Functionalized azirine based scaffolds as endothelin inhibitors for the selective anti-angiogenic activity
Singh, H. Satish, N. Babu, T.R. Singh, A. Yadav, B. Singh, S.K. Siddiqui, M.I. Jagavelu, K. Sudhakar, G.
Singh, H.
Satish, N.
Babu, T.R.
Singh, A.
Yadav, B.
Singh, S.K.
Siddiqui, M.I.
Jagavelu, K.
Sudhakar, G.
Publication Date
2024-08-05
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2024-05-16
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Abstract
Anti-angiogenic therapy has long been used as an adjunct therapy for the resolution of tumor burden. The current findings describe the synthesis of novel marine-based azirine-containing compounds that exhibit anti-angiogenic mediated anti-tumor activity. Azirine-2-carboxylate inhibited HUVEC-mediated tubulogenesis without causing cell death in a dose-dependent manner. Ex-vivo CAM, in-vivo Matrigel implantation, and ear angiogenesis experiments have all shown that azirine-2-carboxylate effectively inhibits angiogenesis. Furthermore, azirine-2-carboxylate inhibits the migration of ECs without disrupting the preformed tubule network. Azirine-2-carboxylate had adequate intramuscular systemic exposure and inhibited tumor growth in a xenograft mouse model. DARTS analysis, competitive binding assay, and gene expression investigations revealed that azirine-2-carboxylate inhibits endothelin-1-mediated angiogenesis. Overall, the discovery of azirine-2-carboxylate demonstrated a potent inhibition of angiogenesis targeting ET1 and a possible application in anti-angiogenic therapy.
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Singh H, Satish N, Babu TR, et aL (2024) Functionalized azirine based scaffolds as endothelin inhibitors for the selective anti-angiogenic activity. European Journal of Medicinal Chemistry. 274: 116510
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