Synthesis and Biological Evaluation of Novel Heterocyclic Imines Linked Coumarin- Thiazole Hybrids as Anticancer Agents

Author(s): Nerella S. Goud, Mahammad S. Ghouse, Jatoth Vishnu, Jakkula Pranay, Ravi Alvala, Venu Talla, Insaf A. Qureshi, Mallika Alvala*.

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

Volume 19 , Issue 4 , 2019

Become EABM
Become Reviewer

Graphical Abstract:


Abstract:

Background: Human Galectin-1, a protein of lectin family showing affinity towards β-galactosides has emerged as a critical regulator of tumor progression and metastasis, by modulating diverse biological events including homotypic cell aggregation, migration, apoptosis, angiogenesis and immune escape. Therefore, galectin-1 inhibitors might represent novel therapeutic agents for cancer.

Methods: A new series of heterocyclic imines linked coumarin-thiazole hybrids (6a-6r) was synthesized and evaluated for its cytotoxic potential against a panel of six human cancer cell lines namely, lung (A549), prostate (DU-145), breast (MCF-7 & MDA-MB-231), colon (HCT-15 & HT-29) using MTT assay. Characteristic apoptotic assays like DAPI staining, cell cycle, annexin V and Mitochondrial membrane potential studies were performed for the most active compound. Furthermore, Gal-1 inhibition was confirmed by ELISA and fluorescence spectroscopy.

Results: Among all, compound 6g {3-(2-(2-(pyridin-2-ylmethylene) hydrazineyl) thiazol-4-yl)-2H-chromen-2- one} exhibited promising growth inhibition against HCT-15 colorectal cancer cells with an IC50 value of 1.28 ± 0.14 µM. The characteristic apoptotic morphological features like chromatin condensation, membrane blebbing and apoptotic body formation were clearly observed with compound 6g on HCT-15 cells using DAPI staining studies. Further, annexin V-FITC/PI assay confirmed effective early apoptosis induction by treatment with compound 6g. Loss of mitochondrial membrane potential and enhanced ROS generation were confirmed with JC-1 and DCFDA staining method, respectively by treatment with compound 6g, suggesting a possible mechanism for inducing apoptosis. Moreover, flow cytometric analysis revealed that compound 6g blocked G0/G1 phase of the cell cycle in a dose-dependent manner. Compound 6g effectively reduced the levels of Gal-1 protein in a dose-dependent manner. The binding constant (Ka) of 6g with Gal-1 was calculated from the intercept value which was observed as 1.9 x 107 M-1 by Fluorescence spectroscopy. Molecular docking studies showed strong interactions of compound 6g with Gal-1 protein.

Conclusion: Our studies demonstrate the anticancer potential and Gal-1 inhibition of heterocyclic imines linked coumarin-thiazole hybrids.

Keywords: Coumarin, thiazole, heterocycles, apoptosis, galectin-1, binding constant, novel heterocyclic imines.

