituted aromatic rings displayed superior activity with
standard drug, vincristine (IC50 ¼ 0.46 mg/mL). respect to their phenyl analogues. SAR suggested the dependence
of anticancer potential on the nature and position of substituent on
2.8. Quinazoline based hybrids phenylacetic acid. The presence of electron releasing substituents
(CH3 or OCH3) increased VEGFR2 inhibitory activity more than
Alafeefy and co-workers synthesized a series of quinazoline- electron withdrawing substituents (such as F, Cl, Br). Compounds
indole hybrids (39, Fig. 31) via intramolecular condensation reac- with a methoxy substituent at m- or p-position of phenylacetic acid
tion of the corresponding benzamides (37) [52]. The antitumor displayed higher antitumor activity than at o-position against MCF-
evaluation of both sets (38 and 39) disclosed three compounds 38a 7. Furthermore, a comparison of halogen group (F, Cl, Br) at the p-
(IC50 ¼ 1.86 mg/mL), 38b (IC50 ¼ 4.42 mg/mL) and 39a position on phenylacetic acid revealed the potency order of VEGFR2
(IC50 ¼ 1.46 mg/mL) with potent anticancer activity against the Daoy inhibitory activity as: F < Cl < Br. Compound 40a emerged as the
(medulloblastoma) cancer cell line. The presence of a p-tolyl group most potent compound (IC50 ¼ 0.230 mM for MCF-7, 0.38 mM for
N. Kerru et al. / European Journal of Medicinal Chemistry 142 (2017) 179e212 195
O
O
Anthraquinone
R
O
O O
O
Chalcone
36 36a
O
O
R = H, 2-CH3, 3-CH3, 4-CH3, 2-OCH3, 3-OCH3, 4-OCH3, 2-F, 4-F, 2-NO2
O CH3 O NO2
O O
O O
36b 36c
O O
O Lactone
R O
N O O O
H
N N O O
H H
O N
H
O O
Pyran
37 O
37a
Quinone
N
R= N N
N N O O
O Boc
Fig. 30. Quinone-pyran-lactone hybrids (37) with the potent anticancer compound 37a.
A549 and 0.32 mM for HeLa) of the series with comparable activity 2.9. Pyridine based hybrids
to the positive control Tivozanib. In silico docking simulations
further disclosed the importance of four amino acids (Lys868, Pyridine constitutes imperative class of heterocycles with
Cys919, His1026 and Asp1046) in the host-guest relationship be- interesting anticancer profiles. Sorafenib, Regorafenib, Vismodegib
tween 40a and VEGFR through pp interactions and hydrogen and Crizotinib are few important clinically approved pyridine-
bonding. containing anticancer drugs [54]. Pyridine-based hydrazone has
196 N. Kerru et al. / European Journal of Medicinal Chemistry 142 (2017) 179e212
R
R
O
NH O
N NH
N N
H O N
NH O
N Ar
O Ar
39
38 R = H, Cl, Me, MeO, NO2
R = H, Cl, Me, MeO, NO2 Ar = 4-MeC6H4, thiophen-2-yl
Ar = 4-MeC6H4, 4-NO2C6H4
Cl O Cl Isatin
Quinazoline
O O O
N NH NH NH
N N
N N N
H O H O O
NH NH N
O O CH3
CH3 CH3 39a
38a 38b
N N Oxadiazole
O O N
N
O O
N N
R O
N N
40 40a O
Quinazoline
Br O
Cl NO2 F OCH3 Br
R=
OCH3
Fig. 32. Quinazoline-oxadiazole hybrids (40) with the potent analogue 40a.
shown to inhibit the growth of tested cancer cell lines at the NCI, (42, Fig. 33), prepared from corresponding hydrazone (41), for their
USA with no apparent animal toxicity. Pyridine-tethered com- anticancer potential against human liver (HepG2) cancer cell line
bretastatin-A4 hybrids have shown potent anticancer activities [56]. Three compounds 41 and 42a-b of the series showed superior
with the most potent compound displaying modest activities activity (IC50 ¼ 8.0, 8.4 and 10.3 mM) compared to the positive
against A549 lung cancer, MDA-MB-231 breast cancer and Hela control doxorubicin. The sulfonamide and pyridine moieties posi-
cervical cancer cell lines [55]. tively influenced the anticancer activity. Additionally, these potent
Ghorab et al. screened a series of pyridine-sulfonamide hybrids compounds showed interesting radio-sensitizing activity when g-
N. Kerru et al. / European Journal of Medicinal Chemistry 142 (2017) 179e212 197
O
H H2N O
N O O
N
O N N Ar
HN CN
O S O Ar CN HN O CN
O S O
41 42
Cl
Cl
O O
H2N O H2N O
N N N N
CH3
O HN O CN
HN O CN
O S O O S O
Pyridone
Sulfonamide
42b
42a
Cl Cl
Ar = C C O
O H H
Cl O O NO2
Cl N NO2
O
N
N
N R = 4-OMe, 3,4-diOMe, 3,5-diOMe, 3-OPh, 4-F
N NH R
R1 = 4-OMe, 3,4-diOMe, 3,5-diOMe, 4-F
R1 44
O Triazole O O
N N N
N N N
O O O
N N N NH N
N NH N NH
O
Pyridine O
44c
F 44a F 44b F
polymerization assay and immune-fluorescence analysis showed Shah and his team performed the conjugation of pyridine with
that these compounds effectively inhibited microtubule assembly sunitinib (an antitumor hybrid targeting tyrosine kinases), and
in human prostate cancer cells (DU-145). The authors also tested the cytotoxicity of resultant hybrids (46, Fig. 37) against
demonstrated favourable binding of 44c in the colchicine binding panel of cancer cell lines [60]. Prototype of series 46a
site of tubulin in silico. (IC50 ¼ 3.21 mM) exhibited superior anticancer activity to sunitinib
The same authors in another study coupled the pyridine and (IC50 ¼ 6.98 mM) against MDA-MB-231 through apoptosis induc-
chalcone motifs to generate hybrids 45 (Fig. 36) [59]. The cytotox- tion. This was interceded via an increase in p53 level and down-
icity evaluation of resultant hybrids against HeLa (cervical), A549 regulation of phospho-signal transducer and activator of tran-
(lung), MCF-7 (breast) and HCT116 (colon) cell lines revealed two scription 3 (STAT3) and its phosphorylation. The importance of the
potent compounds (45a and 45b) with IC50 values ranging from hydroxyl group at C-5 position in the anticancer activity was
0.51 to 1.29 mM. Flow cytometry results established that com- further established.
pounds 45a-b triggered G2/M cell-cycle arrest in A549 cell line. Liu et al. reported the synthesis of pyridine-indazole hybrids (47,
Moreover, 45a (IC50 ¼ 1.34 mM) displayed significant inhibition of Fig. 38) as potent inhibitors of threonine tyrosine kinases (TTK)
tubulin polymerization with respect to the standard drug, noco- [61]. Compound 47a displayed potent inhibition of a panel of 278
dazole (IC50 ¼ 2.64 mM) which was further supported by docking kinases, and was the most efficacious in an HCT 116 tumour xeno
studies. graft model (77% TGI at 35 mg/kg PO). Compound 47a impressively
Fig. 36. Pyridine-indole hybrids (45) with the potent cytotoxic hybrids 45a-b.
N. Kerru et al. / European Journal of Medicinal Chemistry 142 (2017) 179e212 199
Fig. 37. Pyridinol-Sunitinib hybrids (46) with the potent cytotoxic compound 46a.
OH
R''
N
O Pyridine Indazole
R''' O
N
H N
N N
H H N
N N
47 H
47a
N * *
R'' = * * * *
* F N N
F N
Cl
* N N
* * * * * *
N N N
N N N
OH OH
O O
R''' = O
N N
N N N
* *
* * *
Fig. 38. Pyridine-indazole-5-carboxamides hybrids (47) with the potent anticancer hybrid 47a.
attenuated the growth of BT-474 (GI50 ¼ 0.015 mM), MDA-MB-231 2.10. Triazole based hybrids
(GI50 ¼ 0.070 mM), MCF-7 (GI50 ¼ 0.015 mM), OV-90
(GI50 ¼ 0.030 mM), SKOV-3 (GI50 ¼ 0.017 mM) and TOV-21G A suite of 1,2,4-triazolo-quinoxalines analogues (48, Fig. 39)
(GI50 ¼ 0.016 mM). The authors demonstrated a rational separa- were designed, synthesized and tested for their anticancer poten-
tion of effects between TTK potency, human CYP and hERG activity tial against the NCI-60 cell panel by Issa et al. [62]. A representative
(1000-fold) for this compound. compound, 48a showed effective activity toward non-small cell
200 N. Kerru et al. / European Journal of Medicinal Chemistry 142 (2017) 179e212
Triazole
Cl
R1
N
N
N N
N N
N
N
48 Quinoxaline
48a
R1 = H, CH3, 2-ClC6H4, 4-NO2C6H4, CH2CH2COOH, 2-COOHC6H4, COOEt, CH2COOEt
Fig. 39. Triazole-quinoxaline hybrids (48) with the potent compound 48a.
