Hybrid Compounds & Oxidative Stress Induced Apoptosis in Cancer Therapy

Author(s): Aysegul Hanikoglu, Hakan Ozben, Ferhat Hanikoglu, Tomris Ozben*

Journal Name: Current Medicinal Chemistry

Volume 27 , Issue 13 , 2020

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Elevated Reactive Oxygen Species (ROS) generated by the conventional cancer therapies and the endogenous production of ROS have been observed in various types of cancers. In contrast to the harmful effects of oxidative stress in different pathologies other than cancer, ROS can speed anti-tumorigenic signaling and cause apoptosis of tumor cells via oxidative stress as demonstrated in several studies. The primary actions of antioxidants in cells are to provide a redox balance between reduction-oxidation reactions. Antioxidants in tumor cells can scavenge excess ROS, causing resistance to ROS induced apoptosis. Various chemotherapeutic drugs, in their clinical use, have evoked drug resistance and serious side effects. Consequently, drugs having single-targets are not able to provide an effective cancer therapy. Recently, developed hybrid anticancer drugs promise great therapeutic advantages due to their capacity to overcome the limitations encountered with conventional chemotherapeutic agents. Hybrid compounds have advantages in comparison to the single cancer drugs which have usually low solubility, adverse side effects, and drug resistance. This review addresses two important treatments strategies in cancer therapy: oxidative stress induced apoptosis and hybrid anticancer drugs.

Keywords: Cancer, oxidative stress, antioxidants, redox, apoptosis, hybrid compounds.

Rehman, S.U.; Choe, K.; Yoo, H.H. Review on a traditional herbal medicine, eurycoma longifolia jack (Tongkat Ali): its traditional uses, chemistry, evidence-based pharmacology and toxicology. Molecules, 2016, 21(3), 331.
[http://dx.doi.org/10.3390/molecules21030331] [PMID: 26978330]
Phull, A.R.; Nasir, B.; Haq, I.U.; Kim, S.J. Oxidative stress, consequences and ROS mediated cellular signaling in rheumatoid arthritis. Chem. Biol. Interact., 2018, 281, 121-136.
[http://dx.doi.org/10.1016/j.cbi.2017.12.024] [PMID: 29258867]
Vallejo, M.J.; Salazar, L.; Grijalva, M. Oxidative stress modulation and ROS-mediated toxicity in cancer: a review on in vitro models for plant-derived compounds. Oxid. Med. Cell. Longev., 2017, 20174586068
[http://dx.doi.org/10.1155/2017/4586068] [PMID: 29204247]
Yan, Y.; Finkel, T. Autophagy as a regulator of cardiovascular redox homeostasis. Free Radic. Biol. Med., 2017, 109, 108-113.
[http://dx.doi.org/10.1016/j.freeradbiomed.2016.12.003] [PMID: 27940349]
Kawanishi, S.; Ohnishi, S.; Ma, N.; Hiraku, Y.; Oikawa, S.; Murata, M. Nitrative and oxidative DNA damage in infection-related carcinogenesis in relation to cancer stem cells. Genes Environ., 2017, 38, 26.
[http://dx.doi.org/10.1186/s41021-016-0055-7] [PMID: 28050219]
Morry, J.; Ngamcherdtrakul, W.; Yantasee, W. Oxidative stress in cancer and fibrosis: Opportunity for therapeutic intervention with antioxidant compounds, enzymes, and nanoparticles. Redox Biol., 2017, 11, 240-253.
[http://dx.doi.org/10.1016/j.redox.2016.12.011] [PMID: 28012439]
Raj, L.; Ide, T.; Gurkar, A.U.; Foley, M.; Schenone, M.; Li, X.; Tolliday, N.J.; Golub, T.R.; Carr, S.A.; Shamji, A.F.; Stern, A.M.; Mandinova, A.; Schreiber, S.L.; Lee, S.W. Selective killing of cancer cells by a small molecule targeting the stress response to ROS. Nature, 2011, 475(7355), 231-234.
[http://dx.doi.org/10.1038/nature10167] [PMID: 21753854]
Huang, G.; Chen, H.; Dong, Y.; Luo, X.; Yu, H.; Moore, Z.; Bey, E.A.; Boothman, D.A.; Gao, J. Superparamagnetic iron oxide nanoparticles: amplifying ROS stress to improve anticancer drug efficacy. Theranostics, 2013, 3(2), 116-126.
[http://dx.doi.org/10.7150/thno.5411] [PMID: 23423156]
Ling, S.; Shan, Q.; Liu, P.; Feng, T.; Zhang, X.; Xiang, P.; Chen, K.; Xie, H.; Song, P.; Zhou, L.; Liu, J.; Zheng, S.; Xu, X. Metformin ameliorates arsenic trioxide hepatotoxicity via inhibiting mitochondrial complex I. Cell Death Dis., 2017, 8(11)e3159
[http://dx.doi.org/10.1038/cddis.2017.482] [PMID: 29095437]
Martinez Molina, D.; Jafari, R.; Ignatushchenko, M.; Seki, T.; Larsson, E.A.; Dan, C.; Sreekumar, L.; Cao, Y.; Nordlund, P. Monitoring drug target engagement in cells and tissues using the cellular thermal shift assay. Science, 2013, 341(6141), 84-87.
[http://dx.doi.org/10.1126/science.1233606] [PMID: 23828940]
Gottesman, M.M.; Fojo, T.; Bates, S.E. Multidrug resistance in cancer: role of ATP-dependent transporters. Nat. Rev. Cancer, 2002, 2(1), 48-58.