[1]
Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics: 2018. Cancer J. Clin., 2018, 68, 7-30.
[2]
He, J.; Wang, X.; Zhao, X.; Liang, Y.; He, H.; Fu, L. Synthesis and antitumor activity of novel quinazoline derivatives containing thiosemicarbazide moiety. Eur. J. Med. Chem., 2012, 54, 925-930.
[3]
Astorgues-Xerri, L.; Riveiro, M.E.; Tijeras-Raballand, A.; Serova, M.; Neuzillet, C.; Albert, S.; Raymond, E.; Faivre, S. Unraveling Galectin-1 as a novel therapeutic target for cancer. Cancer Treat. Rev., 2014, 40, 307-319.
[4]
Elola, M.T.; Wolfenstein-Todel, C.; Troncoso, M.F.; Vasta, G.R.; Rabinovich, G.A. Galectins: Matricellular glycan-binding proteins linking cell adhesion, migration. Cell. Mol. Life Sci., 2007, 64, 1679-1700.
[5]
Nathan, A.K.; Robert, J. Griffin.; Ruud, P.M. Dings.; Galectin-1 inhibitor OTX008 induces tumor vessel normalization and tumor growth inhibition in human head and neck squamous cell carcinoma models. Int. J. Mol. Sci., 2017, 18(12), 2671.
[6]
Thakur, A.; Singla, R.; Jaitak, V. Coumarins as anticancer agents: A review on synthetic strategies, mechanism of action and SAR studies. Eur. J. Med. Chem., 2015, 101, 476-495.
[7]
Al-Majedy, Y.; Al-Duhaidahawi, D.; Al-Azawi, K.; Al-Amiery, A.; Kadhum, A.; Mohamad, A. Coumarins as potential antioxidant agents complemented with suggested mechanisms and approved by molecular modeling studies. Molecules, 2016, 21, 135.
[8]
Singh, L.K.; Priyanka, N.; Singh, V.; Katiyar, D. Design, synthesis and biological evaluation of some new coumarin derivatives as potential antimicrobial agents. Med. Chem., 2015, 11, 128-134.
[9]
Garro, H.A.; Pungitore, C.R. Coumarins as potential inhibitors of DNA polymerases and reverse transcriptases. Searching new antiretroviral and antitumoral drugs. Curr. Drug Discov. Technol., 2015, 12, 66-79.
[10]
Iyer, D.; Patil, U.K. Evaluation of antihyperlipidemic and antitumor activities of isolated coumarins from Salvadora Indica. Pharm. Biol., 2014, 52, 78-85.
[11]
Togna, A.R.; Firuzi, O.; Latina, V.; Parmar, V.S.; Prasad, A.K.; Salemme, A.; Togna, G.I.; Saso, L. 4-Methylcoumarin derivatives with anti-inflammatory effects in activated microglial cells. Biol. Pharm. Bull., 2014, 37, 60-66.
[12]
Sashidhara, K.V.; Modukuri, R.K.; Singh, S.; Bhaskara Rao, K.; Aruna Teja, G.; Gupta, S.; Shukla, S. Design and synthesis of new series of coumarin–aminopyran derivatives possessing potential anti-depressant-like activity. Bioorg. Med. Chem. Lett., 2015, 25, 337-341.
[13]
Mangasuli, S.N.; Hosamani, K.M.; Devarajegowda, H.C.; Kurjogi, M.M.; Joshi, S.D. Synthesis of coumarin-theophylline hybrids as a new class of anti-tubercular and anti-microbial agents. Eur. J. Med. Chem., 2018, 146, 747-756.
[14]
Nasr, T.; Bondock, S.; Youns, M. Anticancer activity of new coumarin substituted hydrazide-hydrazone derivatives. Eur. J. Med. Chem., 2014, 76, 539-548.
[15]
Kim, E-K.; Kwon, K-B.; Shin, B-C.; Seo, E-A.; Lee, Y-R.; Kim, J-S.; Park, J-W.; Park, B-H.; Ryu, D-G. Scopoletin induces apoptosis in human promyeloleukemic cells, accompanied by activations of nuclear factor KB and caspase-3. Life Sci., 2005, 77, 824-836.
[16]
