Evaluation of Anticancer and Anti-Mitotic Properties of Quinazoline and Quinazolino-Benzothiadiazine Derivatives

Author(s): Thoukhir B. Shaik, M. Shaheer Malik, Sunitha R. Routhu, Zaki S. Seddigi, Ismail I. Althagafi, Ahmed Kamal*

Journal Name: Anti-Cancer Agents in Medicinal Chemistry
(Formerly Current Medicinal Chemistry - Anti-Cancer Agents)

Volume 20 , Issue 5 , 2020

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Graphical Abstract:


Background: Cancer is one of the major health and social-economic problems despite considerable progress in its early diagnosis and treatment. Owing to the emergence and increase of multidrug resistance to various conventional drugs, and the continuing importance of health-care expenditure, many researchers have focused on developing novel and effective anticancer compounds.

Objective: Chemical repositories provide a good platform to evaluate and exploit known chemical entities for the identification of other biological activities. In the present study, we have selected an in-house library of synthesized compounds based on two different pharmacophoric scaffolds to evaluate their cytotoxic potency on various cancer cell lines and mechanisms of action.

Methods: A series of in-house synthesized quinazoline and quinazolino-benzothiadiazine derivatives were investigated for their anticancer efficacy against a panel of five cancer (DU145, MCF7, HepG2, SKOV3 and MDA-MB-231) and one normal (MRC5) cell lines. Furthermore, the active compound of the study was investigated to elucidate the mechanism of cytotoxicity by performing series of experiments such as cell cycle analysis, inhibition of tubulin polymerization, alteration of mitochondrial membrane potential, determination of endocytic pathway for drug uptake pathway and combination drug treatment.

Results: Among all the tested compounds, fifteen of them exhibited promising growth-inhibitory effect (0.15- 5.0μM) and induced cell cycle arrest in the G2/M phase. In addition, the selected compounds inhibited the microtubule assembly; altered mitochondrial membrane potential and enhanced the levels of caspase-9 in MCF-7 cells. Furthermore, the active compound with a combination of drugs showed a synergistic effect at lower concentrations, and the drug uptake was mediated through clathrin-mediated endocytic pathway.

Conclusion: Our results indicated that quinazoline and quinazolino-benzothiadiazine conjugates could serve as potential leads in the development of new anticancer agents.

Keywords: Cancer, quinazoline, tubulin, endocytic pathway, apoptosis, MRC5.