[http://dx.doi.org/10.1038/nrc706] [PMID: 11902585]
Kucuksayan, E.; Ozben, T. Hybrid compounds as multitarget directed anticancer agents. Curr. Top. Med. Chem., 2017, 17(8), 907-918.
[http://dx.doi.org/10.2174/1568026616666160927155515] [PMID: 27697050]
Kurutas, E.B. The importance of antioxidants which play the role in cellular response against oxidative/nitrosative stress: current state. Nutr. J., 2016, 15(1), 71.
[http://dx.doi.org/10.1186/s12937-016-0186-5] [PMID: 27456681]
Varadharaj, S.; Kelly, O.J.; Khayat, R.N.; Kumar, P.S.; Ahmed, N.; Zweier, J.L. Role of dietary antioxidants in the preservation of vascular function and the modulation of health and disease. Front. Cardiovasc. Med., 2017, 4, 64.
[http://dx.doi.org/10.3389/fcvm.2017.00064] [PMID: 29164133]
Gupta, R.K.; Singh, N. Morinda citrifolia (Noni) alters oxidative stress marker and antioxidant activity in cervical cancer cell lines. Asian Pac. J. Cancer Prev., 2013, 14(8), 4603-4606.
[http://dx.doi.org/10.7314/APJCP.2013.14.8.4603] [PMID: 24083710]
Donaldson, M.S. Nutrition and cancer: a review of the evidence for an anti-cancer diet. Nutr. J., 2004, 3, 19.
[http://dx.doi.org/10.1186/1475-2891-3-19] [PMID: 15496224]
Kioukia-Fougia, N.; Georgiadis, N.; Tsarouhas, K.; Vasilaki, F.; Fragiadaki, P.; Meimeti, E.; Tsitsimpikou, C. Synthetic and natural nutritional supplements: health “allies” or risks to public health? Recent Pat. Inflamm. Allergy Drug Discov., 2017, 10(2), 72-85.
[http://dx.doi.org/10.2174/1872213X10666160923163700] [PMID: 27670346]
Robbins, D.; Zhao, Y. Manganese superoxide dismutase in cancer prevention. Antioxid. Redox Signal., 2014, 20(10), 1628-1645.
[http://dx.doi.org/10.1089/ars.2013.5297] [PMID: 23706068]
Wang, D.D.; Liu, Y.; Li, N.; Zhang, Y.; Jin, Q.; Hao, D.C.; Piao, H.L.; Dai, Z.R.; Ge, G.B.; Yang, L. Induction of CYP1A1 increases gefitinib-induced oxidative stress and apoptosis in A549 cells. Toxicol. In Vitro, 2017, 44, 36-43.
[http://dx.doi.org/10.1016/j.tiv.2017.06.022] [PMID: 28652202]
Zhou, B.; Wang, X.; Li, F.; Wang, Y.; Yang, L.; Zhen, X.; Tan, W. Mitochondrial activity and oxidative stress functions are influenced by the activation of AhR-induced CYP1A1 overexpression in cardiomyocytes. Mol. Med. Rep., 2017, 16(1), 174-180.
[http://dx.doi.org/10.3892/mmr.2017.6580] [PMID: 28498411]
Hagen, H.; Marzenell, P.; Jentzsch, E.; Wenz, F.; Veldwijk, M.R.; Mokhir, A. Aminoferrocene-based prodrugs activated by reactive oxygen species. J. Med. Chem., 2012, 55(2), 924-934.
[http://dx.doi.org/10.1021/jm2014937] [PMID: 22185340]
Ciftci, H.; Verit, A.; Savas, M.; Yeni, E.; Erel, O. Effects of N-acetylcysteine on semen parameters and oxidative/antioxidant status. Urology, 2009, 74(1), 73-76.
[http://dx.doi.org/10.1016/j.urology.2009.02.034] [PMID: 19428083]
Cort, A.; Timur, M.; Dursun, E.; Kucuksayan, E.; Aslan, M.; Ozben, T. Effects of N-acetylcystein on bleomycin-induced apoptosis in malignant testicular germ cell tumors. J. Physiol. Biochem., 2012, 68(4), 555-562.
[http://dx.doi.org/10.1007/s13105-012-0173-z] [PMID: 22562160]
Dalla Via, L.; García-Argáez, A.N.; Martínez-Vázquez, M.; Grancara, S.; Martinis, P.; Toninello, A. Mitochondrial permeability transition as target of anticancer drugs. Curr. Pharm. Des., 2014, 20(2), 223-244.
[http://dx.doi.org/10.2174/13816128113199990033] [PMID: 23701547]
Hanikoglu, F.; Cort, A.; Ozben, H.; Hanikoglu, A.; Ozben, T. Epoxomicin sensitizes resistant osteosarcoma cells to TRAIL induced apoptosis. Anticancer. Agents Med. Chem., 2015, 15(4), 527-533.
[http://dx.doi.org/10.2174/1871520615666150209111650] [PMID: 25666501]
Trachootham, D.; Alexandre, J.; Huang, P. Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach? Nat. Rev. Drug Discov., 2009, 8(7), 579-591.
[http://dx.doi.org/10.1038/nrd2803] [PMID: 19478820]
Özben, H.; Eralp, L.; Baysal, G.; Cort, A.; Sarkalkan, N.; Özben, T. Cisplatin loaded PMMA: mechanical properties, surface analysis and effects on Saos-2 cell culture. Acta Orthop. Traumatol. Turc., 2013, 47(3), 184-192.
[http://dx.doi.org/10.3944/AOTT.2013.2828] [PMID: 23748618]
Jones, R.G.; Thompson, C.B. Tumor suppressors and cell metabolism: a recipe for cancer growth. Genes Dev., 2009, 23(5), 537-548.