lung cancer HOP-92, prostate cancer PC-3, renal cancer A498, HCT- active compound of series (49a) exhibited respective GI50 values of
15, leukemia SR, colon cancer HCT-116, CNS cancer U251, NCI-H460, 52.5 and 41.3 mg/mL for HCT-15 and NCI-H226 cell lines. These
melanoma LOX IMVI and breast cancer MDA-MB-468 cell lines with hybrids were also tested for non-cancerous human embryonic
GI50 values of 3.91, 3.45, 3.49, 1.96, 5.18, 3.69, 1.80, 5.19 and 5.55 mM, kidney cells HEK-293. None of the hybrid displayed significant ef-
respectively. Generally, the hybrids with chloro-substitution, irre- fect on HEK-293 cells indicating their selectivity towards cancerous
spective of its position, showed higher potency against most of the cells.
cancer cell lines investigated. The triazole-dibenzodiazipinone hybrid 50a (50, Fig. 41) syn-
Novel 2,3-triazole-benzoxepine hybrids (49, Fig. 40) synthesized thesized by Kumar et al. displayed potent tumour growth inhibition
by Kuntala et al. were evaluated for their cytotoxicity against HCT- in five human cancer cell lines [64]. Most potent compound 50a
15 (colon) and NCI-H226 (lung) cancer cell lines [63]. The most exhibited IC50 values in range from 0.71 to 7.29 mM for various
Benzoxepine
R1
O O O
R3 O
O
R2
N N N
Cl N N Triazole
Cl N
49 49a
R1 = Me, H
R2 = Me, H, Cl
R3 = C6H4CH3-P, Ph, CH2O(quinolin-8-yl), CH2O(2-oxo-2H-chromen-7-yl),
CH2O(4-methyl-2-oxo-2H-chromen-7-yl)
Fig. 40. Triazole-benzoxepine hybrids (49) with the potent compound 49a.
Triazole
NH
NH
N N N
N N N
N
O N
O
50
50a
R Dibenzodiazipinone
cancer cells. In addition, 50a induced cell cycle arrest in the G2/M [69]. Cyototoxic data confirmed that electron withdrawing groups
phase for both A549 and MDA-MB-231 cell lines, and induced (halogen or nitro) either at isatin or phenyl ring was not encour-
apoptosis through drop in mitochondrial membrane potential aging whereas grafting electron donating groups (methyl or
(DJm) and an increase in ROS generation. methoxy) at isatin or phenyl ring were found to result in
enhancement of cytotoxcity. Among tested compounds, hybrid 53a
having methyl group on isatin ring and three methoxy group on
2.11. Isatin based hybrids phenyl ring emerged as an excellent inhibitor against all the
tumour cell lines and showed toxicity against REH (IC50 ¼ 0.5 mM)
Isatin is one of the most promising classes of heterocyclic sys- and K562 (IC50 ¼ 2 mM). Flow cytometric analysis revealed that 53a
tem with interesting pharmacological activities and well toleration induced apoptosis without arresting the cell cycle.
in humans. Currently, an isatin-based triple angio-kinase inhibitor New isatin-dehydroepiandrosterone hybrids (54, Fig. 44)
BIBF1120 II, is in phase III clinical trials in non-small cell lung cancer showed good antitumor activities against tested cancer cell lines
[65]. Further, Sunitinib, III, (Sutent) is a multikinase inhibitor tar- [70]. Synthesized hybrids exhibited better inhibitory activities
geting VEGFR-1, VEGFR-2, PDGFRb and c-Kit and was approved by against all screened cells at 20 mg/mL as compared to the positive
FDA for the treatment of gastrointestinal stromal tumors (GIST) and control 5-FU. The prototype 54a of the series displayed consider-
advanced renal cell carcinoma (RCC) [66]. Literature rationale has able inhibition activity (IC50 ¼ 5.97 mM) against BEL-7402/5-FU cell
shown the emergence of isatin hybrids viz. isatin-benzothiazole, line. It also exhibited IC50 values of 16.22, 13.90 and 14.83 mM
isatin-chalcone, isatin-thiazoline, isatin-benzimidazole, 1H-1,2,3- against HepG2, Huh-7 and A875 cell lines, respectively.
triazole-tethered isatin hybrids with potent antiproliferative ac- Sharma and co-workers tested the novel isatin-tetrazole hybrids
tivities [67]. (55, Fig. 45) for their anticancer activity against five human cancer
Eldehna and co-workers reported the synthesis and in vitro cell lines [71]. Compounds 55a and 55b exhibited potent anticancer
testing of novel isatin-pyridine hybrids (51 and 52, Fig. 42) against activity against DU-145 cell line with IC50 values in the range of
three human cancer cell lines including MCF-7 breast cancer, 4.26e7.01 mM, while the remaining compounds displayed moder-
HepG2 hepato-cellular carcinoma and A549 lung cancer [68]. ate to less cytotoxicity on human normal prostate epithelial
Compound 51 emerged as the most potent hybrid against the (RWPE-1) cells. Compound 55b effectively inhibited colony for-
HepG2 cell line (IC50 ¼ 2.5 mM) with 2.7-fold improved efficacy than mation of DU-145 cells and detained the cells in the G2/M phase of
doxorubicin, the reference drug (IC50 ¼ 6.9 mM). Compound 52a, on the cell cycle. Further studies such as AO/EB staining, DAPI nuclear
the other hand, was found to be the most active hybrid against staining, Annexin V binding assay, DNA fragmentation analysis,
A549 and MCF-7 cell lines with IC50 values of 10.8 and 6.3 mM, demonstrated that the scaffold 55b acts via induction of apoptosis
respectively. The incorporation of isatin and fluorine groups in the in DU-145 cell lines. This compound also resulted in collapse of
hybrids was found to be important in increasing their anticancer mitochondrial membrane potential along with raised intracellular
activity. ROS levels in DU-145 cells which confirmed that it has a potential to
Arpit et al. prepared new isatin-hydrazone hybrids (53, Fig. 43) provide lead for the treatment of prostate cancer.
and evaluated their cytotoxicity against the human cancer cells
N
N N
O N N
X N N
Cl
HN O
O
Isatin N
O Pyridine H N
51 52 H 52a
X = H, F, Cl, Br
Fig. 42. Isatin-pyridine hybrids (51 and 52) with the potent antiproliferative hybrid 52a.
Fig. 43. Isatin-hydrazone hybrids (53) with the potent compound 53a.
202 N. Kerru et al. / European Journal of Medicinal Chemistry 142 (2017) 179e212
Fig. 44. Isatin-dehydroepiandrosterone hybrids (54) with the potent compound 54a.
Fig. 45. Isatin-tetrazole hybrids (55) with the potent compounds 55a-b.
The molecular hybrids of isatin-triazole motifs (56, Fig. 46) highest potency against MGC-803 (IC50 ¼ 9.78 mM) by inducing cell
prepared by Yu et al. [72] exhibited selective inhibition against the cycle arrest at the G2/M phase, cellular ROS generation and was
MGC-803 (gastric) cell line in comparison to other cancer cell lines least toxic to normal cell lines HL-7702 (IC50 ¼ 40.27 mM) and GES-1
(TE-1 (human squamous cell carcinoma), MCF-7 (breast), and (IC50 ¼ 35.97 mM).
SW780 (urinary)). Compound 56a of the series displayed the A series of podophyllotoxin-isatin hybrids (57, Fig. 47) was
synthesized and screened for their cytotoxicity against adriamycin-
resistant K562/ADR cells and human leukemia K562 cells using the
CCK-8 assay [73]. All the synthesized hybrids showed higher anti-
proliferative potency against both cell lines than the control
Cl drugs viz. etoposide and adriamycin. SAR studies revealed that
Cl O O substitution at C-4 and C-6 positions of the isatin ring was suitable
Isatin for anticancer activities while substitutions at C-5 and C-7 positions
O O results in reduction of anticancer activity. Bromo-substitution at 4-
N N position or chloro-substitution at 6-position have shown to in-
crease anticancer potency. Among the synthesized hybrids, the
Cl Cl
cytotoxicity of the hybrid 57a was worth mentioning against
Triazole
N N N resistant K562/ADR cells with an IC50 value of 67 nM. Furthermore,
N N cell cycle analysis suggested that 57a remarkably induced K562/
N
R O ADR cell cycle arrest in the G2/M phase.
O O
56 A series of steroidal hybrids (58, Fig. 48) with different terminal
56a bioactives was synthesized using molecular hybridization approach
and screened for their anti-proliferative activity against a panel of
cancer cell lines of different origins using the MTT assay [74].
O HN HN Among the tested scaffolds, hybrid 58a (IC50 ¼ 4.06 mM) exhibited
N N potent inhibitory activity against SH-SY5Y (human neuroblastoma)
N
R= cells. It also arrested cell cycle at the G2/M phase via induction of
apoptosis accompanied with a decrease in mitochondrial mem-
O brane potential, thus inhibiting LSD1 (lysine-specific demethylase
Fig. 46. Isatin-triazole hybrids (56) with the potent compound 56a.
1) at low micromolar levels (IC50 ¼ 3.18 mM). Docking simulations
N. Kerru et al. / European Journal of Medicinal Chemistry 142 (2017) 179e212 203
Isatin
O O
O O
O O Br
N N
O O
O R O
O O
O O
O O
O O O O Podophyllotoxin
O
57 57a O
Fig. 47. Podophyllotoxin-isatin hybrids (57) with the potent compound 57a.
Isatin Steroidal
O O
O O
Cl
O
O
N N N O
R N N N O
N
O N
58 Cl O
58a
R = H, 5-Cl, 5-Br, 5-F, 4-Cl, 4-Br, 4,7-diCl, 7-Cl
Fig. 48. Steroidal-isatin hybrids (58) with the potent antiproliferative hybrid 58a.
showed that the steroid motif played vital role in LSD1 inactivation. transduction might be the mechanism of action of these hybrids
[78].
