Design, synthesis, and identification of a novel napthalamide-isoselenocyanate compound NISC-6 as a dual Topoisomerase-IIα and Akt pathway inhibitor, and evaluation of its anti-melanoma activity

Deepkamal N. Karelia, Ugir Hossain Sk, Parvesh Singh, A. S.Prakasha Gowda, Manoj K. Pandey, Srinivasa R. Ramisetti, Shantu Amin, Arun Sharma

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

Synthesis and anti-melanoma activity of novel naphthalimide isoselenocyanate (NISC) and naphthalimide selenourea (NSU) analogs are described. The novel agents were screened for growth inhibition of different human melanoma cell lines including those having BRAFV600E mutation (UACC903, 1205Lu, and A375M) and BRAFWT (CHL-1). In general, the NISC analogs (4a-d) were more effective in inhibiting the cell viability than the NSU analogs (7a-b). Overall, NISC-6 (4d), having a six-carbon alkyl chain, was identified as the most cytotoxic compound in both BRAFV600E mutated and BRAFWT cells. NISC-6 docked strongly into the binding sites of Akt1 and human topoisomerase IIα (Topo-IIα), and the docking results were supported by experimental findings showing NISC-6 to inhibit of both Akt pathway and Topo-IIα activity in a dose dependent manner. Furthermore, NISC-6 effectively induced apoptosis in human melanoma cells, inhibited tumor growth by ∼69% in a melanoma mouse xenograft model, and showed excellent compliance with the Lipinski’ rule of five, suggesting both its efficacy and drug-like behavior under physiological conditions.

Original languageEnglish (US)
Pages (from-to)282-295
Number of pages14
JournalEuropean Journal of Medicinal Chemistry
Volume135
DOIs
StatePublished - Jan 1 2017

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

Fingerprint Dive into the research topics of 'Design, synthesis, and identification of a novel napthalamide-isoselenocyanate compound NISC-6 as a dual Topoisomerase-IIα and Akt pathway inhibitor, and evaluation of its anti-melanoma activity'. Together they form a unique fingerprint.

Cite this