Kamal, A.; Shaik, T.B.; Malik, M.S. Embracing synthetic lethality of novel anticancer therapies. Expert Opin. Drug Discov., 2015, 10(10), 1119-1132.
[http://dx.doi.org/10.1517/17460441.2015.1072167] [PMID: 26211783]
The Hematologist ash news and reports. hematology. hematology.org/Thehematologist/Profiles/4513.aspx (Accessed Oct 20, 2015)
Tiwary, B.K.; Pradhan, K.; Nanda, A.K.; Chakraborty, R. Implication of quinazoline-4 (3H)-ones in medicinal chemistry: A brief review. J. Chem. Biol. Ther., 2015, 1, 104.
Hoskin, D.W.; Ramamoorthy, A. Studies on anticancer activities of antimicrobial peptides. Biochim. Biophys. Acta (BBA)-. Biomembranes, 2008, 1778, 357-375.
[http://dx.doi.org/10.1016/j.bbamem.2007.11.008] [PMID: 18078805]
Holbeck, S.L.; Collins, J.M.; Doroshow, J.H. Analysis of Food and Drug Administration-approved anticancer agents in the NCI60 panel of human tumor cell lines. Mol. Cancer Ther., 2010, 9(5), 1451-1460.
[http://dx.doi.org/10.1158/1535-7163.MCT-10-0106] [PMID: 20442306]
Open source drug discovery: Open access repository. repository.osdd.net/research-development/open-access-repositories
NIMH Chemical Synthesis and Drug Supply Program. nimh-repository.rti.org/assets/catalog.pdf
Liu, X.; Campillos, M. Unveiling new biological relationships using shared hits of chemical screening assay pairs. Bioinformatics, 2014, 30(17), i579-i586.
[http://dx.doi.org/10.1093/bioinformatics/btu468] [PMID: 25161250]
Srivastava, S.; Srivastava, S. Biological activity of quinazoline: A review. Int. J. Pharm. Sci. Res., 2015, 6, 1206-1213.
Son, J.K.; Chang, H.W.; Jahng, Y. Progress in studies on Rutaecarpine. II. Synthesis and structure-biological activity relationships. Molecules, 2015, 20(6), 10800-10821.
[http://dx.doi.org/10.3390/molecules200610800] [PMID: 26111170]
Zayed, M.F.; Ahmed, H.E.; Ihmaid, S.; Omar, A.S.M.; Abdelrahim, A.S. Synthesis and screening of some new fluorinated quinazolinone–sulphonamide hybrids as anticancer agents. J. Taibah Univ. Med. Sci., 2015, 10, 333-339.
Kamal, A.; Reddy, M.K.; Reddy, T.S.; Santos, L.S.; Shankaraiah, N. Total synthesis of rutaecarpine and analogues by tandem azido reductive cyclization assisted by microwave irradiation. Synlett, 2011, 01, 61-64.
Kuroiwa, K.; Ishii, H.; Matsuno, K.; Asai, A.; Suzuki, Y. Synthesis and structure-activity relationship study of 1-Phenyl-1-(quinazolin-4-yl)ethanols as anticancer agents. ACS Med. Chem. Lett., 2015, 6(3), 287-291.
[http://dx.doi.org/10.1021/ml5004684] [PMID: 25815147]
Wang, X.F.; Guan, F.; Ohkoshi, E.; Guo, W.; Wang, L.; Zhu, D.Q.; Wang, S.B.; Wang, L.T.; Hamel, E.; Yang, D.; Li, L.; Qian, K.; Morris-Natschke, S.L.; Yuan, S.; Lee, K.H.; Xie, L. Optimization of 4-(N-cycloamino)phenylquinazolines as a novel class of tubulin-polymerization inhibitors targeting the colchicine site. J. Med. Chem., 2014, 57(4), 1390-1402.
[http://dx.doi.org/10.1021/jm4016526] [PMID: 24502232]
Zahedifard, M.; Faraj, F.L.; Paydar, M.; Yeng Looi, C.; Hajrezaei, M.; Hasanpourghadi, M.; Kamalidehghan, B.; Abdul Majid, N.; Mohd Ali, H.; Ameen Abdulla, M. Synthesis, characterization and apoptotic activity of quinazolinone Schiff base derivatives toward MCF-7 cells via intrinsic and extrinsic apoptosis pathways. Sci. Rep., 2015, 5, 11544.