[http://dx.doi.org/10.1101/gad.1756509] [PMID: 19270154]
Halliwell, B. Oxidative stress and cancer: have we moved forward? Biochem. J., 2007, 401(1), 1-11.
[http://dx.doi.org/10.1042/BJ20061131] [PMID: 17150040]
Cort, A.; Ozben, T.; Saso, L.; De Luca, C.; Korkina, L. Redox control of multidrug resistance and its possible modulation by antioxidants. Oxid. Med. Cell. Longev., 2016, 20164251912
[http://dx.doi.org/10.1155/2016/4251912] [PMID: 26881027]
Chauhan, S.S.; Sharma, M.; Chauhan, P.M. Trioxaquines: hybrid molecules for the treatment of malaria. Drug News Perspect., 2010, 23(10), 632-646.
[http://dx.doi.org/10.1358/dnp.2010.23.10.1468390] [PMID: 21180649]
Kong, D.X.; Li, X.J.; Zhang, H.Y. Where is the hope for drug discovery? Let history tell the future. Drug Discov. Today, 2009, 14(3-4), 115-119.
[http://dx.doi.org/10.1016/j.drudis.2008.07.002] [PMID: 18687410]
Jia, J.; Zhu, F.; Ma, X.; Cao, Z.; Cao, Z.W.; Li, Y.; Li, Y.X.; Chen, Y.Z. Mechanisms of drug combinations: interaction and network perspectives. Nat. Rev. Drug Discov., 2009, 8(2), 111-128.
[http://dx.doi.org/10.1038/nrd2683] [PMID: 19180105]
Fortin, S.; Bérubé, G. Advances in the development of hybrid anticancer drugs. Expert Opin. Drug Discov., 2013, 8(8), 1029-1047.
[http://dx.doi.org/10.1517/17460441.2013.798296] [PMID: 23646979]
Noh, J.; Kwon, B.; Han, E.; Park, M.; Yang, W.; Cho, W.; Yoo, W.; Khang, G.; Lee, D. Amplification of oxidative stress by a dual stimuli-responsive hybrid drug enhances cancer cell death. Nat. Commun., 2015, 6, 6907.
[http://dx.doi.org/10.1038/ncomms7907] [PMID: 25892552]
Gonzales, P.R.; Mikhail, F.M. Diagnostic and prognostic utility of fluorescence in situ hybridization (FISH) analysis in acute myeloid leukemia. Curr. Hematol. Malig. Rep., 2017, 12(6), 568-573.
[http://dx.doi.org/10.1007/s11899-017-0426-6] [PMID: 29064023]
Agarwal, D.; Gupta, R.D.; Awasthi, S.K. Are antimalarial hybrid molecules a close reality or a distant dream? Antimicrob. Agents Chemother., 2017, 61(5), e00249-e17.
[http://dx.doi.org/10.1128/AAC.00249-17] [PMID: 28289029]
Muregi, F.W.; Ishih, A. Next-generation antimalarial drugs: hybrid molecules as a new strategy in drug design. Drug Dev. Res., 2010, 71(1), 20-32.
[http://dx.doi.org/10.1002/ddr.20345] [PMID: 21399701]
Meunier, B. Hybrid molecules with a dual mode of action: dream or reality? Acc. Chem. Res., 2008, 41(1), 69-77.
[http://dx.doi.org/10.1021/ar7000843] [PMID: 17665872]
Teiten, M.H.; Dicato, M.; Diederich, M. Hybrid curcumin compounds: a new strategy for cancer treatment. Molecules, 2014, 19(12), 20839-20863.
[http://dx.doi.org/10.3390/molecules191220839] [PMID: 25514225]
Wei, G.; Luan, W.; Wang, S.; Cui, S.; Li, F.; Liu, Y.; Liu, Y.; Cheng, M. A library of 1,2,3-triazole-substituted oleanolic acid derivatives as anticancer agents: design, synthesis, and biological evaluation. Org. Biomol. Chem., 2015, 13(5), 1507-1514.
[http://dx.doi.org/10.1039/C4OB01605J] [PMID: 25476168]
Cheng, K.G.; Su, C.H.; Yang, L.D.; Liu, J.; Chen, Z.F. Synthesis of oleanolic acid dimers linked at C-28 and evaluation of anti-tumor activity. Eur. J. Med. Chem., 2015, 89, 480-489.
[http://dx.doi.org/10.1016/j.ejmech.2014.10.066] [PMID: 25462260]
Cai, H.; Huang, X.; Xu, S.; Shen, H.; Zhang, P.; Huang, Y.; Jiang, J.; Sun, Y.; Jiang, B.; Wu, X.; Yao, H.; Xu, J. Discovery of novel hybrids of diaryl-1,2,4-triazoles and caffeic acid as dual inhibitors of cyclooxygenase-2 and 5-lipoxygenase for cancer therapy. Eur. J. Med. Chem., 2016, 108, 89-103.
[http://dx.doi.org/10.1016/j.ejmech.2015.11.013] [PMID: 26638042]
Zhang, Y.; Tortorella, M.D.; Liao, J.; Qin, X.; Chen, T.; Luo, J.; Guan, J.; Talley, J.J.; Tu, Z. Synthesis and evaluation of novel erlotinib-NSAID conjugates as more comprehensive anticancer agents. ACS Med. Chem. Lett., 2015, 6(10), 1086-1090.
[http://dx.doi.org/10.1021/acsmedchemlett.5b00286] [PMID: 26487917]
Cort, A.; Timur, M.; Ozdemir, E.; Ozben, T. Effects of curcumin on bleomycin-induced apoptosis in human malignant testicular germ cells. J. Physiol. Biochem., 2013, 69(2), 289-296.