2.11.1. Chalcone based hybrids Chen et al. synthesized chalcone-based hybrids (59, Fig. 49) via
Chalcones (1,3-diaryl-2- propen-1-ones) belong to the flavonoid aldol condensation of indamines' and indole carbaldehydes [79].
family and spectacle interesting biological activities. The tempta- Most of these hybrids displayed moderate to good anti-proliferative
tion of working with chalcones stems from their synthetic conve- activities in micromolar to submicromolar range. SAR studies sug-
nience, the diverse ways the core structure can be varied and their gested that the hybrids synthesized from 4,5,6-trimethoxy inda-
knack to confer drug-like activities to compound libraries appen- none with different indole carbaldehydes usually gave more potent
ded on them [75]. Chalcones received momentous attention for antiproliferative activities than the corresponding 5,6,7-trimethoxy
their anti-tumour properties, particularly in view of their identical indanone derivatives. Representative compound 59a, displayed
mode of action to the structurally related natural combretastatin impressive anticancer activity (GI50 ¼ 0.026e0.035 mM) against the
[76]. Chalcone is also deemed to be a promising template to A549 (lung), HeLa (cervical), Bel-7402 (liver carcinoma), PC-3
develop inhibitors of HIF-1 [77], a major mechanism for the survival (prostate) and K562 (gastric) cell lines. Mechanistic studies estab-
and evasion of tumour cells. A large number of literary reports have lished that 59a effectively inhibited in vitro cellular tubulin poly-
emerged on hybridization of chalcone with diverse heterocylic merization and caused cell cycle arrest in G2/M cell cycle.
moieties possessing promising anti-tumour activities. Disruption of In another study, a series of chalcone-b-carboline hybrids (60,
the cell cycle, induction of apoptosis, interference with p53-MDM2 Fig. 50) displayed potent activity (IC50 < 10 mM) and selectivity
interaction, antiangiogenesis, NF-kB pathway and cell signal against A-549 cell line after testing among a panel of cancer cell
R1 R9 Chalcone
N OCH3 H
R2 N
H3CO
R3
H3CO
R4 O
O 59a Indole
59
R1 = R2 = R3 = R4 = H, OCH3
R9 = H, CH3
Fig. 49. Chalcone-indole hybrids (59) with the potent compound 59a.
204 N. Kerru et al. / European Journal of Medicinal Chemistry 142 (2017) 179e212
Fig. 50. Chalcone- b-Carboline based hybrids (60) with the potent compound 60a.
lines [80]. SAR, based on the cytotoxicity and DNA-binding studies, fluorinated chalcone exhibited the highest cytotoxicity with good
revealed the presence of fluoro and methoxy substituents at C-1 selectively against SW-620 and SKN-SH cell lines with IC50 values of
position of b-carboline for improved cytotoxicity as well as DNA- 0.35 and 0.39 mM, respectively.
binding potential whereas nitro, amino, trimethoxy and hydroxyl
substituents on the chalcone ring were encouraging for imparting 2.12. Imidazole based hybrid
significant cytotoxicity activities. Compound 60a, a prototype of the
series, showed superior activity (IC50 ¼ 5.30 mM) than harmine Four imidazole-based hybrids (63a-c and 64a) viz. imidazo-
against A-549 cell line. Further, docking studies have shown thiadiazole and imidazo-thiazoles (63e64, Fig. 53) prepared by
binding of these hybrids to DNA base pairs via H-bonding while b- Romagnoli et al. had IC50s in the range of 0.17e0.67, 0.042e0.61,
carboline moiety is essential for DNA intercalation. 0.25e0.87 and 0.20e0.86 mM against the L1210 (leukemia), FM3A
Zhang and co-workers also assessed the anticancer potential of (murine mammary carcinoma), CEM (human T-lymphocyte) and
chalcones coupled to benzoxaborole (61, Fig. 51) against human HeLa (cervix) cancer cell lines respectively [83]. These compounds
breast (MDA-MB231), ovary (SKOV-3) and colon (HCT-116) cancer at IC50 < 1 mM were highly cytotoxic to leukemia (HL-60 and U937),
lines [81]. They found that hybrid 61a (IC50 < 4.2 mM) had a higher melanoma (SKMEL-1) and the human leukemia U937 cell line over-
potency than cisplatin against SKOV-3 as well as low toxicity expressing Bcl-2 (U937/Bcl-2). Anticancer data revealed that ac-
(IC50 > 100 mM) to normal lung fibroblasts (WI-38). SAR studies tivity and selectivity was affected by the nature of substituents and
revealed that the introduction of hydrogen bond donors (-OH, their relative position on the phenyl ring tethered on imidazo[2,1-
-NH2) and electron withdrawing groups (-CF3, -NO2, -COOH) b] [1,3,4]thiadiazole and imidazo [2,1-b] [1,3]thiazole systems with
negatively influenced the anticancer activity. In contrast, the a preference for halogen (chlorine) substituent over methoxy.
replacement of iodine at the para-position increased selectivity 25- Further bio-isosteric replacement of phenyl with a thien-2-yl ring
folds toward SKOV-3 by decreasing toxicity to WI-38. improved efficacy. Cell death was found to be associated with the
Epipodophyllotoxin-chalcone scaffolds (62, Fig. 52) were syn- release of cytochrome c and activation of caspases.
thesized by Banday et al. and tested for anticancer activity against
six cancer cell lines [82]. Most of synthesized compounds have 2.13. Selenium/sulfur based hybrids
shown improved in vitro cytotoxicity than etoposide. Enhanced
potency may be either due to better target binding or increased Yan et al. reported the synthesis and anticancer activity of
solubility leading to better bioavailability. Compound 62a with a benzoselenazole-stilbene hybrids (65, Fig. 54) prepared by
Fig. 51. Chalcone-oxaborole hybrids (61) with the potent compound 61a.
N. Kerru et al. / European Journal of Medicinal Chemistry 142 (2017) 179e212 205
O Epipodophyllotoxin O
N R'' N
N N
N N
O O
O O
O
O O
O O F
O O O O O
R = H, CH3
R'' =
OCH3
O O O O
F F
O
F
OCH3
Fig. 52. Epipodophyllotoxin-chalcone based hybrids (62) with the potent compound 62a.
Br Imidazole Br Br
O Thiadiazole O O
NH NH NH
N N N N N N
R F
S N S S N S N
63 63a 63b
R = C6H5, C6H5CH2, C6H5(CH2)2, Thien-2-yl, p-F-C6H4, p-Cl-C6H4, p-Cl-C6H4CH2, p-CH3-C6H4, p-C2H5-C6H4, p-OCH3-
C6H4, p-OCH3-C6H4CH2, m-OCH3-C6H4, m-OCH3-C6H4CH2, m,p-(OCH3)2-C6H3, p-OC2H5-C6H4
O
Br Br Br
O O O
NH R NH NH
N N N
O N
S N S N S N
O 63c 64 64a
R = C6H5, p-Cl-C6H4, p-OCH3-C6H4
R1 Benzoselenazole
O O
R1' R2 O
N O
Se R3 N
R2'
Se
65
R1 = H, OCH3; R2 = H, OCH3; R3 = H, OCH3 65a Stilbene
R1' = H, OCH3, Cl; R2' = H, OCH3
Fig. 54. Benzoselenazole-stilbene hybrids (65) with the potent anticancer hybrid 65a.
combining the pharmacophores resveratrol and ebselen [84]. 2.14. Nitric oxide (NO) releasing hybrids
Compound 65a with IC50 values of 1.01, 1.53, 1.52 and 3.37 mM
against the Bel-7402 (liver carcinoma), A549 (lung), HeLa (epithe- Huang et al. synthesized a series of nitric oxide (NO) releasing
lial cervical) and MCF-7 (breast) respectively, displayed promising furoxan-pyrazo annulated steroidal hybrids (67, Fig. 56) and eval-
anti-proliferative activities and established good TrxR inhibitory uated their in vitro anti-proliferative activity against five cancer cell
activities. The presence of methoxy substituents on the ring A of lines [86]. Amongst them, 67b displayed enhanced activity with
stilbene was crucial for anticancer activity with activity further IC50 values of 1.4, 3.4, 3.5 and 20 nM against four cell lines viz. MDA-
increasing with the introduction of 3,4-dimethoxy substituents. MB-231, SKOV-3, HUVEC and DU145. It also showed activity against
However, introduction of methoxy group on ring C reversed the a tamoxifen resistant breast cancer cell line (HCC 1806)
activity effects. It is interesting to observe that fluoro and chloro (IC50 ¼ 1.03 mM). SAR of the synthesized hybrids suggested that the
group on the ring C increased the anti-proliferative potency. linker at C-3 position of steroidal scaffolds with furoxan group was
Mechanistically, 65a exhibited cell apoptosis via G2/M cell cycle crucial for anti-tumour activity. Further, smaller substituents such
arrest in the human liver carcinoma Bel-7402 cell line. as hydrogen, methyl at 20th position of hybrid 67 were found to be
Mudududdla and co-workers prepared a series of thiophene- favourable for anti-proliferative activity. Furthermore, 67a and 67b
based hybrids (66, Fig. 55) and examined their in vitro VEGFR displayed better activity than 2-methoxystradiol (2-ME) in
(vascular endothelial growth factor receptors) and P-gp (P-glyco- reducing levels of VEGFR secreted by a MDA-MB-23 cell line. Both
protein) inhibition activity [85]. Compounds 66a and 66b displayed compounds suppressed the tubule formation.