[http://dx.doi.org/10.1038/srep11544] [PMID: 26108872]
Sak, K. Chemotherapy and dietary phytochemical agents. Chemother. Res. Pract., 2012, 2012 282570
[http://dx.doi.org/10.1155/2012/282570] [PMID: 23320169]
Manasa, K.; Sidhaye, R.V.; Radhika, G.; Nalini, C.N. Synthesis, antioxidant and anticancer activity of quinazoline derivatives. Curr. Pharma Res., 2011, 1, 101-105.
Nerkar, A.G.; Saxena, A.K.; Ghone, S.A.; Thaker, A.K. In silico screening, synthesis and in vitro evaluation of some quinazolinone and pyridine derivatives as dihydrofolate reductase inhibitors for anticancer activity. J. Chem., 2015, 6, S97-S102.
Wang, X.F.; Xie, L. Vascular disrpting agents targeting at tubulin: A novel class of antitumor drug. J. Int. Pharm. Res., 2012, 39, 445-454.
Wang, X.F.; Tian, X.T.; Ohkoshi, E.; Qin, B.; Liu, Y.N.; Wu, P.C.; Hour, M.J.; Hung, H.Y.; Qian, K.; Huang, R.; Bastow, K.F.; Janzen, W.P.; Jin, J.; Morris-Natschke, S.L.; Lee, K.H.; Xie, L. Design and synthesis of diarylamines and diarylethers as cytotoxic antitumor agents. Bioorg. Med. Chem. Lett., 2012, 22(19), 6224-6228.
[http://dx.doi.org/10.1016/j.bmcl.2012.08.014] [PMID: 22932313]
Reddy, A.V.N.; Kamal, A.; Sattur, P.B. Synthesis biological activity of 3-pyrazolyl-4-substituted-2H-1,2,4-benzothiadiazine 1,1- dioxides. I.J.C-B., 1985, 24, 1295-1297.
Reddy, A.V.N.; Kamal, A.; Bhaskar, R.A.; Sattur, P.B. Synthesis and biological evaluation of 10-substituted imidazo[1,2-b][1,2,]benzothiadiazine 5,5-dioxides and their 2,10-dihydro analogs. Eur. J. Med. Chem., 1987, 22, 157-160.
Kamal, A.; Khan, M.N.A.; Reddy, K.S.; Ahmed, S.K.; Kumar, M.S.; Juvekar, A.; Sen, S.; Zingde, S. 1,2,4-benzothiadiazine linked pyrrolo[2,1-c][1,4]benzodiazepine conjugates: synthesis, DNA-binding affinity and cytotoxicity. Bioorg. Med. Chem. Lett., 2007, 17(19), 5345-5348.
[http://dx.doi.org/10.1016/j.bmcl.2007.08.018] [PMID: 17723301]
Wang, X.F.; Ohkoshi, E.; Wang, S.B.; Hamel, E.; Bastow, K.F.; Morris-Natschke, S.L.; Lee, K.H.; Xie, L. Synthesis and biological evaluation of N-alkyl-N-(4-methoxyphenyl)pyridin-2-amines as a new class of tubulin polymerization inhibitors. Bioorg. Med. Chem., 2013, 21(3), 632-642.
[http://dx.doi.org/10.1016/j.bmc.2012.11.047] [PMID: 23274123]
Vichai, V.; Kirtikara, K. Sulforhodamine B colorimetric assay for cytotoxicity screening. Nat. Protoc., 2006, 1(3), 1112-1116.
[http://dx.doi.org/10.1038/nprot.2006.179] [PMID: 17406391]
Ashraf, M.; Shaik, T.B.; Malik, M.S.; Syed, R.; Mallipeddi, P.L.; Vardhan, M.V.P.S.V.; Kamal, A. Design and synthesis of cis-restricted benzimidazole and benzothiazole mimics of combretastatin A-4 as antimitotic agents with apoptosis inducing ability. Bioorg. Med. Chem. Lett., 2016, 26(18), 4527-4535.
[http://dx.doi.org/10.1016/j.bmcl.2016.06.044] [PMID: 27515320]
Kamal, A.; Srikanth, Y.V.V.; Khan, M.N.A.; Shaik, T.B.; Ashraf, M. Synthesis of 3,3-diindolyl oxyindoles efficiently catalysed by FeCl3 and their in vitro evaluation for anticancer activity. Bioorg. Med. Chem. Lett., 2010, 20(17), 5229-5231.