[http://dx.doi.org/10.1007/s13105-012-0211-x] [PMID: 23001851]
Tsai, K.D.; Lin, J.C.; Yang, S.M.; Tseng, M.J.; Hsu, J.D.; Lee, Y.J.; Cherng, J.M. Curcumin protects against UVB-induced skin cancers in SKH-1 hairless mouse: analysis of early molecular markers in carcinogenesis. Evid. Based Complement. Alternat. Med., 2012, 2012593952
[http://dx.doi.org/10.1155/2012/593952] [PMID: 22888366]
Azuine, M.A.; Bhide, S.V. Adjuvant chemoprevention of experimental cancer: catechin and dietary turmeric in forestomach and oral cancer models. J. Ethnopharmacol., 1994, 44(3), 211-217.
[http://dx.doi.org/10.1016/0378-8741(94)01188-5] [PMID: 7898128]
Huang, M.T.; Lou, Y.R.; Ma, W.; Newmark, H.L.; Reuhl, K.R.; Conney, A.H. Inhibitory effects of dietary curcumin on forestomach, duodenal, and colon carcinogenesis in mice. Cancer Res., 1994, 54(22), 5841-5847.
[PMID: 7954412]
Chuang, S.E.; Kuo, M.L.; Hsu, C.H.; Chen, C.R.; Lin, J.K.; Lai, G.M.; Hsieh, C.Y.; Cheng, A.L. Curcumin-containing diet inhibits diethylnitrosamine-induced murine hepatocarcinogenesis. Carcinogenesis, 2000, 21(2), 331-335.
[http://dx.doi.org/10.1093/carcin/21.2.331] [PMID: 10657978]
Raghavan, S.; Manogaran, P.; Gadepalli Narasimha, K.K.; Kalpattu Kuppusami, B.; Mariyappan, P.; Gopalakrishnan, A.; Venkatraman, G. Synthesis and anticancer activity of novel curcumin-quinolone hybrids. Bioorg. Med. Chem. Lett., 2015, 25(17), 3601-3605.
[http://dx.doi.org/10.1016/j.bmcl.2015.06.068] [PMID: 26174555]
Sharma, S.; Gupta, M.K.; Saxena, A.K.; Bedi, P.M. Triazole linked mono carbonyl curcumin-isatin bifunctional hybrids as novel anti tubulin agents: Design, synthesis, biological evaluation and molecular modeling studies. Bioorg. Med. Chem., 2015, 23(22), 7165-7180.
[http://dx.doi.org/10.1016/j.bmc.2015.10.013] [PMID: 26515041]
Chen, Q.H.; Yu, K.; Zhang, X.; Chen, G.; Hoover, A.; Leon, F.; Wang, R.; Subrahmanyam, N.; Addo Mekuria, E.; Harinantenaina Rakotondraibe, L. A new class of hybrid anticancer agents inspired by the synergistic effects of curcumin and genistein: Design, synthesis, and anti-proliferative evaluation. Bioorg. Med. Chem. Lett., 2015, 25(20), 4553-4556.
[http://dx.doi.org/10.1016/j.bmcl.2015.08.064] [PMID: 26341135]
Mandalapu, D.; Saini, K.S.; Gupta, S.; Sharma, V.; Yaseen Malik, M.; Chaturvedi, S.; Bala, V.; Hamidullah, ; Thakur, S.; Maikhuri, J.P.; Wahajuddin, M.; Konwar, R.; Gupta, G.; Sharma, V.L. Synthesis and biological evaluation of some novel triazole hybrids of curcumin mimics and their selective anticancer activity against breast and prostate cancer cell lines. Bioorg. Med. Chem. Lett., 2016, 26(17), 4223-4232.
[http://dx.doi.org/10.1016/j.bmcl.2016.07.053] [PMID: 27496212]
Husain, A.; Rashid, M.; Shaharyar, M.; Siddiqui, A.A.; Mishra, R. Benzimidazole clubbed with triazolo-thiadiazoles and triazolo-thiadiazines: new anticancer agents. Eur. J. Med. Chem., 2013, 62, 785-798.
[http://dx.doi.org/10.1016/j.ejmech.2012.07.011] [PMID: 23333063]
Singla, P.; Luxami, V.; Paul, K. Triazine-benzimidazole hybrids: anticancer activity, DNA interaction and dihydrofolate reductase inhibitors. Bioorg. Med. Chem., 2015, 23(8), 1691-1700.
[http://dx.doi.org/10.1016/j.bmc.2015.03.012] [PMID: 25792141]
Detroja, D.; Chen, T.L.; Lin, Y.W.; Yen, T.Y.; Wu, M.H.; Tsai, T.H.; Mehariya, K.; Kakadiya, R.; Lee, T.C.; Shah, A.; Su, T.L. Novel N-mustard-benzimidazoles/benzothiazoles hybrids, synthesis and anticancer evaluation. Anticancer. Agents Med. Chem., 2017, 17(13), 1741-1755.
[http://dx.doi.org/10.2174/1871520617666170522120200] [PMID: 28530540]
Reddy, T.S.; Kulhari, H.; Reddy, V.G.; Bansal, V.; Kamal, A.; Shukla, R. Design, synthesis and biological evaluation of 1,3-diphenyl-1H-pyrazole derivatives containing benzimidazole skeleton as potential anticancer and apoptosis inducing agents. Eur. J. Med. Chem., 2015, 101, 790-805.
