Login Register Cart 0
Generic placeholder image

Anti-Cancer Agents in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Synthesis of Substituted Cinnamido Linked Quinazolinone Congeners as Potential Anticancer Agents via Mitochondrial Dependent Intrinsic Apoptotic Pathway

Author(s): Kesari L. Manasa, Mohd A. Saifi, Yellaiah Tangella, Chandraiah Godugu and Mallika Alvala*

Volume 19, Issue 16, 2019

Page: [1935 - 1948] Pages: 14

DOI: 10.2174/1871520619666190906162537

Price: $65

Abstract

Background: The synthesis of novel heterocyclic scaffolds with amide functionality is a key research area due to their plethora of medicinal applications. The present study aims to explore the synthesis of new cinnamido linked quinazolinone congeners and their potential as anticancer agents.

Methods: Cytotoxicity evaluation, Cell cycle analysis, JC-1 staining, ROS, Annexin V assays, AO/EB, DAPI nuclear staining, Colony-forming assay and Western blot analysis.

Results: Among the synthesized compounds, 5eb and 5fc have shown promising cytotoxic activity with an IC50 value of 3.89±1.01µM and 4.05±0.62µM against HeLa cell lines. The flow-cytometry analysis demonstrated that the compound 5eb arrested the sub-G1 phase of the cell cycle and induced apoptosis. Furthermore, the compound 5eb triggered the collapse of mitochondrial membrane potential (ΔΨm), which was assessed by JC-1 staining and also induced the generation of Reactive Oxygen Species. An increase in the expression of proapoptotic proteins such as Bax, p53, cleaved PARP and cleaved caspase-3 by 5eb confirmed the activation of the mitochondrial-dependent intrinsic apoptosis pathway.

Conclusion: Our results suggest that compound 5eb and 5fc of cinnamido linked quinazolinone derivatives could serve as potential leads in the development of novel chemotherapeutic agents.

Keywords: Quinazolinones, cinnamic acids, cinnamides, cytotoxicity, apoptosis mechanism, cancer.