[http://dx.doi.org/10.1016/j.bmcl.2010.06.152] [PMID: 20673629]
Hwang, J.H.; Takagi, M.; Murakami, H.; Sekido, Y.; Shin-ya, K. Induction of tubulin polymerization and apoptosis in malignant mesothelioma cells by a new compound JBIR-23. Cancer Lett., 2011, 300(2), 189-196.
[http://dx.doi.org/10.1016/j.canlet.2010.10.005] [PMID: 21055871]
Kamal, A.; Reddy, M.K.; Shaik, T.B.; Rajender, ; Srikanth, Y.V.; Reddy, V.S.; Kumar, G.B.; Kalivendi, S.V. Synthesis of terphenyl benzimidazoles as tubulin polymerization inhibitors. Eur. J. Med. Chem., 2012, 50, 9-17.
[http://dx.doi.org/10.1016/j.ejmech.2012.01.004] [PMID: 22361684]
Kamal, A.; Srikanth, Y.V.V.; Shaik, T.B.; Khan, M.N.A.; Ashraf, M.; Reddy, M.K.; Kumar, K.A.; Kalivendi, S.V. 2-Anilinonicotinyl linked 1, 3, 4-oxadiazole derivatives: Synthesis, antitumour activity and inhibition of tubulin polymerization. MedChemComm, 2011, 2, 819-823.
Vassilis, R.; Gianluca, F.; Ty, C.V.; Misteli, T. Cell cycle staging of individual cells by fluorescence microscopy. Nat. Protoc., 2015, 10, 334-348.
Debbage, P.L.; O’Dell, D.S.; Fraser, D.; James, D.W. Tubulin immunohistochemistry. Fixation methods affect the response of spinal cord cells in vitro. Histochemistry, 1980, 68(2), 183-195.
[http://dx.doi.org/10.1007/BF00489513] [PMID: 7419440]
Budihardjo, I.; Oliver, H.; Lutter, M.; Luo, X.; Wang, X. Biochemical pathways of caspase activation during apoptosis. Annu. Rev. Cell Dev. Biol., 1999, 15, 269-290.
[http://dx.doi.org/10.1146/annurev.cellbio.15.1.269] [PMID: 10611963]
Liang, Y.; Yan, C.; Schor, N.F. Apoptosis in the absence of caspase 3. Oncogene, 2001, 20(45), 6570-6578.
[http://dx.doi.org/10.1038/sj.onc.1204815] [PMID: 11641782]
Mc Gee, M.M.; Hyland, E.; Campiani, G.; Ramunno, A.; Nacci, V.; Zisterer, D.M. Caspase-3 is not essential for DNA fragmentation in MCF-7 cells during apoptosis induced by the pyrrolo-1,5-benzoxazepine, PBOX-6. FEBS Lett., 2002, 515(1-3), 66-70.
[http://dx.doi.org/10.1016/S0014-5793(02)02440-7] [PMID: 11943196]
Riva, G.; Baronchelli, S.; Paoletta, L.; Butta, V.; Biunno, I.; Lavitrano, M.; Dalprà, L.; Bentivegna, A. In vitro anticancer drug test: A new method emerges from the model of glioma stem cells. Toxicol. Rep., 2014, 1, 188-199.
[http://dx.doi.org/10.1016/j.toxrep.2014.05.005] [PMID: 28962238]
Hahm, H.A.; Dunn, V.R.; Butash, K.A.; Deveraux, W.L.; Woster, P.M.; Casero, R.A., Jr; Davidson, N.E. Combination of standard cytotoxic agents with polyamine analogues in the treatment of breast cancer cell lines. Clin. Cancer Res., 2001, 7(2), 391-399.
[PMID: 11234895]
Khalil, I.A.; Kogure, K.; Akita, H.; Harashima, H. Uptake pathways and subsequent intracellular trafficking in nonviral gene delivery. Pharmacol. Rev., 2006, 58(1), 32-45.
[http://dx.doi.org/10.1124/pr.58.1.8] [PMID: 16507881]
Qu, D.; Ma, Y.; Sun, W.; Chen, Y.; Zhou, J.; Liu, C.; Huang, M. Microemulsion-based synergistic dual-drug codelivery system for enhanced apoptosis of tumor cells. Int. J. Nanomedicine, 2015, 10, 1173-1187.