[http://dx.doi.org/10.1016/j.ejmech.2015.07.031] [PMID: 26231080]
Ma, L.Y.; Wang, B.; Pang, L.P.; Zhang, M.; Wang, S.Q.; Zheng, Y.C.; Shao, K.P.; Xue, D.Q.; Liu, H.M. Design and synthesis of novel 1,2,3-triazole-pyrimidine-urea hybrids as potential anticancer agents. Bioorg. Med. Chem. Lett., 2015, 25(5), 1124-1128.
[http://dx.doi.org/10.1016/j.bmcl.2014.12.087] [PMID: 25655718]
Aeluri, R.; Alla, M.; Polepalli, S.; Jain, N. Synthesis and antiproliferative activity of imidazo[1,2-a]pyrimidine Mannich bases. Eur. J. Med. Chem., 2015, 100, 18-23.
[http://dx.doi.org/10.1016/j.ejmech.2015.05.037] [PMID: 26067381]
Zhou, W.; Huang, A.; Zhang, Y.; Lin, Q.; Guo, W.; You, Z.; Yi, Z.; Liu, M.; Chen, Y. Design and optimization of hybrid of 2,4-diaminopyrimidine and arylthiazole scaffold as anticancer cell proliferation and migration agents. Eur. J. Med. Chem., 2015, 96, 269-280.
[http://dx.doi.org/10.1016/j.ejmech.2015.04.027] [PMID: 25899332]
Kumbhare, R.M.; Dadmal, T.L.; Ramaiah, M.J.; Kishore, K.S.; Pushpa Valli, S.N.; Tiwari, S.K.; Appalanaidu, K.; Rao, Y.K.; Bhadra, M.P. Synthesis and anticancer evaluation of novel triazole linked N-(pyrimidin-2-yl)benzo[d]thiazol-2-amine derivatives as inhibitors of cell survival proteins and inducers of apoptosis in MCF-7 breast cancer cells. Bioorg. Med. Chem. Lett., 2015, 25(3), 654-658.
[http://dx.doi.org/10.1016/j.bmcl.2014.11.083] [PMID: 25563891]
Koca, İ.; Özgür, A.; Er, M.; Gümüş, M.; Açikalin Coşkun, K.; Tutar, Y. Design and synthesis of pyrimidinyl acyl thioureas as novel Hsp90 inhibitors in invasive ductal breast cancer and its bone metastasis. Eur. J. Med. Chem., 2016, 122, 280-290.
[http://dx.doi.org/10.1016/j.ejmech.2016.06.032] [PMID: 27376491]
Kamath, P.R.; Sunil, D.; Ajees, A.A.; Pai, K.S.; Das, S. Some new indole-coumarin hybrids; Synthesis, anticancer and Bcl-2 docking studies. Bioorg. Chem., 2015, 63, 101-109.
[http://dx.doi.org/10.1016/j.bioorg.2015.10.001] [PMID: 26469742]
Amin, K.M.; Abou-Seri, S.M.; Awadallah, F.M.; Eissa, A.A.; Hassan, G.S.; Abdulla, M.M. Synthesis and anticancer activity of some 8-substituted-7-methoxy-2H-chromen-2-one derivatives toward hepatocellular carcinoma HepG2 cells. Eur. J. Med. Chem., 2015, 90, 221-231.
[http://dx.doi.org/10.1016/j.ejmech.2014.11.027] [PMID: 25461322]
Chen, Y.F.; Lin, Y.C.; Morris-Natschke, S.L.; Wei, C.F.; Shen, T.C.; Lin, H.Y.; Hsu, M.H.; Chou, L.C.; Zhao, Y.; Kuo, S.C.; Lee, K.H.; Huang, L.J. Synthesis and SAR studies of novel 6,7,8-substituted 4-substituted benzyloxyquinolin-2(1H)-one derivatives for anticancer activity. Br. J. Pharmacol., 2015, 172(5), 1195-1221.
[http://dx.doi.org/10.1111/bph.12992] [PMID: 25363404]
Abd El-Karim, S.S.; Anwar, M.M.; Mohamed, N.A.; Nasr, T.; Elseginy, S.A. Design, synthesis, biological evaluation and molecular docking studies of novel benzofuran-pyrazole derivatives as anticancer agents. Bioorg. Chem., 2015, 63, 1-12.
[http://dx.doi.org/10.1016/j.bioorg.2015.08.006] [PMID: 26368040]
Srinivasa Reddy, T.; Kulhari, H.; Ganga Reddy, V.; Subba Rao, A.V.; Bansal, V.; Kamal, A.; Shukla, R. Synthesis and biological evaluation of pyrazolo-triazole hybrids as cytotoxic and apoptosis inducing agents. Org. Biomol. Chem., 2015, 13(40), 10136-10149.
[http://dx.doi.org/10.1039/C5OB00842E] [PMID: 26346902]
Shi, J.B.; Tang, W.J.; Qi, X.B.; Li, R.; Liu, X.H. Novel pyrazole-5-carboxamide and pyrazole-pyrimidine derivatives: synthesis and anticancer activity. Eur. J. Med. Chem., 2015, 90, 889-896.
[http://dx.doi.org/10.1016/j.ejmech.2014.12.013] [PMID: 25554922]
Srivastava, V.; Lee, H. Synthesis and bio-evaluation of novel quinolino-stilbene derivatives as potential anticancer agents. Bioorg. Med. Chem., 2015, 23(24), 7629-7640.