VEGFR1 inhibition with IC50 values of 2.5 and 1.9 mM respectively, in Vannini and co-workers reported the synthesis of NOSH-aspirin
the cell-free enzyme assay. These two hybrids significantly inhibi- hybrids (68e70, Fig. 57) with ability to release hydrogen sulfide
ted VEGF-induced HUVEC (human umbilical vein endothelial cells) (H2S) and nitric oxide (NO) [87]. These compounds inhibited the
migration and decreased the number of migrated cell percentage growth of two human colon cancer cells (HT-29 and HCT-15) by
from 100 to 20%. Both compounds (66a and 66b) not only showed generating reactive oxygen species leading to cancer cell regres-
inhibition of P-gp efflux pumps but also synergized the anticancer sion. The growth inhibitory effect of 68a, 69a and 70a was associ-
activity of doxorubicin in human colorectal carcinoma LS180 cells. ated with G1 to S cell cycle arrest along with inhibition of
Compound 66a showed fourteen folds enhanced IC50 of doxoru- proliferation and induction of apoptosis. These ortho (68a), meta
bicin in LS180 cells. (69a) and para (70a) NOSH-aspirin hybrids displayed IC50 values of
Fig. 55. Thiophene-benzdioxole hybrids (66) with the potent hybrids 66a-b.
N. Kerru et al. / European Journal of Medicinal Chemistry 142 (2017) 179e212 207
Fig. 56. Nitric oxide (NO) releasing-furoxan hybrids (67) with the active antiproliferative compounds 67a and 67b.
S
S
S O O
S O S
O S
R O S
O S S
R
R1 R2
O O
O ONO2
ONO2 ONO2
O O
O
68 69 70
R1 = R2
=H R = H, OMe, Cl
R = H, OMe, Cl R1 = OMe, R2 = H
R1 = H, R2 = Cl
S
S
Aspirin S O O
S O S
O S
O S
S S
O NOSH
68a 69a O
O O ONO2
ONO2
ONO2 O 70a
O O
48, 220 and 450 nM, respectively against HT-29 (colon) cancer cell observed against the HCT-15 (colon) cell line. o-NOSH-aspirin was
line; while the respective IC50 values of 57, 110 and 380 nM were the most potent amongst the positional isomers followed by m-
208 N. Kerru et al. / European Journal of Medicinal Chemistry 142 (2017) 179e212
O
H O- O
O H O-
O O N+ R1
O O n N N O O O N+
O O 3 N N
OH O O R2
H OH O O O
OH H
71 OH 71a
n = 2, 3
N
R1R2N = NH
O
Fig. 58. Nitric oxide (NO)-releasing oridonin hybrids (71) with the potent antiproliferative hybrid 71a.
NOSH-aspirin (69a) and p-NOSH-aspirin (70a). line. In addition, 73b strongly inhibited the growth of Hep-G2, A549
A number of nitric oxide (NO) releasing oridonin-diketoester and MCF-7 cells lines. A combination of fluorescent staining ex-
hybrids (71, Fig. 58) were synthesized and evaluated for their amination and flow cytometric analysis confirmed that 73a
anti-proliferative activity by Xu et al. [88]. Most compounds
exhibited anti-proliferative activity in human leukemia Bel-
7402 cells with IC50 values ranging from 1.84 to 17.01 mM.
Conspicuously, the most active compound 71a displayed good
inhibitory activity (IC50 ¼ 1.84 mM) against the Bel-7402 cancer cell H H
line. Nitric oxide (NO) release assay revealed that synthesized O O
compounds have potent anti-proliferative activities due to high n
O O
levels of NO production from diazeniumdiolates, and the synergic
effects of oridonin and NO donor moiety. Moreover, preliminary HO 73 OH
mechanistic studies found that the most potent compound, 71a
n = 2, 4, 6, 8
induced apoptosis and arrested cell cycle at the S phase in Bel-
7402 cells.
H H
2.15. Natural product based hybrids
O O
6
Oleanolic acid coupled 1H-1,2,3-triazole hybrids (72, Fig. 59) O O
displayed potent anticancer activity relative to 5-FU against five
human cancer cell lines [89]. Generally, hybrids bearing para sub- HO 73a OH
stituents (preferably electron withdrawing) on the aromatic ring
Oleanolic acid
were observed to be more potent in comparison to those bearing
ortho or meta substituents. Compound 72a displayed excellent
inhibitory activity (IC50 ¼ 3.51 mM) against HT1080 cancer cells and
was shown to be a potent apoptosis inducer. H
H H H
Five dimeric oleanolic acid tagged diamines (73, Fig. 60) were N N
synthesized and tested for their antitumor potential against five 6
human cancer cell lines using MTT assay [90]. Cytotoxicity data O O
suggested that anti-proliferative potency did not depend on the
AcO 73b OAc
length of alkyl chain between two carboxyl groups of the dimer.
The hybrids, 73a (IC50 ¼ 0.51 mM) and 73b (IC50 ¼ 0.1 mM) showed
superior anti-proliferative profiles than 5-FU against the A549 cell Fig. 60. Dimeric oleanolic acid hybrids (73) with the potent antitumor hybrids 73a-b.
Triazole
R N N
N N N
N O NO2
O
O
O
HO Oleanolic acid
HO
72 72a
R = o--Me, m-OMe, p-OMe, o-Me, p-Me, p-OEt, o-F, m-F, p-F, m-Cl, p-Cl, o-Br, m-Br, p-Br, o-Ac,
m-Ac, p-Ac, o-NO2, m-NO2, p-NO2, o-CN, m-CN, p-CN, m-COOMe, H
Fig. 59. Oleanolic acid based hybrids (72) with the potent compound 72a.
N. Kerru et al. / European Journal of Medicinal Chemistry 142 (2017) 179e212 209
induced Hep-G2 cell apoptosis by cell cycle arrest at the G1 phase. 2.15.1. Drug modified anticancer hybrids
Cai and co-workers designed and synthesized diaryl-1,2,4- Molecular hybrids (76 and 77, Fig. 62) of different non-steroidal
triazole-caffeic acid (CA) hybrids (74 and 75, Fig. 61) as anti-inflammatory (NSAIDs) drugs with tyrosine kinase inhibitor of
cyclooxygenase-2 (COX-2)/5-LOX dual inhibitors for cancer treat- epidermal growth factor receptor (EGFR), Erlotinib were synthe-
ment [91]. Anti-proliferative activity data revealed that compounds sized and evaluated for their anti-proliferative and pharmacoki-
with electron withdrawing group proved to be favourable for netic activity against HCC827 (lung) and A431 (squamous
enhancement of COX-2 inhibitory activity while compounds having carcinoma) tumour cell lines [92]. Anti-proliferative data indicated
hydroxyl group was found to be critical for 5-LOX activity. Com- the synthesized compounds possess comparable activity to the
pounds 74a (COX-2, IC50 ¼ 0.29 mM) and 75a (IC50 ¼ 6.78e9.05 mM) positive control, erlotinib. Among the synthesized hybrids, 76a and
exhibited excellent COX-1/COX-2 selectivity against A549 (lung), 77a exhibited excellent potency with both compounds exhibiting
Caco-2 (colon), PC-3 (prostate) and B16-F10 (murine-melanoma). IC50 values of 0.3 mM against HCC827 (lung) cancer cell line.
Mechanistic studies revealed that 74a blocked the cell cycle in the
G2 phase and induced apoptosis in A549 cells in a dose dependent
manner. 3. Conclusion
R1
F Caffeic acid
Triazole
O R3
N N O OH
N N
S nO OH
N O S 3O OH
R2 N
74 R1 = H, Br, F H3C S
R2 = CH3SO2, NH2SO2 O
74a
R3 = OH, OCH3, OAc
n = 2,3
R1 F3C
O R3 O OH
N N N N
O OCH3 O O OCH3
S 2 N S 2
N
R2 R1 H3C S
75
= H, CH3 75a
O
R2 = CH3SO2
R3 = OH, OCH3, OAc
Fig. 61. Caffeic acid-triazole hybrids (74 and 75) with the potent antitumor hybrids 74a, 75a.
HN O HN
O R O
O N O N
R O O
O N O N
O 77
76 R = Aspirin, Ibuprofen, sulindac, Naproxen,
R = Aspirin, Ibuprofen, sulindac, Naproxen, Indomethcin, Ketoprofen
Indomethcin, Tamibarotene
Erlotinib
HN
O HN
O
O N O
O N
O
O N O H3C O
O N
O O O 76a
77a
Fig. 62. Erlotinib-NSAID hybrids (76 and 77) with the potent compounds 76a and 77a.
210 N. Kerru et al. / European Journal of Medicinal Chemistry 142 (2017) 179e212
innovative for the development of promising drugs. The intent of curcuminequinolone hybrids, Bioorg. Med. Chem. Lett. 25 (2015) 3601e3605.
