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 and Screening of Pro-apoptotic and Angio-inhibitory Activity of Novel Benzisoxazole Derivatives both In Vitro and In Vivo

Author(s): Sathish Byrappa, Kavitha Rachaiah, Sumana Y. Kotian, Yashaswini Balaraju, Samudyata C. Prabhuswamimath, Kuriya M.L. Rai and Bharathi P. Salimath*

Volume 19, Issue 6, 2019

Page: [827 - 839] Pages: 13

DOI: 10.2174/1871520619666190114170621

Price: $65

Abstract

Background: Triple Negative Breast Cancer (TNBC) tends to be more aggressive than other types of breast cancer. Resistance to chemotherapy is a major obstacle hence there is a significant need for new antineoplastic drugs with multi-target potency. Numerous Benzoisoxazole moieties have been found to possess a broad spectrum of pharmacological activities. In the present study, we have synthesized 9 novel derivatives of Benzisoxazole 7(a-i) and screened them for their biological potential.

Methods: Chemical synthesis, Mass spectrometry (HRMS), cell proliferation and cytotoxicity assay, wound healing assay, flow cytometry and nuclear staining. Angio-inhibitory activity assessed by corneal micropocket assay and in vivo peritoneal angiogenesis assay.

Results: The Benzisoxazole derivatives 7(a-i) were synthesized and screened for their biological potency by both in vitro and in vivo experimental models. Among the series, compound 3-(1-((3-(3(Benzyloxy)-4-methoxyphenyl)- 4,5-dihydroisoxazole-5-yl)methyl)piperidine-4-yl)6-fluorobenzo[d] isoxazole (7e) was found to be most promising, with an average IC50 value of 50.36 ± 1.7 µM in MTT assay and showed 81.3% cell death. The compound 7e also showed 60-70% inhibition on a recombinant Metastasis-Associated protein (MTA1) induced proliferation and cell migration in MDAMB-231 cells, which is known to play a major role in angiogenesis. The anti-tumour studies inferred the regression of tumour activity. This was due to inhibition of neovascularization and evoking apoptosis process as assessed by corneal vascularization, peritoneal angiogenesis and apoptotic hallmarks in 7e treated cells.

Conclusion: These findings not only show the biological efficacy of compound 7e but it is also an effective beginning to explore the mechanism of metastasis and cancer therapy strategy targeting MTA1. The observed biological activity makes compound 7e an attractive drug candidate.

Keywords: Benzisoxazole, piperidine, cytotoxicity, breast cancer, antiproliferative, apoptosis, anti-angiogenesis, anti-cancer.