[PMID: 25709440]
Wang, X.F.; Wang, S.B.; Ohkoshi, E.; Wang, L.T.; Hamel, E.; Qian, K.; Morris-Natschke, S.L.; Lee, K.H.; Xie, L. N-aryl-6-methoxy-1,2,3,4-tetrahydroquinolines: a novel class of antitumor agents targeting the colchicine site on tubulin. Eur. J. Med. Chem., 2013, 67, 196-207.
[http://dx.doi.org/10.1016/j.ejmech.2013.06.041] [PMID: 23867604]
Park, M.T.; Lee, S.J. Cell cycle and cancer. J. Biochem. Mol. Biol., 2003, 36(1), 60-65.
[PMID: 12542976]
Cubedo, E.; Cordeu, L.; Bandres, E.; Rebollo, A.; Malumbres, R.; Sanmartin, C.; Font, M.; Palop, J.A.; Gacía-Foncillas, J. New symmetrical quinazoline derivatives selectively induce apoptosis in human cancer cells. Cancer Biol. Ther., 2006, 5(7), 850-859.
[http://dx.doi.org/10.4161/cbt.5.7.2841] [PMID: 16760648]
Iyer, S.; Chaplin, D.J.; Rosenthal, D.S.; Boulares, A.H.; Li, L.Y.; Smulson, M.E. Induction of apoptosis in proliferating human endothelial cells by the tumor-specific antiangiogenesis agent combretastatin A-4. Cancer Res., 1998, 58(20), 4510-4514.
[PMID: 9788591]
Weir, N.M.; Selvendiran, K.; Kutala, V.K.; Tong, L.; Vishwanath, S.; Rajaram, M.; Tridandapani, S.; Anant, S.; Kuppusamy, P. Curcumin induces G2/M arrest and apoptosis in cisplatin-resistant human ovarian cancer cells by modulating Akt and p38 MAPK. Cancer Biol. Ther., 2007, 6(2), 178-184.
[http://dx.doi.org/10.4161/cbt.6.2.3577] [PMID: 17218783]
Konecny, G.; Untch, M.; Slamon, D.; Beryt, M.; Kahlert, S.; Felber, M.; Langer, E.; Lude, S.; Hepp, H.; Pegram, M. Drug interactions and cytotoxic effects of paclitaxel in combination with carboplatin, epirubicin, gemcitabine or vinorelbine in breast cancer cell lines and tumor samples. Breast Cancer Res. Treat., 2001, 67(3), 223-233.
[http://dx.doi.org/10.1023/A:1017980411398] [PMID: 11561768]
Pegram, M.D.; Konecny, G.E.; O’Callaghan, C.; Beryt, M.; Pietras, R.; Slamon, D.J. Rational combinations of trastuzumab with chemotherapeutic drugs used in the treatment of breast cancer. J. Natl. Cancer Inst., 2004, 96(10), 739-749.
[http://dx.doi.org/10.1093/jnci/djh131] [PMID: 15150302]
Haucke, V. Cell biology: On the endocytosis rollercoaster. Nature, 2015, 517(7535), 446-447.
[http://dx.doi.org/10.1038/nature14081] [PMID: 25517097]
McShane, M.P.; Friedrichson, T.; Giner, A.; Meyenhofer, F.; Barsacchi, R.; Bickle, M.; Zerial, M. A combination of screening and computational approaches for the identification of novel compounds that decrease mast cell degranulation. J. Biomol. Screen., 2015, 20(6), 720-728.
[http://dx.doi.org/10.1177/1087057115579613] [PMID: 25838434]
Romero-Canelón, I.; Pizarro, A.M.; Habtemariam, A.; Sadler, P.J. Contrasting cellular uptake pathways for chlorido and iodido iminopyridine ruthenium arene anticancer complexes. Metallomics, 2012, 4(12), 1271-1279.
[http://dx.doi.org/10.1039/c2mt20189e] [PMID: 23138378]

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Year: 2020
Published on: 29 May, 2020
Page: [599 - 611]
Pages: 13
DOI: 10.2174/1871520620666191224122204
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