[19] S. Sharma, M.K. Gupta, A.K. Saxena, P.M.S. Bedi, Triazole linked mono carbonyl
this approach is to synthesize new molecular frameworks via
curcumin-isatin bifunctional hybrids as novel anti tubulin hybrids: design,
covalent-amalgamation of two or more active compounds with synthesis, biological evaluation and molecular modeling studies, Bioorg. Med.
specific mechanism of action and biological targets, so as to achieve Chem. 23 (2015) 7165e7180.
improved activity and selectivity. The necessity for the develop- [20] Q.H. Chen, K. Yu, X. Zhang, G. Chen, A. Hoover, F. Leon, R. Wang,
N. Subrahmanyam, E.A. Mekuria, L.H. Rakotondraibe, A new class of hybrid
ment of a single hybrid molecule having competence to interact anticancer hybrids inspired by the synergistic effects of curcumin and gen-
with several biological targets might show substantial and even istein: design, synthesis, and anti-proliferative evaluation, Bioorg, Med. Chem.
synergistic anticancer activities than aiming at a single biological Lett. 25 (2015) 4553e4556.
[21] R. Wang, X. Zhang, C. Chen, G. Chen, Q. Zhong, Q. Zhang, S. Zheng, G. Wang,
target. The pre-requisite to the design of such multi-factorial anti- Q.H. Chen, Synthesis and evaluation of 1,7-diheteroarylhepta-1,4,6-trien-3-
cancer compounds, however include the in-depth knowledge of ones as curcumin- based anticancer hybrids, Eur. J. Med. Chem. 110 (2016)
synthetic strategies, SAR as well as disease-associated signaling 164e180.
[22] A. Husain, M. Rashid, M. Shaharyar, A.A. Siddiqui, R. Mishra, Benzimidazole
pathways. Taking into account the recent advances enlisted in the clubbed with triazolo-thiadiazoles and triazolo-thiadiazines: new anticancer
present review article (2015e16); it is obvious that developing agents, Eur. J. Med. Chem. 62 (2013) 785e798.
anticancer hybrids of conventional compounds could strengthen [23] P. Singla, V. Luxami, K. Paul, Triazine-benzimidazole hybrids: anticancer ac-
tivity, DNA interaction and dihydrofolate reductase inhibitors, Bioorg. Med.
their efficacy and overcome the drug resistance. Chem. 23 (2015) 1691e1700.
[24] V.K.A. Kalalbandi, J. Seetharamappa, 1-[(2E)-3-Phenylprop-2-enoyl]-1H-
Acknowledgments benzimidazoles as anticancer hybrids: synthesis, crystal structure analysis
and binding studies of the most potent anticancer molecule with serum al-
bumin, Med. Chem. Commun. 6 (2015) 1942e1953.
The author (PS) acknowledges the KIC grant (KIC170419227697) [25] A. Sharma, V. Luxami, K. Paul, Purine-benzimidazole hybrids: synthesis, single
from the National Research Foundation (South Africa), and the crystal determination and in vitro evaluation of antitumor activities, Eur. J.
Med. Chem. 93 (2015) 414e422.
Dean’s discretionary award (UKZN) for financial assistance. Finan- [26] P. Singla, V. Luxami, K. Paul, Synthesis and in vitro evaluation of novel triazine
cial assistance from SERB under Start-Up Research grant Scheme analogues as anticancer hybrids and their interaction studies with bovine
No. YSS/2015/000879/CS (RR) is also gratefully acknowledged. serum albumin, Eur. J. Med. Chem. 117 (2015) 59e69.
[27] T.S. Reddy, H. Kulhari, V.G. Reddy, V. Bansal, A. Kamal, R. Shukla, Design,
synthesis and biological evaluation of 1,3-diphenyl-1H-pyrazole derivatives
References containing benzimidazole skeleton as potential anticancer and apoptosis
inducing hybrids, Eur. J. Med. Chem. 101 (2015) 790e805.
[1] WHO Global Cancer report. http://www.who.int/cancer/en/, 2015. Accessed [28] V.A. Sontakke, A.N. Kate, S. Ghosh, P. More, R. Gonnade, N.M. Kumbhar,
May 16, 2017. A.A. Kumbhar, B.A. Chopade, V.S. Shinde, Synthesis, DNA interaction and
[2] WHO Global Cancer report. http://www.who.int/mediacentre/factsheets/ anticancer activity of 2-anthryl substituted benzimidazole derivatives, New J.
fs297/en/, 2012. Accessed on May 14, 2017. Chem. 39 (2015) 4882e4890.
[3] M. Mareel, A. Leroy, Clinical, cellular, and molecular aspects of cancer invasion, [29] D.B. Longley, D.P. Harkin, P.G. Johnston, 5-Fluorouracil: mechanisms of action
Physiol. Rev. 83 (2003) 337e376. and clinical strategies, Nat. Rev. Cancer 3 (2003) 330e338.
[4] J. Wesche, K. Haglund, E.M. Haugsten, Fibroblast growth factors and their [30] (a) T.H. Marsilje, W. Pei, B. Chen, W. Lu, T. Uno, Y. Jin, T. Jiang, S. Kim, N. Li,
receptors in cancer, Biochem. J. 437 (2011) 199e213. M. Warmuth, Y. Sarkisova, F. Sun, A. Steffy, A.C. Pferdekamper, A.G. Li,
[5] S.K. Grant, Therapeutic protein kinase inhibitors, Cell. Mol. Life. Sci. 66 (2009) S.B. Joseph, Y. Kim, B. Liu, T. Tuntland, X. Cui, N.S. Gray, R. Steensma, Y. Wan,
1163e1177. J. Jiang, G. Chopiuk, J. Li, W.P. Gordon, W. Richmond, K. Johnson, J. Chang,
[6] G.I. Solyanik, Multifactorial nature of tumor drug resistance, Exp. Oncol. 32 T. Groessl, Y.Q. He, A. Phimister, A. Aycinena, C.C. Lee, B. Bursulaya,
(2011) 181e185. D.S. Karanewsky, H.M. Seidel, J.L. Harris, P.Y. Michellys, Synthesis, structur-
[7] S. Vijayaraghavalu, C. Peetla, S. Lu, V. Labhasetwar, Epigenetic modulation of eactivity relationships, and in vivo efficacy of the novel potent and selective
the biophysical properties of drug-resistant cell lipids to restore drug trans- anaplastic lymphoma kinase (ALK) inhibitor 5-chloro-N2-(2-isopropoxy-5-
port and endocytic functions, Mol. Pharm. 9 (2012) 2730e2742. methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(iso-propylsulfonyl)phenyl)pyrimi-
[8] M.M. Gottesman, T. Fojo, S.E. Bates, Multidrug resistance in cancer: role of dine-2,4-diamine (LDK378) currently in phase 1 and phase 2 clinical trials,
ATP-dependent transporters, Nat. Rev. Cancer 2 (2002) 48e58. J. Med. Chem. 56 (2013) 5675e5690;
[9] D.M. Molina, R. Jafari, M. Ignatushchenko, T. Seki, E.A. Larsson, C. Dan, (b) P.A. Harris, A. Boloor, M. Cheung, R. Kumar, R.M. Crosby, R.G. Davis-Ward,
L. Sreekumar, Y. Cao, P. Nordlund, Monitoring drug target engagement in cells A.H. Epperly, K.W. Hinkle, R.N. Hunter 3rd, J.H. Johnson, V.B. Knick,
and tissues using the cellular thermal shift assay, Science 341 (2013) 84e87. C.P. Laudeman, D.K. Luttrell, R.A. Mook, R.T. Nolte, S.K. Rudolph, J.R. Szewczyk,
[10] S.W. Fesik, Promoting apoptosis as a strategy for cancer drug discovery, Nat. A.T. Truesdale, J.M. Veal, L. Wang, J.A. Stafford, Discovery of 5-[[4-[(2,3-
Rev. Cancer 5 (2005) 876e885. dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-
[11] D. Sloane, Cancer epidemiology in the United States: racial, social, and eco- methylbenzenesulfonamide (Pazopanib), a novel and potent vascular endo-
nomic factors, Methods Mol. Biol. 471 (2009) 65e83. thelial growth factor receptor inhibitor, J. Med. Chem. 51 (2008) 4632e4640.
[12] G. kibria, H. Hatakeyama, H. Harashima, Cancer multidrug resistance mech- [31] L.Y. Ma, B. Wang, L.P. Pang, M. Zhang, S.Q. Wang, Y.C. Zheng, K.P. Shao,
anisms involved and strategies for circumvention using a drug delivery sys- D.Q. Xue, H.M. Liu, Design and synthesis of novel 1,2,3-
tem, Arch. Pharm. Res. 37 (2014) 4e15. triazoleepyrimidineeurea hybrids as potential anticancer hybrids, Bioorg.
[13] B.A. Larder, S.D. Kemp, P.R. Harrigan, Potential mechanism for sustained an- Med. Chem. Lett. 25 (2015) 1124e1128.
tiretroviral efficacy of AZT-3TC combination therapy, Science 269 (1995) [32] N.S. Abdou, R.A.T. Serya, A. Esmat, M.F. Tolba, N.S.M. Ismaila, K.A.M. Abouzida,
696e699. Synthesis and in vitro anti-proliferative activity of novel pyrazoloij3,4-d]py-
[14] S.A. Eisen, D.K. Miller, R.S. Woodward, E. Spitznagel, T.R. Przybeck, The effect rimidine derivatives, Med. Chem. Commun. 6 (2015) 1518e1534.
of prescribed daily dose frequency on patient medication compliance, Arch. [33] W. Zhou, A. Huang, Y. Zhang, Q. Lin, W. Guo, Z. You, Z. Yi, M. Liu, Y. Chen,
Intern. Med. 150 (1990) 1881e1884. Design and optimization of hybrid of 2,4-diaminopyrimidine and arylthiazole
[15] M.-H. Teiten, F. Gaascht, S. Eifes, M. Dicato, M. Diederich, Chemopreventive scaffold as anticancer cell proliferation and migration agents, Eur. J. Med.
potential of curcumin in prostate cancer, Genes Nutr. 5 (2010) 61e74. Chem. 96 (2015) 269e280.