« Previous
Graphical Abstract

[1]
Breast Cancer Facts & Figures 2015-2016, 2015.
[2]
Hurvitz, S.; Mead, M. Triple-Negative Breast Cancer. Curr. Opin. Obstet. Gynecol., 2016. 28(1), 59-69.
[3]
Rivera, E.; Gomez, H. Chemotherapy Resistance in Metastatic Breast Cancer: The Evolving Role of Ixabepilone. Breast Cancer Res., 2010, 12(Suppl. 2), S2.
[4]
Rakesh, K.P.; Shantharam, C.S.; Sridhara, M.B.; Manukumar, H.M.; Qin, H.L. Benzisoxazole: A Privileged Scaffold for Medicinal Chemistry. MedChemComm, 2017, 8(11), 2023-2039.
[5]
Shivaprasad, C.M.; Swamy, J.; Swaroop, T.R.; Dhananjaya, M.C.; Roopashree, R.; Kumar, S.S.K.; Subbegowda, R.K. Synthesis of New Benzisoxazole Derivatives and Their Antimicrobial, Antioxidant and Anti‐inflammatory Activities. Eur. J. Chem., 2014, 5(1), 91-95.
[6]
Suhas, R.; Chandrashekar, S.; Gowda, D.C. Synthesis of Elastin Based Peptides Conjugated to Benzisoxazole as a New Class of Potent Antimicrobials -A Novel Approach to Enhance Biocompatibility. Eur. J. Med. Chem., 2011, 46(2), 704-711.
[7]
Priya, B.S. Basappa; Swamy, S.N.; Rangappa, K.S. Synthesis and Characterization of Novel 6-Fluoro-4-Piperidinyl-1,2-Benzisoxazole Amides and 6-Fluoro-Chroman-2Carboxamides: Antimicrobial Studies. Bioorg. Med. Chem., 2005, 13(7), 2623-2628.
[8]
Pagadala, L.R.; Mukkara, L.D.; Singireddi, S.; Singh, A.; Thummaluru, V.R.; Jagarlamudi, P.S.; Guttala, R.S.; Perumal, Y.; Dharmarajan, S.; Upadhyayula, S.M.; Ummanni, R. Design, synthesis and anti-mycobacterial activity of 1, 2, 3, 5-tetrasubstituted pyrrolyl-N-acetic acid derivatives. Eur. J. Med. Chem., 2014, 84, 118-126.
[9]
Mahalakshmi, K.; Srinivasarao, S.; Agnieszka, N.; Murali, M.; Kumar, K.; Venkata, K.; Chandra, G. Seeking Potent Anti-Tubercular Agents: Design, Synthesis, Anti-Tubercular Activity and Docking Study of Various ((Triazoles / Indole) -Piperazin-1-Yl / 1, 4-Diazepan-1-Yl) Benzo [ d ] Isoxazole Derivatives. Bioorg. Med. Chem. Lett., 2016, 26, 2245-2250.
[10]
Orjales, A.; Mosquera, R.; Toledo, A.; Pumar, C.; Labeaga, L.; Innerárity, A. New 3Benzisothiazolyl and 3-Benzisoxazolylpiperazine Derivatives with Atypical Antipsychotic Binding Profile. Eur. J. Med. Chem., 2002, 37(9), 721-730.
[11]
Chen, Y. Songlin Wang, X.X.; Xin Liu, M.Y.; Song Zhao, S.L.; Qiu, Y.; Tan Zhang, B.-F.L.; Zhang, G. Synthesis and Biological Investigation of Coumarin Piperazine (Piperidine) Derivatives as Potential Multireceptor Atypical Antipsychotics. J. Med. Chem., 2013, 56, 4671-4690.
[12]
Malik, S.; Ahuja, P.; Sahu, K.; Khan, S.A. Design and Synthesis of New of 3-(Benzo [ d ] Isoxazol-3-Yl) -1-Substituted Pyrrolidine-2, 5-Dione derivatives as Anticonvulsants. Eur. J. Med. Chem., 2014, 84, 42-50.
[13]
Chen, X.; Zhan, P.; Pannecouque, C.; Balzarini, J.; De Clercq, E.; Liu, X. Synthesis and biological evaluation of Piperidine-substituted Triazine derivatives as HIV-1 non-nucleoside Reverse Transcriptase Inhibitors. Eur. J. Med. Chem., 2012, 51, 60-66.
[14]
Hu, S.; Gu, Q.; Wang, Z.; Weng, Z.; Cai, Y.; Dong, X.; Hu, Y.; Liu, T.; Xie, X. Design, Synthesis, and biological evaluation of novel Piperidine-4-Carboxamide Derivatives as Potent CCR5 Inhibitors. Eur. J. Med. Chem., 2014, 71, 259-266.
[15]
Lee, J.H.; Seo, S.H.; Lim, E.J.; Cho, N.C.; Nam, G.; Kang, S.B.; Pae, A.N.; Jeong, N.; Keum, G. Synthesis and Biological Evaluation of 1-(Isoxazol-5-Ylmethylaminoethyl)-4-Phenyl Tetrahydropyridine and Piperidine Derivatives as Potent T-Type Calcium Channel Blockers with Antinociceptive Effect in a Neuropathic Pain Model. Eur. J. Med. Chem., 2014, 74, 246-257.