Finn, G.; Creaven, B.; Egan, D. Modulation of mitogen-activated protein kinases by 6-nitro-7-hydroxycoumarin mediates apoptosis in renal carcinoma cells. Eur. J. Pharmacol., 2003, 481, 159-167.
[17]
McKie, J.A.; Bhagwat, S.S.; Brady, H.; Doubleday, M.; Gayo, L.; Hickman, M.; Jalluri, R.K.; Khammungkhune, S.; Kois, A.; Mortensen, D.; Richard, N.; Sapienza, J.; Shevlin, G.; Stein, B.; Sutherland, M. Lead identification of a potent benzopyranone selective estrogen receptor modulator. Bioorg. Med. Chem. Lett., 2004, 14, 3407-3410.
[18]
Nasr, T.; Bondock, S.; Rashed, H.M.; Fayad, W.; Youns, M.; Sakr, T.M. Novel Hydrazide-Hydrazone and amide substituted coumarin derivatives: Synthesis, cytotoxicity screening, microarray, radiolabeling and in vivo pharmacokinetic studies. Eur. J. Med. Chem., 2018, 151, 723-739.
[19]
Rajput, V.K.; Leffler, H.; Nilsson, U.J.; Mukhopadhyay, B. Synthesis and evaluation of iminocoumaryl and coumaryl derivatized glycosides as galectin antagonists. Bioorg. Med. Chem. Lett., 2014, 24, 3516-3520.
[20]
Ayati, A.; Emami, S.; Asadipour, A.; Shafiee, A.; Foroumadi, A. Recent applications of 1,3-Thiazole core structure in the identification of new lead compounds and drug discovery. Eur. J. Med. Chem., 2015, 97, 699-718.
[21]
Fox, L.M.; Saravolatz, L.D. Nitazoxanide: A new thiazolide antiparasitic agent. Clin. Infect. Dis., 2005, 40, 1173-1180.
[22]
Thore, S.N.; Gupta, S.V.; Baheti, K.G. Synthesis and pharmacological evaluation of 5-Methyl-2-Phenylthiazole-4-Substituted heteroazoles as a potential anti-inflammatory and analgesic agents. J. Saudi Chem. Soc., 2016, 20, S46-S52.
[23]
Zeldin, R.K. Pharmacological and therapeutic properties of ritonavir-boosted protease inhibitor therapy in HIV-infected patients. J. Antimicrob. Chemother., 2003, 53, 4-9.
[24]
Iwakiri, K.; Kawami, N.; Sano, H.; Tanaka, Y.; Umezawa, M.; Futagami, S.; Hoshihara, Y.; Sakamoto, C. The effects of nizatidine on Transient Lower Esophageal Sphincter Relaxations (TLESRs) and acid reflux in healthy subjects. J. Smooth Muscle Res., 2011, 47, 157-166.
[25]
Laycock, I.; Cotterell, K.C.; O’Shea-Wheller, T.A.; Cresswell, J.E. Effects of the neonicotinoid pesticide thiamethoxam at field-realistic levels on microcolonies of bombus terrestris worker bumble bees. Ecotoxicol. Environ. Saf., 2014, 100, 153-158.
[26]
Pasqualotto, A.C.; Thiele, K.O.; Goldani, L.Z. Novel Triazole Antifungal Drugs: Focus on Isavuconazole, Ravuconazole and Albaconazole. Curr. Opin. Investig. Drugs, 2010, 11, 165-174.
[27]
Popsavin, M.; Kojić, V.; Torović, L.; Svirčev, M.; Spaić, S.; Jakimov, D.; Aleksić, L.; Bogdanović, G.; Popsavin, V. Synthesis and in vitro antitumour activity of tiazofurin analogues with nitrogen functionalities at the C-2′ position. Eur. J. Med. Chem., 2016, 111, 114-125.
[28]
Cai, J.; Zhang, S.; Zheng, M.; Wu, X.; Chen, J.; Ji, M. Design, synthesis, and in vitro antiproliferative activity of novel dasatinib derivatives. Bioorg. Med. Chem. Lett., 2012, 22, 806-810.
[29]
de Santana, T.I.; Barbosa, M.O.; Gomes, P.A.T.M.; da Cruz, A.C.N.; da Silva, T.G.; Leite, A.C.L. Synthesis, anticancer activity and mechanism of action of new thiazole derivatives. Eur. J. Med. Chem., 2018, 144, 874-886.
[30]
