Synthesis of novel heterocyclic compounds bearing tetralin moiety of potential anticancer activity targeting the intrinsic apoptotic pathway

Abstract

This study deals with the readily reaction of the enaminone derivative 3 with different reagents to give the corresponding pyrazolo[3,4-b]pyridine, pyrazolo[1,5-a]pyrimidine, pyrazole, pyrazolopyridazine, dienamide, and pyranone derivatives. In-vitro cytotoxic screening was performed for all analogs against several human cancer cell lines. Compound 21 showed significant anti-breast cancer activity and a safety profile against the normal human cell lines (BJ-1). Furthermore, compound 21 was chosen as a representative example to study its potential apoptotic mechanism in the MCF-7 cancer cell line. It enhanced DNA fragmentation alongside its characteristic effect on tubulin polymerization. In addition, compound 21 up-regulated the pro-apoptotic Bax protein, decreased the Bcl-2 anti-apoptotic protein, and increased p53 and Caspase-7 levels confirming its mitochondrial intrinsic apoptotic activation.

Graphical Abstract

Keywords:

• Anticancer activity
• apoptotic proteins
• dienamide
• pyranone
• pyrazolo[1,5-a]pyrimidine

Acknowledgments

The authors thank the Leibniz Institute of Plant Biochemistry (IPB) Halle Germany specifically the group of Prof. Wessjohann with Dr. Andrea Porzel and Gudrun Hahn for measurements of the NMR, IR, and the MS Spectra.

Disclosure statement

No potential conflict of interest was reported by the author(s).