2. Academic Validation
  3. 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

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

  • Eur J Med Chem. 2017 Jul 28:135:282-295. doi: 10.1016/j.ejmech.2017.04.052.
Deepkamal N Karelia 1,  Ugir Hossain Sk 2,  Parvesh Singh 3,  A S Prakasha Gowda 4,  Manoj K Pandey 1,  Srinivasa R Ramisetti 1,  Shantu Amin 1,  Arun K Sharma 5
Affiliations

Affiliations

  • 1 Department of Pharmacology, Penn State Cancer Institute, CH72, Penn State College of Medicine, 500 University Drive, Hershey, PA 17033, USA.
  • 2 CSIR-Institute of Himalayan Bioresource Technology, Palampur, HP, India.
  • 3 School of Chemistry and Physics, University of Kwa-Zulu Natal (UKZN), Westville Campus, Durban 4000, South Africa.
  • 4 Department of Biochemistry and Molecular Biology, Penn State College of Medicine, 500 University Drive, Hershey, PA 17033, USA.
  • 5 Department of Pharmacology, Penn State Cancer Institute, CH72, Penn State College of Medicine, 500 University Drive, Hershey, PA 17033, USA. Electronic address: aks14@psu.edu.
PMID: 28458134 DOI: 10.1016/j.ejmech.2017.04.052
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.

Keywords

Anti-Tumor; Apoptosis; Isoselenocyanate; Melanoma; Naphthalimide; Selenourea.

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