[http://dx.doi.org/10.1016/j.bmc.2015.11.007] [PMID: 26602827]
Marković, V.; Debeljak, N.; Stanojković, T.; Kolundžija, B.; Sladić, D.; Vujčić, M.; Janović, B.; Tanić, N.; Perović, M.; Tešić, V.; Antić, J.; Joksović, M.D. Anthraquinone-chalcone hybrids: synthesis, preliminary antiproliferative evaluation and DNA-interaction studies. Eur. J. Med. Chem., 2015, 89, 401-410.
[http://dx.doi.org/10.1016/j.ejmech.2014.10.055] [PMID: 25462255]
Kutty, S.K.; Barraud, N.; Ho, K.K.; Iskander, G.M.; Griffith, R.; Rice, S.A.; Bhadbhade, M.; Willcox, M.D.; Black, D.S.; Kumar, N. Hybrids of acylated homoserine lactone and nitric oxide donors as inhibitors of quorum sensing and virulence factors in Pseudomonas aeruginosa. Org. Biomol. Chem., 2015, 13(38), 9850-9861.
[http://dx.doi.org/10.1039/C5OB01373A] [PMID: 26282835]
Jiang, X.; Wang, M.; Song, S.; Xu, Y.; Miao, Z.; Zhang, A. Design, synthesis, and anticancer activities of new compounds bearing the quinone-pyran-lactone tricyclic pharmacophore. RSC Advances, 2015, 5, 27502-27508.
Alafeefy, A.M.; Ashour, A.E.; Prasad, O.; Sinha, L.; Pathak, S.; Alasmari, F.A.; Rishi, A.K.; Abdel-Aziz, H.A. Development of certain novel N-(2-(2-(2-oxoindolin-3-ylidene)hydrazinecarbonyl)phenyl)-benzamides and 3-(2-oxoindolin-3-ylideneamino)-2-substituted quinazolin-4(3H)-ones as CFM-1 analogs: design, synthesis, QSAR analysis and anticancer activity. Eur. J. Med. Chem., 2015, 92, 191-201.
[http://dx.doi.org/10.1016/j.ejmech.2014.12.048] [PMID: 25555142]
Bold, G.; Schnell, C.; Furet, P.; McSheehy, P.; Brüggen, J.; Mestan, J.; Manley, P.W.; Drückes, P.; Burglin, M.; Dürler, U.; Loretan, J.; Reuter, R.; Wartmann, M.; Theuer, A.; Bauer-Probst, B.; Martiny-Baron, G.; Allegrini, P.; Goepfert, A.; Wood, J.; Littlewood-Evans, A. A novel potent oral series of VEGFR2 inhibitors abrogate tumor growth by inhibiting angiogenesis. J. Med. Chem., 2016, 59(1), 132-146.
[http://dx.doi.org/10.1021/acs.jmedchem.5b01582] [PMID: 26629594]
Wilhelm, S.; Carter, C.; Lynch, M.; Lowinger, T.; Dumas, J.; Smith, R.A.; Schwartz, B.; Simantov, R.; Kelley, S. Discovery and development of sorafenib: a multikinase inhibitor for treating cancer. Nat. Rev. Drug Discov., 2006, 5(10), 835-844.
[http://dx.doi.org/10.1038/nrd2130] [PMID: 17016424]
Ghorab, M.M.; Ragab, F.A.; Heiba, H.I.; Soliman, A.M. Design and synthesis of some novel 4-Chloro-N-(4-(1-(2-(2-cyanoacetyl)hydrazono)ethyl)phenyl) benzenesulfonamide derivatives as anticancer and radiosensitizing agents. Eur. J. Med. Chem., 2016, 117, 8-18.
[http://dx.doi.org/10.1016/j.ejmech.2016.04.009] [PMID: 27085944]
Pourbasheer, E.; Aalizadeh, R.; Shiri, H.M.; Banaei, A.; Ganjali, M.R. 2D and 3D-QSAR analysis of pyrazole-thiazolinone derivatives as EGFR kinase inhibitors by CoMFA and CoMSIA. Curr Comput Aided Drug Des, 2015, 11(4), 292-303.
[http://dx.doi.org/10.2174/1573409912666151106120058] [PMID: 26548551]
Ren, Y.J.; Wang, Z.C.; Zhang, X.; Qiu, H.Y.; Wang, P.F.; Gong, H.B.; Jiang, A.Q.; Zhu, H.L. EGFR/HER-2 inhibitors: synthesis, biological evaluation and 3DQSAR analysis of dihydropyridine-containing thiazolinone derivatives. RSC Advances, 2015, 5, 21445-21454.
Shah, S.; Lee, C.; Choi, H.; Gautam, J.; Jang, H.; Kim, G.J.; Lee, Y.J.; Chaudhary, C.L.; Park, S.W.; Nam, T.G.; Kim, J.A.; Jeong, B.S. 5-Hydroxy-7-azaindolin-2-one, a novel hybrid of pyridinol and sunitinib: design, synthesis and cytotoxicity against cancer cells. Org. Biomol. Chem., 2016, 14(21), 4829-4841.
[http://dx.doi.org/10.1039/C6OB00406G] [PMID: 27145715]
Liu, Y.; Lang, Y.; Patel, N.K.; Ng, G.; Laufer, R.; Li, S.W.; Edwards, L.; Forrest, B.; Sampson, P.B.; Feher, M.; Ban, F.; Awrey, D.E.; Beletskaya, I.; Mao, G.; Hodgson, R.; Plotnikova, O.; Qiu, W.; Chirgadze, N.Y.; Mason, J.M.; Wei, X.; Lin, D.C.; Che, Y.; Kiarash, R.; Madeira, B.; Fletcher, G.C.; Mak, T.W.; Bray, M.R.; Pauls, H.W. The discovery of orally bioavailable tyrosine threonine kinase (TTK) inhibitors: 3-(4-(heterocyclyl)phenyl)-1H-indazole-5-carboxamides as anticancer agents. J. Med. Chem., 2015, 58(8), 3366-3392.