[16] S. Chakraborti, L. Das, N. Kapoor, A. Das, V. Dwivedi, A. Poddar, G. Chakraborti, [34] R.M. Kumbhare, T.L. Dadmal, M.J. Ramaiah, K.S.V. Kishore, S.N.C.V.L.P. Valli,
M. Janik, G. Basu, D. Panda, P. Chakrabarti, A. Surolia, B.J. Bhattacharyya, S.K. Tiwari, K. Appalanaidu, Y.K. Rao, M. Bhadra, Synthesis and anticancer
Curcumin recognizes a unique binding site of tubulin, J. Med. Chem. 54 (2011) evaluation of novel triazole linked N-(pyrimidin-2-yl)benzo[d]thiazol-2-
6183e6196. amine derivatives as inhibitors of cell survival proteins and inducers of
[17] (a) S. Manohar, S.I. Khan, S.K. Kandi, K. Raj, G. Sun, X. Yang, A.D.C. Molina, apoptosis in MCF-7 breast cancer cells, Bioorg. Med. Chem. Lett. 25 (2015)
N. Ni, B. Wang, D.S. Rawat, Synthesis, antimalarial activity and cytotoxic po- 654e658.
tential of new monocarbonyl analogues of curcumin, Bioorg. Med. Chem. Lett. [35] I. Koca, A. Ozgur, M. Er, M. Gumus, K.A. Coskun, Y. Tutar, Design and synthesis
23 (2013) 112e116; of pyrimidinyl acyl thioureas as novel Hsp90 inhibitors in invasive ductal
(b) F.H. Sarkar, Y. Li, Harnessing the fruits of nature for the development of breast cancer and its bone metastasis, Eur. J. Med. Chem. 122 (2016) 280e290.
multi-targeted cancer therapeutics, Cancer Treat. Rev. 35 (2009) 597e607; [36] (a) A. Behrenswerth, N. Volz, J. Tora€ng, S. Hinz, S. Br€
ase, C.E. Müller, Synthesis
(c) P. Anand, A.B. Kunnumakkara, R.A. Newman, B.B. Aggarwal, Bioavailability and pharmacological evaluation of coumarin derivatives as cannabinoid re-
of curcumin: problems and promises, Mol. Pharm. 4 (2007) 807e818; ceptor antagonists and inverse agonists, Bioorg. Med. Chem. 17 (2009)
(d) E. Burgos-Moron, J.M. Calderon-Montano, J. Salvador, A. Robles, M. Lopez- 2842e2851;
Lazaro, The dark side of Curcumin, Int. J. Cancer 126 (2010) 1771e1775. (b) B.C. Raju, A.K. Tiwari, J.A. Kumar, A.Z. Ali, S.B. Agawane, G. Saidachary,
[18] S. Raghavan, P. Manogaran, K.K.G. Narasimha, B.K. Kuppusami, P. Mariyappan, K. Madhusudana, a-Glucosidase inhibitory antihyperglycemic activity of
A. Gopalakrishnan, G. Venkatraman, Synthesis and anticancer activity of novel substituted chromenone derivatives, Bioorg. Med. Chem. 18 (2010) 358e365.
N. Kerru et al. / European Journal of Medicinal Chemistry 142 (2017) 179e212 211
[37] (a) F. Chimenti, B. Bizzarri, A. Bolasco, D. Secci, P. Chimenti, A. Granese, some novel 4-Chloro-N-(4-(1-(2-(2-cyanoacetyl)hydrazono)ethyl)phenyl)
S. Carradori, D. Rivanera, A. Zicari, M.M. Scaltrito, F. Sisto, Synthesis, selective benzenesulfonamide derivatives as anticancer and radiosensitizing agents,
anti-Helicobacter pylori activity, and cytotoxicity of novel N-substituted-2- Eur. J. Med. Chem. 117 (2016) 8e18.
oxo-2H-1-benzopyran-3-carboxamides, Bioorg. Med. Chem. Lett. 20 (2010) [57] Y.J. Ren, Z.C. Wang, X. Zhang, H.Y. Qiu, P.F. Wang, H.B. Gong, A.Q. Jiang,
4922e4926; H.L. Zhu, EGFR/HER-2 inhibitors: synthesis, biological evaluation and 3D-
(b) X. Liu, H. Liu, J. Chen, Y. Yang, B. Song, L. Bai, J. Liu, H. Zhu, X. Qi, Synthesis QSAR analysis of dihydropyridine-containing thiazolinone derivatives, RSC
and molecular docking study of novel coumarin derivatives containing 4,5- Adv. 5 (2015) 21445e21454.
dihydropyrazole moiety as potential antitumor agents, Bioorg. Med. Chem. [58] A. Kamal, A.V.S. Rao, M.V.P.S. Vishnuvardhan, T.S. Reddy, K. Swapna, C. Bagul,
Lett. 20 (2010) 5705e5708. N.V.S. Reddya, V. Srinivasulu, Synthesis of 2-anilinopyridyletriazole hybrids
[38] P.R. Kamath, D. Sunil, A.A. Ajees, K.S.R. Pai, S. Das, Some new indoleecoumarin as antimitotic hybrids, Org. Biomol. Chem. 13 (2015) 4879e4895.
hybrids; Synthesis, anticancer and Bcl-2 docking studies, Bioorg. Chem. 63 [59] A. Kamal, V.S. Reddy, M.V.P.S. Vishnuvardhan, G.B. Kumar, A.B. Shaik,
(2015) 101e109. S.S. Chourasiya, M.K. Reddy, I.B. Sayeed, P.R. Adiyalaa, N. Jainb, Synthesis of 2-
[39] O. Galayev, Y. Garazd, M. Garazd, R. Lesyk, Synthesis and anticancer activity of anilinopyridineearylpropenone hybrids as tubulin inhibitors and apoptotic
6-heteroarylcoumarins, Eur. J. Med. Chem. 105 (2015) 171e181. inducers, RSC Adv. 5 (2015) 97367e97380.
[40] K.M. Amin, S.M.A. Seri, F.M. Awadallah, A.A.M. Eissa, G.S. Hassan, [60] S. Shah, C. Lee, H. Choi, J. Gautam, H. Jang, G.J. Kim, Y.J. Lee, C.L. Chaudhary,
M.M. Abdulla, Synthesis and anticancer activity of some 8-substituted-7- S.W. Park, T. Nam, J.A. Kim, B.S. Jeong, 5-Hydroxy-7-azaindolin-2-one, a novel
methoxy- 2H-chromen-2-one derivatives toward hepatocellular carcinoma hybrid of pyridinol and sunitinib: design, synthesis and cytotoxicity against
HepG2 cells, Eur. J. Med. Chem. 90 (2015) 221e231. cancer cells, Org. Biomol. Chem. 14 (2016) 4829e4841.
[41] R. Goel, V. Luxami, K. Paul, Synthesis, in vitro anticancer activity and SAR [61] Y. Liu, Y. Lang, N.K. Patel, G. Ng, R. Laufer, S.W. Li, L. Edwards, B. Forrest,
studies of arylated imidazo[1,2-a]pyrazineecoumarin hybrids, RSC Adv. 5 P.B. Sampson, M. Feher, F. Ban, D.E. Awrey, I. Beletskaya, G. Mao, R. Hodgson,
(2015) 37887e37895. O. Plotnikova, W. Qiu, N.Y. Chirgadze, J.M. Mason, X. Wei, D.C.C. Lin, Y. Che,
[42] T.G. Kraljevic, A. Harej, M. Sedic, S.K. Pavelic, V. Stepanic, D. Drenjancevic, R. Kiarash, B. Madeira, G.C. Fletcher, T.W. Mak, M.R. Bray, H.W. Pauls, The
J. Talapko, S.R. Malic, Synthesis, in vitro anticancer and antibacterial activities discovery of orally bioavailable tyrosine threonine kinase (TTK) inhibitors: 3-
and in silico studies of new 4-substituted 1,2,3-triazoleecoumarin hybrids, (4-(heterocyclyl)phenyl)-1H-indazole-5-carboxamides as anticancer hybrids,
Eur. J. Med. Chem. 124 (2016) 794e808. J. Med. Chem. 58 (2015) 3366e3392.
[43] S.S. Abd El-Karim, M.M. Anwar, N.A. Mohamed, T. Nasr, S.A. Elseginy, Design, [62] D.A.E. Issa, N.S. Habiba, A.E.A. Wahab, Design, synthesis and biological eval-
synthesis, biological evaluation and molecular docking studies of novel ben- uation of novel 1,2,4-triazolo and 1,2,4-triazino[4,3-a]quinoxalines as poten-
zofuranepyrazole derivatives as anticancer hybrids, Bioorg. Chem. 63 (2015) tial anticancer and antimicrobial hybrids, Med. Chem. Commun. 6 (2015)
1e12. 202e211.