[16]
Ashwini, N.; Garg, M.; Mohan, C.D.; Fuchs, J.E.; Rangappa, S.; Anusha, S.; Swaroop, T.R.; Rakesh, K.S.; Kanojia, D.; Madan, V. Synthesis of 1,2-benzisoxazole tethered 1,2,3triazoles that exhibit anticancer activity in acute myeloid leukemia cell lines by inhibiting histone deacetylases, and inducing P21 and tubulin acetylation. Bioorg. Med. Chem., 2015, 23(18), 6157-6165.
[17]
Byrappa, S.; Harsha Raj, M.; Kungyal, T.; Kudva, N.N.U.; Salimath, B.P.; Rai, L.K.M. Synthesis and Biological Evaluation of Novel Isoxazolines Linked via Piperazine to 2Benzoisothiazoles as Potent Apoptotic Agents. Eur. J. Med. Chem., 2017, 126, 218-224.
[18]
Prasad, B.S.B.; Vinaya, K.; Ananda Kumar, C.S.; Swarup, S.; Rangappa, K.S. Synthesis of novel 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole derivatives as antiproliferative agents: A structure-activity relationship study. Invest. New Drugs, 2009, 27(6), 534-542.
[19]
Liu, X.H.; Li, J.; Shi, J.B.; Song, B.A.; Qi, X.B. Design and synthesis of novel 5-Phenyl-N-Piperidine Ethanone containing 4,5-Dihydropyrazole derivatives as potential antitumor agents. Eur. J. Med. Chem., 2012, 51, 294-299.
[20]
Wang, P.; Cai, J.; Chen, J.; Ji, M. Synthesis and anticancer activities of ceritinib analogs modified in the terminal piperidine ring. Eur. J. Med. Chem., 2015, 93, 1-8.
[21]
Jayashankara, B.; Rai, K.M.L. Synthesis and evaluation of antimicrobial activity of a new series of bis (isoxazoline) derivatives. ARKIVOC, 2008, 11, 75-85.
[22]
Musad, E.A.; Mohamed, R.; Ali Saeed, B.; Vishwanath, B.S.; Lokanatha Rai, K.M. Synthesis and evaluation of antioxidant and antibacterial activities of new substituted bis(1,3,4oxadiazoles), 3,5-bis(substituted) pyrazoles and isoxazoles. Bioorg. Med. Chem. Lett., 2011, 21(12), 3536-3540.
[23]
Xue, C.B.; Roderick, J.; Mousa, S.; Olson, R.E.; DeGrado, W.F. Synthesis and antiplatelet effects of an isoxazole series of glycoprotein IIb/IIIa antagonists. Bioorg. Med. Chem. Lett., 1998, 8(24), 3499-3504.
[24]
Gutiérrez, M.; Amigo, J.; Fuentes, E.; Palomo, I.; Astudillo, L. Synthetic Isoxazole as Antiplatelet Agent. Platelets, 2014, 25(4), 234-238.
[25]
Neelarapu, R.; Holzle, D.L.; Velaparthi, S.; Bai, H.; Brunsteiner, M.; Blond, S.Y.; Petukhov, P.A. Design, synthesis, docking, and biological evaluation of novel diazide-containing isoxazole-and pyrazole-based histone deacetylase probes. J. Med. Chem., 54(13), 4350-4364.
[26]
Shi, W.; Hu, J.; Bao, N.; Li, D.; Chen, L.; Sun, J. Design, synthesis and cytotoxic activities of scopoletin-isoxazole and scopoletin-pyrazole hybrids. Bioorg. Med. Chem. Lett., 2017, 27(2), 147-151.
[27]
Jian-Ping Yong, Can-Zhong Lu, and X. W. Potential Anticancer Agents. I. Synthesis of isoxazole moiety containing quinazoline derivatives and preliminarily in vitro anticancer activity. Anticancer. Agents Med. Chem., 2015, 15, 131-136.
[28]
Abu-Bakr, S.M.; Abd El-Karim, S.S.; Said, M.M.; Youns, M.M. Synthesis and anticancer evaluation of novel isoxazole/pyrazole derivatives. Res. Chem. Intermed., 2016, 42(2), 1387-1399.
[29]
Burra, S.; Voora, V.; Rao, C.P.; Vijay Kumar, P.; Kancha, R.K.; David Krupadanam, G.L. Synthesis of novel forskolin isoxazole derivatives with potent anti-cancer activity against breast cancer cell lines. Bioorg. Med. Chem. Lett., 2017, 27(18), 4314-4318.
[30]
Li, S.; Tian, H.; Yue, W.; Li, L.; Gao, C.; Si, L.; Li, W.; Hu, W.; Qi, L.; Lu, M. Down-regulation of MTA1 protein leads to the inhibition of migration, invasion, and angiogenesis of non-small-cell lung cancer cell line. Acta Biochim. Biophys, 2013, 45(2), 115-122.