[http://dx.doi.org/10.1021/jm501740a] [PMID: 25763473]
Issa, D.A.E.; Habib, N.S.; Wahab, A.E.A. Design, synthesis and biological evaluation of novel 1,2,4-triazolo and 1,2,4-triazino[4,3-a]quinoxalines as potential anticancer and antimicrobial hybrids. Med. Chem., 2015, 6, 202-211.
Shah, D.R.; Lakum, H.P.; Chikhalia, K.H. Synthesis and in vitro antimicrobial evaluation of piperazine substituted quinazoline-based thiourea/thiazolidinone/chalcone hybrids. Bioorg. Khim., 2015, 41(2), 235-248.
[http://dx.doi.org/10.7868/S013234231502013X] [PMID: 26165131]
Kuntala, N.; Telu, J.R.; Banothu, V.; Nallapati, S.B.; Anireddya, J.S.; Pal, S. Novel benzoxepine-1,2,3-triazole hybrids: synthesis and pharmacological evaluation as potential antibacterial and anticancer hybrids. MedChemComm, 2015, 6, 1612-1619.
Praveen Kumar, C.; Reddy, T.S.; Mainkar, P.S.; Bansal, V.; Shukla, R.; Chandrasekhar, S.; Hügel, H.M. Synthesis and biological evaluation of 5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one structural derivatives as anti-cancer and apoptosis inducing agents. Eur. J. Med. Chem., 2016, 108, 674-686.
[http://dx.doi.org/10.1016/j.ejmech.2015.12.007] [PMID: 26735909]
Eldehna, W.M.; Altoukhy, A.; Mahrous, H.; Abdel-Aziz, H.A. Design, synthesis and QSAR study of certain isatin-pyridine hybrids as potential anti-proliferative agents. Eur. J. Med. Chem., 2015, 90, 684-694.
[http://dx.doi.org/10.1016/j.ejmech.2014.12.010] [PMID: 25499988]
Katiyar, A.; Hegde, M.; Kumar, S.; Gopalakrishnan, V.; Bhatelia, K.D.; Ananthaswamy, K.; Ramareddy, S.A.; Clercq, E.D.; Choudhary, B.; Schols, D.; Raghavan, S.C.; Karki, S.S. Synthesis and evaluation of the biological activity of N′-[2-oxo-1,2 dihydro-3H-indol-3-ylidene] benzohydrazides as potential anticancer hybrids. RSC Advances, 2015, 5, 45492-45501.
Ke, S.; Shi, L.; Yang, Z. Discovery of novel isatin-dehydroepiandrosterone conjugates as potential anticancer agents. Bioorg. Med. Chem. Lett., 2015, 25(20), 4628-4631.
[http://dx.doi.org/10.1016/j.bmcl.2015.08.041] [PMID: 26320625]
Sharma, P.; Senwar, K.R.; Jeengar, M.K.; Reddy, T.S.; Naidu, V.G.; Kamal, A.; Shankaraiah, N. H2O-mediated isatin spiro-epoxide ring opening with NaCN: Synthesis of novel 3-tetrazolylmethyl-3-hydroxy-oxindole hybrids and their anticancer evaluation. Eur. J. Med. Chem., 2015, 104, 11-24.
[http://dx.doi.org/10.1016/j.ejmech.2015.09.025] [PMID: 26413726]
Yu, B.; Wang, S.Q.; Qi, P.P.; Yang, D.X.; Tang, K.; Liu, H.M. Design and synthesis of isatin/triazole conjugates that induce apoptosis and inhibit migration of MGC-803 cells. Eur. J. Med. Chem., 2016, 124, 350-360.
[http://dx.doi.org/10.1016/j.ejmech.2016.08.065] [PMID: 27597411]
Yu, B.; Qi, P.P.; Shi, X.J.; Huang, R.; Guo, H.; Zheng, Y.C.; Yu, D.Q.; Liu, H.M. Efficient synthesis of new antiproliferative steroidal hybrids using the molecular hybridization approach. Eur. J. Med. Chem., 2016, 117, 241-255.
[http://dx.doi.org/10.1016/j.ejmech.2016.04.024] [PMID: 27105028]
Chen, J.; Yan, J.; Hu, J.; Pang, Y.; Huang, L.; Li, X. Synthesis, biological evaluation and mechanism study of chalcone analogues as novel anti-cancer hybrids. RSC Advances, 2015, 5, 68128-76835.
Lee, D.; Kim, K.H.; Moon, S.W.; Lee, H.; Kang, K.S.; Lee, J.W. Synthesis and biological evaluation of chalcone analogues as protective agents against cisplatin-induced cytotoxicity in kidney cells. Bioorg. Med. Chem. Lett., 2015, 25(9), 1929-1932.
[http://dx.doi.org/10.1016/j.bmcl.2015.03.026] [PMID: 25824663]
Zhang, J.; Yang, F.; Qiao, Z.; Zhu, M.; Zhou, H. Chalcone-benzoxaborole hybrids as novel anticancer agents. Bioorg. Med. Chem. Lett., 2016, 26(23), 5797-5801.
[http://dx.doi.org/10.1016/j.bmcl.2016.10.024] [PMID: 28327308]
Romagnoli, R.; Baraldi, P.G.; Prencipe, F.; Balzarini, J.; Liekens, S.; Estévez, F. Design, synthesis and antiproliferative activity of novel heterobivalent hybrids based on imidazo[2,1-b][1,3,4]thiadiazole and imidazo[2,1-b][1,3]thiazole scaffolds. Eur. J. Med. Chem., 2015, 101, 205-217.