[44] H.L. Qin, Z.P. Shang, I. Jantan, O.U. Tan, M.A. Hussain, M. Sherd, S.N.A. Bukhari, [63] N. Kuntala, J.R. Telu, V. Banothu, S.B. Nallapati, J.S. Anireddya, S. Pal, Novel
Molecular docking studies and biological evaluation of chalcone based pyr- benzoxepine-1,2,3-triazole hybrids: synthesis and pharmacological evalua-
azolines as tyrosinase inhibitors and potential anticancer hybrids, RSC Adv. 5 tion as potential antibacterial and anticancer hybrids, Med. Chem. Commun. 6
(2015) 46330e46338. (2015) 1612e1619.
[45] T.S. Reddy, H. Kulhari, V.G. Reddy, A.V. Subba Rao, V. Bansal, A. Kamal, [64] C.P. Kumar, T.S. Reddy, P.S. Mainkar, V. Bansal, R. Shukla, S. Chandrasekhar,
R. Shukla, Synthesis and biological evaluation of pyrazoloetriazole hybrids as H.M. Hugel, Synthesis and biological evaluation of 5,10-dihydro-11H-dibenzo
cytotoxic and apoptosis inducing hybrids, Org. Biomol. Chem. 13 (2015) [b,e][1,4]diazepin-11-one structural derivatives as anti-cancer and apoptosis
10136e10149. inducing agents, Eur. J. Med. Chem. 108 (2016) 674e686.
[46] J.B. Shi, W.J. Tang, X.B. Qi, J. Li, R. Li, X.H. Liu, Novel pyrazole-5-carboxamide [65] G.J. Roth, A. Heckel, F. Colbatzky, S. Handschuh, J. Kley, T. Lehmann-Lintz,
and pyrazole-pyrimidine derivatives: synthesis and anticancer activity, Eur. R. Lotz, U. Tontsch-Grunt, R. Walter, F. Hilberg, Design, synthesis, and evalu-
J. Med. Chem. 90 (2015) 889e896. ation of indolinones as triple angiokinase inhibitors and the discovery of a
[47] V. Srivastava, H. Lee, Synthesis and bio-evaluation of novel quinolino-stilbene highly specific 6-methoxycarbonyl-substituted indolinone (BIBF 1120), J. Med.
derivatives as potential anticancer hybrids, Bioorg. Med. Chem. 23 (2015) Chem. 52 (2009) 4466e4480.
7629e7640. [66] (a) R. R Jr., Sunitinib: a VEGF and PDGF receptor protein kinase and angio-
[48] P.C. Lv, M.S.A. Elsayed, K. Agama, C. Marchand, Y. Pmmier, M. Cushman, genesis inhibitor, Biochem. Biophys. Res. Commun. 356 (2007) 323e328;
Design, synthesis and biological evaluation of potential prodrugs related to (b) R.J. Motzer, M.D. Michaelson, B.G. Redman, G.R. Hudes, G. Wilding,
the experimental anticancer hybrid indotecan (LMP400), J. Med. Chem. 59 R.A. Figlin, M.S. Ginsberg, S.T. Kim, C.M. Baum, S.E. DePrimo, J.Z. Li, C.L. Bello,
(2016) 4890e4899. C.P. Theuer, D.J. George, B.I. Rini, Activity of SU11248, a multitargeted inhib-
[49] Z. Tang, C. Wu, T. Wang, K. Lao, Y. Wang, L. Liu, M. Muyaba, P. Xu, C. He, G. Luo, itor of vascular endothelial growth factor receptor and platelet-derived
Z. Qian, S. Niu, L. Wang, Y. Wang, H. Xiao, Q. You, H. Xiang, Design, synthesis growth factor receptor, in patients with metastatic renal cell carcinoma,
and evaluation of 6-aryl-indenoisoquinolone derivatives dual targeting ERa J. Clin. Oncol. 24 (2006) 16e24;
and VEGFR-2 as anti-breast cancer agents, Eur. J. Med. Chem. 118 (2016) (c) H. Prenen, J. Cools, N. Mentens, C. Folens, R. Sciot, P. Scho €ffski,
328e339. A.V. Oosterom, P. Marynen, M. Debiec-Rychter, Efficacy of the kinase inhibitor
[50] V. Markovi, N. Debeljak, T. Stanojkovi, B. Kolundzija, D. Sladic, M. Vujcic, SU11248 against gastrointestinal stromaltumor mutants refractory to imati-
B. Janovic, N. Tanic, M. Perovic, V. Tesic, J. Antic, M.D. Joksovic, Anthraquinone- nib mesylate, Clin. Cancer Res. 12 (2006) 2622e2627.
chalcone hybrids: synthesis, preliminary anti-proliferative evaluation and [67] (a) V.R. Solomon, C. Hu, H. Lee, Hybrid pharmacophore design and synthesis of
DNA-interaction studies, Eur. J. Med. Chem. 89 (2015) 401e410. isatin-benzothiazole analogs for their anti-breast cancer activity, Bioorg. Med.
[51] X. Jiang, M. Wang, S. Song, Y. Xu, Z. Miao, A. Zhang, Design, synthesis, and Chem. 17 (2009) 7585e7592;
anticancer activities of new compounds bearing the quinoneepyranelactone (b) C. Karthikeyan, V.R. Solomon, H. Lee, P. Trivedi, Design, synthesis and
tricyclic pharmacophore, RSC Adv. 5 (2015) 27502e27508. biological evaluation of some isatin-linked chalcones as novel anti-breast
[52] A.M. Alafeefy, A.E. Ashour, O. Prasad, L. Sinha, S. Pathak, F.A. Alasmari, cancer agents: a molecular hybridization approach, Biomed. Prev. Nutr. 3
A.K. Rishi, H.A.A. Aziz, Development of certain novel N-(2-(2-(2-oxoindolin-3- (2013) 325e330;
ylidene)hydrazinecarbonyl)phenyl)-benzamides and 3-(2-oxoindolin-3- (c) A.T. Taher, N.A. Khalil, E.M. Ahmed, Synthesis of novel isatin-thiazoline and
ylideneamino)-2-substituted quinazolin-4(3H)-ones as CFM-1 analogs: isatin-benzimidazole conjugates as anti-breast Cancer agents, Arch. Pharm.
design, synthesis, QSAR analysis and anticancer activity, Eur. J. Med. Chem. 92 Res. 34 (2011) 1615e1621;
(2015) 191e201. (d) P. Singh, P. Sharma, A. Anand, P.M.S. Bedi, T. Kaur, A.K. Saxena, V. Kumar,
[53] F. Qiao, Y. Yin, Y.N. Shen, S.F. Wang, S. Sha, X. Wu, A.M. Lu, C. Xu, W.M. Zhang, Azide-alkyne cycloaddition en route to novel 1H-1,2,3-triazole tethered isatin
H.L. Zhu, Synthesis, molecular modeling, and biological evaluation of quina- conjugates with in vitro cytotoxic evaluation, Eur. J. Med. Chem. 55 (2012)
zoline derivatives containing the 1,3,4-oxadiazole scaffold as novel inhibitors 455e461.
of VEGFR2, RSC Adv. 5 (2015) 19914e19923. [68] W.M. Eldehna, A. Altoukhy, H. Mahrous, H.A.A. Aziz, Design, synthesis and
[54] (a) S. Wilhelm, C. Carter, M. Lynch, T. Lowinger, J. Dumas, R.A. Smith, QSAR study of certain isatin-pyridine hybrids as potential anti-proliferative,
B. Schwartz, R. Simantov, S. Kelley, Discovery and development of sorafenib: a Eur. J. Med. Chem. 90 (2015) 684e694.
multikinase inhibitor for treating cancer, Nat. Rev. Drug Discov. 5 (2006) [69] A. Katiyar, M. Hegde, S. Kumar, V. Gopalakrishnan, K.D. Bhatelia,
835e844; K. Ananthaswamy, S.A. Ramareddy, E.D. Clercq, B. Choudhary, D. Schols,
(b) J.J. Cui, M. Tran-Dub_e, H. Shen, M. Nambu, P.-P. Kung, M. Pairish, L. Jia, S.C. Raghavan, S.S. Karki, Synthesis and evaluation of the biological activity of
J. Meng, L. Funk, I. Botrous, M.M. Tigue, N. Grodsky, K. Ryan, E. Padrique, N'-[2-oxo-1,2 dihydro-3H-indol-3-ylidene] benzohydrazides as potential
G. Alton, S. Timofeevski, S. Yamazaki, Q. Li, H. Zou, J. Christensen, anticancer hybrids, RSC Adv. 5 (2015) 45492e45501.
B. Mroczkowski, S. Bender, R.S. Kania, M.P. Edwards, Structure based drug [70] S. Ke, L. Shi, Z. Yang, Discovery of novel isatinedehydroepiandrosterone hy-
design of crizotinib (PF-02341066), a potent and selective dual inhibitor of brids as potential anticancer hybrids, Bioorg. Med. Chem. Lett. 25 (2015)
mesenchymalepithelial transition factor (c-MET) kinase and anaplastic lym- 4628e4631.
phoma kinase (ALK), J. Med. Chem. 54 (2011) 6342e6363. [71] P. Sharma, K.R. Senwar, M.K. Jeengar, T.S. Reddy, V.G.M. Naidu, A. Kamal,
[55] S. Zheng, Q. Zhong, M. Mottamal, Q. Zhang, C. Zhang, E. LeMelle, H. McFerrin, N. Shankaraiah, H2O-mediated isatin spiro-epoxide ring opening with NaCN:
G. Wang, Design, synthesis, and biological evaluation of novel pyridine synthesis of novel 3-tetrazolylmethyl-3-hydroxy-oxindole hybrids and their
bridged analogues of combretastatin-A4 as anticancer agents, J. Med. Chem. anticancer evaluation, Eur. J. Med. Chem. 104 (2015) 11e24.
