2. Academic Validation
  3. Functionalized azirine based scaffolds as endothelin inhibitors for the selective anti-angiogenic activity

Functionalized azirine based scaffolds as endothelin inhibitors for the selective anti-angiogenic activity

  • Eur J Med Chem. 2024 Aug 5:274:116510. doi: 10.1016/j.ejmech.2024.116510.
Himalaya Singh 1,  Nagam Satish 2,  Tella Ramesh Babu 3,  Abhinav Singh 1,  Babita Yadav 1,  Sandeep Kumar Singh 4,  Mohammad Wahajuddin 4,  Mohammad Imran Siddiqui 5,  Kumaravelu Jagavelu 6,  Gangarajula Sudhakar 7
Affiliations

Affiliations

  • 1 Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India.
  • 2 Department of Organic Synthesis & Process Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500007, Telangana, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India.
  • 3 Department of Organic Synthesis & Process Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500007, Telangana, India.
  • 4 Pharmaceutics and Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India.
  • 5 Molecular and Structural Biology Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India.
  • 6 Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India. Electronic address: [email protected].
  • 7 Department of Organic Synthesis & Process Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500007, Telangana, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India. Electronic address: [email protected].
PMID: 38843585 DOI: 10.1016/j.ejmech.2024.116510
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.

Keywords

Anti-angiogenic property; Azirines; Cancer; Endothelial cells; Endothelin 1 inhibitor.

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