Giguère, D.; Bonin, M-A.; Cloutier, P.; Patnam, R.; St-Pierre, C.; Sato, S.; Roy, R. Synthesis of stable and selective inhibitors of human Galectins-1 and -3. Bioorg. Med. Chem., 2008, 16, 7811-7823.
[31]
Vicini, P.; Incerti, M.; Doytchinova, I.A.; La Colla, P.; Busonera, B.; Loddo, R. Synthesis and antiproliferative activity of Benzo[d]Isothiazole hydrazones. Eur. J. Med. Chem., 2006, 41, 624-632.
[32]
Terzioglu, N.; Gürsoy, A. Synthesis and anticancer evaluation of some new hydrazone derivatives of 2,6-Dimethylimidazo[2,1-b] [1,3,4] Thiadiazole-5-Carbohydrazide. Eur. J. Med. Chem., 2003, 38, 781-786.
[33]
Heravi, M.M.; Sadjadi, S.; Oskooie, H.A.; Shoar, R.H.; Bamoharram, F.F. The synthesis of Coumarin-3-Carboxylic acids and 3-Acetyl-Coumarin derivatives using heteropolyacids as heterogeneous and recyclable catalysts. Catal. Commun., 2008, 9, 470-474.
[34]
Sprung, M.A. A summary of the reactions of aldehydes with amines. Chem. Rev., 1940, 26, 297-338.
[35]
Bikobo, D.S.N.; Vodnar, D.C.; Stana, A.; Tiperciuc, B.; Nastasă, C.; Douchet, M.; Oniga, O. Synthesis of 2-Phenylamino-Thiazole derivatives as antimicrobial agents. J. Saudi Chem. Soc., 2017, 21, 861-868.
[36]
Naidu, V.; Bandari, U.M.; Giddam, A.K.; Babu, K.R.D.; Ding, J.; Babu, K.S.; Ramesh, B.; Pragada, R.R.; Gopalakrishnakone, P. Apoptogenic activity of ethyl acetate extract of leaves of Memecylon Edule on human gastric carcinoma cells via mitochondrial dependent pathway. Asian Pac. J. Trop. Med., 2013, 6, 337-345.
[37]
Tarnowski, B.I.; Spinale, F.G.; Nicholson, J.H. DAPI as a useful stain for nuclear quantitation. Biotech. Histochem., 1991, 66, 297-302.
[38]
Ravi, A.; Mallika, A.; Sama, V.; Begum, A.S.; Khan, R.S.; Reddy, B.M. Antiproliferative activity and standardization of Tecomella Undulata bark extract on K562 cells. J. Ethnopharmacol., 2011, 137, 1353-1359.
[39]
Kumar, N.P.; Sharma, P.; Kumari, S.S.; Brahma, U.; Nekkanti, S.; Shankaraiah, N.; Kamal, A. Synthesis of substituted phenanthrene-9-benzimidazole conjugates: Cytotoxicity evaluation and apoptosis inducing studies. Eur. J. Med. Chem., 2017, 140, 128-140.
[40]
Singh, T.; Sharma, S.D.; Katiyar, S.K. Grape proanthocyanidins induce apoptosis by loss of mitochondrial membrane potential of human non-small cell lung cancer cells in vitro and in vivo. PLoS One, 2011, 6, e27444.
[41]
Marchi, S.; Giorgi, C.; Suski, J.M.; Agnoletto, C.; Bononi, A.; Bonora, M.; De Marchi, E.; Missiroli, S.; Patergnani, S.; Poletti, F.; Rimessi, A.; Duszynski, J.; Wieckowski, M.R.; Pinton, P. Mitochondria-Ros crosstalk in the control of cell death and aging. J. Signal Transduct., 2012, 2012, 1-17.
[42]
Rabinovich, G.A. Galectin-1 as a potential cancer target. Br. J. Cancer, 2005, 92, 1188-1192.
[43]
Wu, R.; Wu, T.; Wang, K.; Luo, S.; Chen, Z.; Fan, M.; Xue, D.; Lu, H.; Zhuang, Q.; Xu, X. Prognostic significance of Galectin-1 expression in patients with cancer: A meta-analysis. Cancer Cell Int., 2018, 18(1), 108.
[44]
Lakowicz, J.R. Principles of fluorescence spectroscopy, 3rd ed; Springer, US, 2006.


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 19
ISSUE: 4
Year: 2019
Page: [557 - 566]
Pages: 10
DOI: 10.2174/1871520619666190207140120
Price: $58

Article Metrics

PDF: 31
HTML: 3