[31]
Li, K.; Dias, S.J.; Rimando, A.M.; Dhar, S.; Mizuno, C.S.; Penman, A.D.; Lewin, J.R.; Levenson, A.S. Pterostilbene Acts through Metastasis-Associated Protein 1 to Inhibit Tumor Growth, Progression and Metastasis in Prostate Cancer. PLoS One, 2013, 8(3)
[32]
Lu, Y.; Wei, C.; Xi, Z. Curcumin Suppresses Proliferation and Invasion in Non-Small Cell Lung Cancer by Modulation of MTA1-Mediated Wnt/β-Catenin Pathway. Vitr. Cell. Dev. Biol., 2014, 50(9), 840-850.
[33]
Kai, L.; Samuel, S.K.; Levenson, A.S. Resveratrol enhances P53 acetylation and apoptosis in prostate cancer by inhibiting MTA1/NuRD complex. Int. J. Cancer, 2010, 126(7), 1538-1548.
[34]
Nagaraj, S.R.M.; Sheela, M.L.; Yashaswini, B.; Kumar, A.; Salimath, B.P. MTA1 Induced Angiogenesis, Migration and Tumor Growth Is Inhibited by Glycyrrhiza Glabra. IOSR J. Pharm., 2012, 2(4), 34-43.
[35]
Nagaraj, S.R.M.; Yashaswini, B.; Shetty, N.; Salimath, B.P. Metastatic events of MDA-MB-231 cells induced by angiogenic factors VEGF or MYA1 are inhibited by Tinospora cordifolia hexane fraction (Tchf). IOSR J. Pharm, 2012, 2(5), 24-30.
[36]
Raj, H.M.; Yashaswini, B.; Rössler, J.; Salimath, B.P. Combinatorial Treatment with Anacardic Acid Followed by TRAIL Augments Induction of Apoptosis in TRAIL Resistant Cancer Cells by the Regulation of P53, MAPK and NFκβ Pathways. Apoptosis, 2016, 21(5), 578-593.
[37]
Furniss, B.S.; Hannaford, A.J.; Smith, P.W.G.; Tatchell, A.R. Vogel’s Text Book of Practical Organic Chemistry; 5th edition.; Longman group UK limited: England, 1989.
[38]
Wang, P.; Henning, S.M.; Heber, D. Limitations of MTT and MTS -Based Assays for Measurement of Antiproliferative Activity of Green Tea Polyphenols. PLoS One, 2010, 5(4), e10202.
[39]
Jang, K.S.; Paik, S.S.; Chung, H.; Oh, Y.H.; Kong, G. MTA1 Overexpression Correlates Significantly with Tumor Grade and Angiogenesis in Human Breast Cancers. Cancer Sci., 2006, 97(5), 374-379.
[40]
Kawasaki, G.; Yanamoto, S.; Yoshitomi, I.; Yamada, S.; Mizuno, A. Overexpression of Metastasis-Associated MTA1 in Oral Squamous Cell Carcinomas: Correlation with Metastasis and Invasion. Int. J. Oral Maxillofac. Surg., 2008, 37(11), 1039-1046.
[41]
Nagaraj, S.R.M.; Shilpa, P.; Rachaiah, K.; Salimath, B.P. Crosstalk between VEGF and MTA1 Signaling Pathways Contribute to Aggressiveness of Breast Carcinoma. Mol. Carcinog., 2015, 54(5)
[42]
Shapiro, G.I.; Harper, J.W. Anticancer Drug Targets: Cell Cycle and Checkpoint Control. J. Clin. Invest., 1999, 104(12), 1645-1653.
[43]
Ma, J.; Waxman, D.J. Combination of antiangiogenesis with chemotherapy for more effective cancer treatment. Molecular cancer therapeutics 2008. 7(12).3670-3684.
[44]
Keshet, E.; Ben-Sasson, S.A. Anticancer drug targets: Approaching angiogenesis. J. Clin. Invest., 1999, 104(11), 1497-1501.
[45]
Sheela, M.L.; Ramakrishna, M.K.; Salimath, B.P. Angiogenic and proliferative effects of the cytokine VEGF in ehrlich ascites tumor cells is inhibited by glycyrrhiza glabra. Int. Immunopharmacol., 2006, 6(3), 494-498.
[46]
Lingaraju, S.M.; Keshavaiah, K.; Salimath, B.P. Involves Repression of the Cytokine VEGF. Gene Expr., 2008, 2(4), 234-244.
[47]
Zamora, A.; Pérez, S.A.; Rodríguez, V.; Janiak, C.; Yellol, G.S.; Ruiz, J. Dual Antitumor and Antiangiogenic Activity of Organoplatinum(II) Complexes. J. Med. Chem., 2015, 58(3), 1320-1336.

Rights & Permissions Print Cite
Article Metrics
50
3
1
© 2024 Bentham Science Publishers | Privacy Policy