« Previous Next »
Graphical Abstract

[1]
Farce, A.; Loge, C.; Gallet, S.; Lebegue, N.; Carato, P.; Chavatte, P.; Berthelot, P.; Lesieur, D. Docking study of ligands into the colchicine binding site of tubulin. J. Enzyme Inhib. Med. Chem., 2004, 19(6), 541-547.
[http://dx.doi.org/10.1080/14756360412331280545] [PMID: 15662957]
[2]
aTorre, L.A.; Siegel, R.L.; Ward, E.M.; Jemal, A. Global cancer incidence and mortality rates and trends-An Update. Cancer Epidemiol. Biomarkers Prev., 2016, 25(1), 16-27.
[http://dx.doi.org/10.1158/1055-9965.EPI-15-0578] [PMID: 26667886]
[3]
Fulda, S. Tumor resistance to apoptosis. Int. J. Cancer, 2009, 124(3), 511-515.
[http://dx.doi.org/10.1002/ijc.24064] [PMID: 19003982]
[4]
Reed, J.C. Apoptosis-based therapies. Nat. Rev. Drug Discov., 2002, 1(2), 111-121.
[http://dx.doi.org/10.1038/nrd726] [PMID: 12120092]
[5]
Ghorab, M.M.; Abdel-Gawad, S.M.; El-Gaby, M.S.A. Synthesis and evaluation of some new fluorinated hydroquinazoline derivatives as antifungal agents. Farmaco, 2000, 55(4), 249-255.
[http://dx.doi.org/10.1016/S0014-827X(00)00029-X] [PMID: 10966155]
[6]
Poojari, S.; Krishnamurthy, G.P.; Naik, P.; Kumara, K.S.J.; Kumar, N.S.; Naik, S. Synthesis and antimicrobial studies of new spiropyran quinazolinone derivatives with amide, urea, and sulfonamide moieties. J. Heterocycl. Chem., 2017, 54, 3527-3537.
[http://dx.doi.org/10.1002/jhet.2976]
[7]
Kumar, A.; Tyagi, M.; Shrivasthava, V.K. Newer potential quinazolinones as hypotensive agents. Indian J. Chem., 2003, 42B, 2142-2145.
[8]
Pandey, V.K.; Sarah, V.K.T.; Zehra, T.; Raghubir, R.; Dixit, M.; Joshi, M.N.; Bajpai, S.K. Thiadiazolyl quinazolones as potential antiviral and antihypertensive agents. Indian J. Chem., 2004, 43B, 180-183.
[http://dx.doi.org/10.1002/chin.200417155]
[9]
Kumar, A.; Sharma, P.; Kumari, P.; Lal Kalal, B. Exploration of antimicrobial and antioxidant potential of newly synthesized 2,3-disubstituted quinazoline-4(3H)-ones. Bioorg. Med. Chem. Lett., 2011, 21(14), 4353-4357.
[http://dx.doi.org/10.1016/j.bmcl.2011.05.031] [PMID: 21658941]
[10]
Hess, H.J.; Cronin, T.H.; Scriabine, A. Antihypertensive 2-amino-4(3H)-quinazolinones. J. Med. Chem., 1968, 11(1), 130-136.
[http://dx.doi.org/10.1021/jm00307a028] [PMID: 5637156]
[11]
Al-Omary, F.A.M.; Abou-Zeid, L.A.; Nagi, M.N.; Habib, S.E.; Abdel-Aziz, A.A-M.; El-Azab, A.S.; Abdel-Hamide, S.G.; Al-Omar, M.A.; Al-Obaid, A.M.; El-Subbagh, H.I. Non-classical antifolates. Part 2: Synthesis, biological evaluation, and molecular modeling study of some new 2,6-substituted-quinazolin-4-ones. Bioorg. Med. Chem., 2010, 18(8), 2849-2863.
[http://dx.doi.org/10.1016/j.bmc.2010.03.019] [PMID: 20350811]
[12]
(a) Jiang, J.B.; Hesson, D.P.; Dusak, B.A.; Dexter, D.L.; Kang, G.J.; Hamel, E. Synthesis and biological evaluation of 2- styrylquinazolin-4(3H)-ones, a new class of antimitotic anticancer agents which inhibit tubulin polymerization. J. Med. Chem., 1990, 33(6), 1721-1728. bKnox
[http://dx.doi.org/10.1021/jm00168a029] [PMID: 2088342]
b) J.J Gill, S.; Synold, T.W.; Biagi, J.J.; Major, P.; Feld, R.; Cripps, C.; Wainman, N.; Eisenhauer, E.; Seymour, L. A phase II and pharmacokinetic study of SB-715992, in patients with metastatic hepatocellular carcinoma: A study of the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG IND.168). Invest. New Drugs, 2008, 26(3), 265-272.
[http://dx.doi.org/10.1007/s10637-007-9103-2] [PMID: 18196204]
[13]
Bezerra, D.P.; Castro, F.O.; Alves, A.P.; Pessoa, C.; Moraes, M.O.; Silveira, E.R.; Lima, M.A.S.; Elmiro, F.J.M.; Costa-Lotufo, L.V. In vivo growth-inhibition of Sarcoma 180 by piplartine and piperine, two alkaloid amides from Piper. Braz. J. Med. Biol. Res., 2006, 39(6), 801-807.
[http://dx.doi.org/10.1590/S0100-879X2006000600014] [PMID: 16751987]
[14]
Chung, H.S.; Shin, J.C. Characterization of antioxidant alkaloids and phenolic acids from anthocyanin-pigmented rice (Oryza sativa cv. Heugjinjubyeo). Food Chem., 2007, 104, 1670-1677.
[http://dx.doi.org/10.1016/j.foodchem.2007.03.020]
[15]
