Design, synthesis and cytotoxic activity studies of alkyne linked analogues of Nimbolide

Abstract

A series of novel nimbolide derivatives bearing various substitutions on 28th position was designed and synthesized using Sonogashira (2a-2p) and Glaser coupling (3a-3e) reactions. The synthesized derivatives were assessed for in vitro cytotoxic activity against four different human cancer cell lines (A549 cells, MCF-7 cells, MDA-MB-231 cells, and HCT15 cells) and normal cell line (HEK cells) using MTT assay. Among the screened derivatives, the compound 3a showed potent activity against A549 cells with IC50 value of 0.23 μM as comparing with parent molecule 1 (1.48 μM) and the standard drug doxorubicin (0.82 μM). As well, the flow cytometry analysis confirmed that the compounds 1 and 3a arrest the cell cycle progress at S phase and induce the early apoptosis in the lung cancer. The qRT-PCR analysis revealed that the compounds 1 and 3a downregulate the BcL2 expression and upregulates the Bax gene expression level in A549 cells. The strong binding affinity of the compounds 1 and 3a with BcL2 was also confirmed using molecular docking analysis. Together, the results suggested that the compound 3a is a promising anticancer agent against lung cancer is deserved for further investigation.