57 (2014) 3369e3381. [72] B. Yu, S.Q. Wang, P.P. Qi, D.X. Yang, K. Tang, H.M. Liu, Design and synthesis of
[56] M.M. Ghorab, F.A. Ragab, H.I. Heiba, A.M. Soliman, Design and synthesis of isatin/triazole hybrids that induce apoptosis and inhibit migration of MGC-
212 N. Kerru et al. / European Journal of Medicinal Chemistry 142 (2017) 179e212
803 cells, Eur. J. Med. Chem. 124 (2016) 350e360. synthesis, Bioorg. Chem. 59 (2015) 130e139.
[73] L. Zhang, F. Chen, J. Wang, Y. Chen, Z. Zhang, Y. Lin, X. Zhu, Novel isatin de- [81] J. Zhang, F. Yang, Z. Qiao, M. Zhu, H. Zhou, Chalconeebenzoxaborole hybrids as
rivatives of podophyllotoxin: synthesis and cytotoxic evaluation against hu- novel anticancer hybrids, Eur. J. Med. Chem. 26 (2016) 5797e5801.
man leukaemia cancer cells as potent anti-MDR hybrids, RSC Adv. 5 (2015) [82] A.H. Banday, V.V. Kulkarni, V.J. Hruby, Design, synthesis, and biological and
97816e97823. docking studies of novel epipodophyllotoxinechalcone hybrids as potential
[74] B. Yu, P.P. Qi, X.J. Shi, R. Huang, H. Guo, Y.C. Zheng, D.Q. Yu, H.M. Liu, Efficient anticancer hybrids, Med. Chem. Commun. 6 (2015) 94e104.
synthesis of new anti-proliferative steroidal hybrids using the molecular hy- [83] R. Romagnoli, P.G. Baraldi, F. Prencipe, J. Balzarini, S. Liekens, F. Estevez,
bridization approach, Eur. J. Med. Chem. 117 (2016) 241e255. Design, synthesis and anti-proliferative activity of novel heterobivalent hy-
[75] P. Singh, A. Anand, V. Kumar, Recent developments in biological activities of brids based on imidazo[2,1-b][1,3,4]thiadiazole and imidazo[2,1-b] [1,3]thia-
chalcones: a mini review, Eur. J. Med. Chem. 85 (2014) 758e777. zole scaffolds, Eur. J. Med. Chem. 101 (2015) 205e217.
[76] G.R. Pettit, M.R. Rhodes, D.L. Herald, E. Hamel, J.M. Schmidt, R.K. Pettit, Anti- [84] J. Yan, Y. Guo, Y. Wang, F. Mao, L. Huang, X. Li, Design, synthesis, and biological
neoplastic agents. 445. Synthesis and evaluation of structural modifications of evaluation of benzoselenazolestilbene hybrids as multi-target-directed anti-
(Z)- and (E)-combretastatin A-41, J. Med. Chem. 48 (2005) 4087e4099. cancer hybrids, Eur. J. Med. Chem. 95 (2015) 220e229.
[77] B. Srinivasan, T.E. Johnson, C. Xing, Chalcone-based inhibitors against [85] R. Mudududdla, S.K. Guru, A. Wani, S. Sharma, P. Joshi, R.A. Vishwakarma,
hypoxia-inducible factor 1-Structure activity relationship studies, Bioorg. A. Kumar, S. Bhushan, S.B. Bharate, 3-(Benzo[d][1,3]dioxol-5-ylamino)-N-(4-
Med. Chem. Lett. 21 (2011) 555e557. fluorophenyl)thiophene-2-carboxamide overcomes cancer chemoresistance
[78] (a) M. Nagaraju, E.G. Deepthi, C. Ashwini, M.V.P.S. Vishnuvardhan, V.L. Nayak, via inhibition of angiogenesis and P-glycoprotein efflux pump activity, Org.
R. Chandra, S. Ramakrishna, B.B. Gawali, Synthesis and selective cytotoxic Biomol. Chem. 13 (2015) 4296e4309.
activity of novel hybrid chalcones against prostate cancer cells, Bioorg. Med. [86] Y. Huang, M. Liu, L. Meng, P. Feng, Y. Guo, M. Ying, X. Zhu, Y. Chen, Synthesis
Chem. Lett. 22 (2012) 4314e4317; and antitumor evaluation of novel hybrids of phenylsulfonylfuroxan and
(b) R. Abonia, D. Insuasty, J. Castillo, B. Insuasty, J. Quiroga, M. Nogueras, epiandrosterone/de hydroepiandrosterone derivatives, Steroids 101 (2015)
J. Cobo, Synthesis of novel quinoline-2-one based chalcones of potential anti- 7e14.
tumor activity, Eur. J. Med. Chem. 57 (2012) 29e40; [87] F. Vannini, A.C.M. Leitch, E.K. Eschbach, M. Chattopadhyay, R. Kodela,
(c) C.H. Tseng, Y.L. Chen, C.Y. Hsu, T.C. Chen, C.M. Cheng, H.C. Tso, Y.J. Lu, K. Kashfi, Synthesis and anti-cancer potential of the positional isomers of
C.C. Tzeng, Synthesis and antiproliferative evaluation of 3- NOSH-aspirin (NBS-1120) a dual nitric oxide and hydrogen sulfide releasing
phenylquinolinylchalcone derivatives against non-small cell lung cancers hybrid, Bioorg. Med. Chem. Lett. 25 (2015) 4677e4682.
and breast cancers, Eur. J. Med. Chem. 59 (2013) 274e282; [88] S. Xu, G. Wang, Y. Lin, Y. Zhang, L. Pei, H. Yao, M. Hu, Y. Qiu, Z. Huang, Y. Zhang,
(d) T.R. Mielcke, A. Mascarello, E.F. Chiela, R.F. Zanin, G. Lenz, P.C. Leal, J. Xu, Novel anticancer oridonin derivatives possessing a diazen-1-ium-1,2-
L.D. Chirardia, R.A. Yunes, R.J. Nunes, A.M.O. Battastini, F.B. Morone, diolate nitric oxide donor moiety: design, synthesis, biological evaluation
M.M. Campos, Activity of novel quinoxaline-derived chalcones on in vitro and nitric oxide release studies, Bioorg. Med. Chem. Lett. 26 (2016)
glioma cell proliferation, Eur. J. Med. Chem. 48 (2012) 255e264; 2795e2800.
(e) A. Kamal, A. Mallareddy, P. Suresh, T.B. Shaik, V.L. Nayak, C. Kishor, [89] G. Wei, W. Luan, S. Wang, S. Cui, F. Li, Y. Liu, Y. Liu, M. Cheng, A library of 1,2,3-
R.V.C.R.N.C. Shetti, N.S. Rao, J.R. Tamboli, S. Ramakrishna, A. Addlagatta, Syn- triazole-substituted oleanolic acid derivatives as anticancer hybrids: design,
thesis of chalcone-amidobenzothiazole conjugates as antimitotic and synthesis, and biological evaluation, Org. Biomol. Chem. 13 (2015)
apoptotic inducing agents, Bioorg. Med. Chem. 20 (2012) 3480e3492; 1507e1514.
(f) P. Singh, R. Raj, V. Kumar, M.P. Mahajan, P.M.S. Bedi, T. Kaur, A.K. Saxena, [90] K.G. Cheng, C.H. Su, L.D. Yang, J. Liu, Z.F. Chen, Synthesis of oleanolic acid
1,2,3-Triazole tethered b-lactam-Chalcone bifunctional hybrids: synthesis and dimers linked at C-28 and evaluation of anti-tumor activity, Eur. J. Med. Chem.
anticancer evaluation, Eur. J. Med. Chem. 47 (2012) 594e600. 89 (2015) 480e489.
[79] J. Chen, J. Yan, J. Hu, Y. Pang, L. Huang, X. Li, Synthesis, biological evaluation [91] H. Cai, X. Huang, S. Xu, H. Shen, P. Zhang, Y. Huang, J. Jiang, Y. Sun, B. Jiang,
and mechanism study of chalcone analogues as novel anti-cancer hybrids, RSC X. Wu, H. Yao, J. Xu, Discovery of novel hybrids of diaryl-1,2,4-triazoles and
Adv. 5 (2015) 68128e76835. caffeic acid as dual inhibitors of cyclooxygenase-2 and 5-lipoxygenase for
[80] N. Shankaraiah, K.P. Siraj, S. Nekkanti, V. Srinivasulu, P. Sharma, K.R. Senwar, cancer therapy, Eur. J. Med. Chem. 108 (2016) 89e103.
M. Sathish, M.V.P.S. Vishnuvardhan, S. Ramakrishna, C. Jadala, N. Nagesh, [92] Y. Zhang, M.D. Tortorella, J. Liao, X. Qin, T. Chen, J. Luo, J. Guan, J.J. Talley, Z. Tu,
A. Kamal, DNA-binding affinity and anticancer activity of b-carboli- Synthesis and evaluation of novel erlotinibNSAID hybrids as more
neechalcone hybrids as potential DNA intercalators: molecular modelling and comprehensive anticancer hybrids, Med. Chem. Lett. 6 (2015) 1086e1090.