Naz, S.; Ahmad, S.; Ajaz Rasool, S.; Asad Sayeed, S.; Siddiqi, R. Antibacterial activity directed isolation of compounds from Onosma hispidum. Microbiol. Res., 2006, 161(1), 43-48.
[http://dx.doi.org/10.1016/j.micres.2005.05.001] [PMID: 16338589]
[16]
Carvalho, S.A.; da Silva, E.F.; de Souza, M.V.N.; Lourenço, M.C.S.; Vicente, F.R. Synthesis and antimycobacterial evaluation of new trans-cinnamic acid hydrazide derivatives. Bioorg. Med. Chem. Lett., 2008, 18(2), 538-541.
[http://dx.doi.org/10.1016/j.bmcl.2007.11.091] [PMID: 18068364]
[17]
(a) Yoshimatsu, K.; Yamaguchi, A.; Yoshino, H.; Koyanagi, N.; Kitoh, K. Mechanism of action of E7010, an orally active sulfonamide antitumor agent: Inhibition of mitosis by binding to the colchicine site of tubulin. Cancer Res., 1997, 57(15), 3208-3213. PMID: 9242451
(b) Tanaka, H.; Ohshima, N.; Ikenoya, M.; Komori, K.; Katoh, F.; Hidaka, H. HMN-176, an active metabolite of the synthetic antitumor agent HMN-214, restores chemosensitivity to multidrug-resistant cells by targeting the transcription factor NF-Y. Cancer Res., 2003, 63(20), 6942-6947.
[PMID: 14583495]
[18]
Zang, L.Y.; Cosma, G.; Gardner, H.; Shi, X.; Castranova, V.; Vallyathan, V. Effect of antioxidant protection by p-coumaric acid on low-density lipoprotein cholesterol oxidation. Am. J. Physiol. Cell Physiol., 2000, 279(4), C954-C960.
[http://dx.doi.org/10.1152/ajpcell.2000.279.4.C954] [PMID: 11003575]
[19]
(a) Cozzi, P.; Baraldi, P.G.; Beria, I.; Caldarelli, M.; Geroni, C.; Pennella, G.; Romagnoli, R. U.S. Patent 6,596,845 B1 2003.
(b) Nagamura, S.; Asai, A.; Amishiro, N.; Kobayashi, E.; Gomi, K.; Saito, H. Synthesis and antitumor activity of duocarmycin derivatives: A-ring pyrrole compounds bearing cinnamoyl groups. J. Med. Chem., 1997, 40(6), 972-979.
[http://dx.doi.org/10.1021/jm9606094] [PMID: 9083487]
(c) Chang, S.; Yin, S.L.; Wang, J.; Jing, Y.K.; Dong, J.H. Design and synthesis of novel 2-phenylaminopyrimidine (PAP) derivatives and their antiproliferative effects in human chronic myeloid leukemia cells. Molecules, 2009, 14(10), 4166-4179.
[http://dx.doi.org/10.3390/molecules14104166] [PMID: 19924055]
(d) De, P.; Baltas, M.; Lamoral-Theys, D.; Bruyère, C.; Kiss, R.; Bedos-Belval, F.; Saffon, N. Synthesis and anticancer activity evaluation of 2(4-alkoxyphenyl)cyclopropyl hydrazides and triazolo phthalazines. Bioorg. Med. Chem., 2010, 18(7), 2537-2548.
[http://dx.doi.org/10.1016/j.bmc.2010.02.041] [PMID: 20303278]
[20]
Leslie, B.J.; Holaday, C.R.; Nguyen, T.; Hergenrother, P.J. Phenylcinnamides as novel antimitotic agents. J. Med. Chem., 2010, 53(10), 3964-3972.
[http://dx.doi.org/10.1021/jm901805m] [PMID: 20411988]
[21]
Kostova, I.; Bhatia, S.; Grigorov, P.; Balkansky, S.; Parmar, V.S.; Prasad, A.K.; Saso, L. Coumarins as antioxidants. Curr. Med. Chem., 2011, 18(25), 3929-3951.
[http://dx.doi.org/10.2174/092986711803414395] [PMID: 21824098]
[22]
Emami, S.; Dadashpour, S. Current developments of coumarin-based anti-cancer agents in medicinal chemistry. Eur. J. Med. Chem., 2015, 102, 611-630.
[http://dx.doi.org/10.1016/j.ejmech.2015.08.033] [PMID: 26318068]
[23]
Nagarsenkar, A.; Prajapti, S.K.; Guggilapu, S.D.; Birineni, S.; Kotapalli, S.S.; Ummanni, R.; Babu, B.N. Investigation of triazole-linked indole and oxindole glycoconjugates as potential anticancer agents: novel Akt/PKB signaling pathway inhibitors. MedChemComm, 2016, 7, 646-653.
[http://dx.doi.org/10.1039/C5MD00513B]
[24]
Guggilapu, S.D.; Guntuku, L.; Reddy, T.S.; Nagarsenkar, A.; Sigalapalli, D.K.; Naidu, V.G.M.; Bhargava, S.K.; Bathini, N.B. Synthesis of thiazole linked indolyl-3-glyoxylamide derivatives as tubulin polymerization inhibitors. Eur. J. Med. Chem., 2017, 138, 83-95.
[http://dx.doi.org/10.1016/j.ejmech.2017.06.025] [PMID: 28648953]
[25]
Lipinski, C.A.; Lombardo, F.; Dominy, B.W.; Feeney, P.J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev., 2001, 46(1-3), 3-26.
[http://dx.doi.org/10.1016/S0169-409X(00)00129-0] [PMID: 11259830]

Rights & Permissions Print Cite
Article Metrics
21
3
© 2024 Bentham Science Publishers | Privacy Policy