[http://dx.doi.org/10.1016/j.ejmech.2015.06.042] [PMID: 26141911]
Yan, J.; Guo, Y.; Wang, Y.; Mao, F.; Huang, L.; Li, X. Design, synthesis, and biological evaluation of benzoselenazole-stilbene hybrids as multi-target-directed anti-cancer agents. Eur. J. Med. Chem., 2015, 95, 220-229.
[http://dx.doi.org/10.1016/j.ejmech.2015.03.030] [PMID: 25817772]
Mudududdla, R.; Guru, S.K.; Wani, A.; Sharma, S.; Joshi, P.; Vishwakarma, R.A.; Kumar, A.; Bhushan, S.; Bharate, S.B. 3-(Benzo[d][1,3]dioxol-5-ylamino)-N-(4-fluorophenyl)thiophene-2-carboxamide overcomes cancer chemoresistance via inhibition of angiogenesis and P-glycoprotein efflux pump activity. Org. Biomol. Chem., 2015, 13(14), 4296-4309.
[http://dx.doi.org/10.1039/C5OB00233H] [PMID: 25758415]
Huang, Y.; Liu, M.; Meng, L.; Feng, P.; Guo, Y.; Ying, M.; Zhu, X.; Chen, Y. Synthesis and antitumor evaluation of novel hybrids of phenylsulfonylfuroxan and epiandrosterone/dehydroepiandrosterone derivatives. Steroids, 2015, 101, 7-14.
[http://dx.doi.org/10.1016/j.steroids.2015.05.003] [PMID: 26004429]
Vannini, F.; MacKessack-Leitch, A.C.; Eschbach, E.K.; Chattopadhyay, M.; Kodela, R.; Kashfi, K. Synthesis and anti-cancer potential of the positional isomers of NOSH-aspirin (NBS-1120) a dual nitric oxide and hydrogen sulfide releasing hybrid. Bioorg. Med. Chem. Lett., 2015, 25(20), 4677-4682.
[http://dx.doi.org/10.1016/j.bmcl.2015.08.023] [PMID: 26323873]
Sengupta, S.; Eavarone, D.; Capila, I.; Zhao, G.; Watson, N.; Kiziltepe, T.; Sasisekharan, R. Temporal targeting of tumour cells and neovasculature with a nanoscale delivery system. Nature, 2005, 436(7050), 568-572.
[http://dx.doi.org/10.1038/nature03794] [PMID: 16049491]
Wu, C.; Zheng, Y.; Szymanski, C.; McNeill, J. Energy transfer in a nanoscale multichromophoric system: fluorescent dye-doped conjugated polymer nanoparticles. J Phys Chem C Nanomater Interfaces, 2008, 112(6), 1772-1781.
[http://dx.doi.org/10.1021/jp074149+] [PMID: 19221582]
Freag, M.S.; Elzoghby, A.O. Protein-inorganic nanohybrids: A potential symbiosis in tissue engineering. Curr. Drug Targets, 2018, 19(16), 1897-1904.
[http://dx.doi.org/10.2174/1389450118666171027111050] [PMID: 29076428]
Rao, K.M.; Kumar, A.; Suneetha, M.; Han, S.S. pH and near-infrared active; chitosan-coated halloysite nanotubes loaded with curcumin-Au hybrid nanoparticles for cancer drug delivery. Int. J. Biol. Macromol., 2018, 112, 119-125.
[http://dx.doi.org/10.1016/j.ijbiomac.2018.01.163] [PMID: 29378273]
Landfester, K. Miniemulsion polymerization and the structure of polymer and hybrid nanoparticles. Angew. Chem. Int. Ed. Engl., 2009, 48(25), 4488-4507.
[http://dx.doi.org/10.1002/anie.200900723] [PMID: 19455531]
Cao, S.; Jiang, Y.; Levy, C.N.; Hughes, S.M.; Zhang, H.; Hladik, F.; Woodrow, K.A. Optimization and comparison of CD4-targeting lipid-polymer hybrid nanoparticles using different binding ligands. J. Biomed. Mater. Res. A, 2018, 106(5), 1177-1188.
[http://dx.doi.org/10.1002/jbm.a.36315] [PMID: 29271128]
Jeong, H.H.; Alarcón-Correa, M.; Mark, A.G.; Son, K.; Lee, T.C.; Fischer, P. Corrosion-protected hybrid nanoparticles. Adv. Sci. (Weinh.), 2017, 4(12)1700234
[http://dx.doi.org/10.1002/advs.201700234] [PMID: 29270338]
Trefzer, U.; Walden, P. Hybrid-cell vaccines for cancer immune therapy. Mol. Biotechnol., 2003, 25(1), 63-69.
[http://dx.doi.org/10.1385/MB:25:1:63] [PMID: 13679636]
Zhu, G.; Liu, Y.; Yang, X.; Kim, Y.H.; Zhang, H.; Jia, R.; Liao, H.S.; Jin, A.; Lin, J.; Aronova, M.; Leapman, R.; Nie, Z.; Niu, G.; Chen, X. DNA-inorganic hybrid nanovaccine for cancer immunotherapy. Nanoscale, 2016, 8(12), 6684-6692.
[http://dx.doi.org/10.1039/C5NR08821F] [PMID: 26947116]
Bérubé, G. An overview of molecular hybrids in drug discovery. Expert Opin. Drug Discov., 2016, 11(3), 281-305.
[http://dx.doi.org/10.1517/17460441.2016.1135125] [PMID: 26727036]

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