Piperazine tethered bergenin heterocyclic hybrids: design, synthesis, anticancer activity, and molecular docking studies.

In an attempt to develop natural product-based anticancer agents, a series of novel piperazine-linked bergenin heterocyclic hybrids bearing arylthiazolyl (5a-e), benzothiazolyl (10a-i), and arylsulfonyl (13a-o) were synthesized using the classical Mannich reaction and evaluated for their anticancer activity. All the synthesized derivatives were assessed for in vitro cytotoxic activity against a panel of human cancer and normal cell lines and the results showed that most of the compounds exhibited significant cytotoxic activity against cancer cells and mild cytotoxicity against normal cells. In particular, the compounds 5a, 5c, 10f, and 13o showed potent cytotoxic activity against tongue and oral cancer cell lines compared to the parent compound (<100 µM). Considering the efficacy, the compounds 5a, 5c, 10f, and 13o were subjected to cell cycle analysis and the results indicated that the compounds mitigated the cell cycle progression at the G0/G1 phase in the tongue and oral cancer cell lines. Subsequently, the annexin V/PI staining assay demonstrated that the compounds 5a, 5c, 10f, and 13o induced early and late apoptosis against tongue cancer and necrosis against oral cancer. Further, gene expression analysis revealed that 5a, 5c, and 13o treatment regulated the BAX and BcL-2 expression and also the selected compounds significantly reduced the expression level of vimentin, oct-4, and nanog. In addition, molecular docking studies revealed that the selected derivatives have strong binding energy with the BcL2 protein and downregulates the expression. Taken together, the study results implied that these compounds are promising anticancer candidates by modulating the epithelial to mesenchymal transition axis and could be considered for further development of novel anticancer drugs.

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

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.

Synthesis and biological evaluation of bergenin-1,2,3-triazole hybrids as novel class of anti-mitotic agents.

In continuation of our investigation of pharmacologically-motivated natural products, we have isolated bergenin (1) as a major compound from Mallotus philippensis, which is deployed in different Indian traditional systems of medicine. Here, a series of bergenin-1,2,3-triazole hybrids were synthesized and evaluated for their potentials against a panel of cancer cell lines. Several of the hybrid derivatives were found more potent in comparison to parent compound bergenin (1). Among them, 4j demonstrated potent activity against A-549 and HeLa cell lines with IC50 values of 1.86 µM and 1.33 µM, respectively, and was equipotent to doxorubicin. Cell cycle analysis showed that 4j arrested HeLa cells at G2/M phase and lead to accumulation of Cyclin B1 protein. Cell based tubulin polymerization assays and docking studies demonstrated that 4j disrupts tubulin assembly by occupying colchicine binding pocket of tubulin.