Discovery of amino acid-conjugated dimethylcardamonin analogues as potent anti-cervical cancer agents on SiHa cells targeting p53 signalling pathway

DMC (1) is a phytochemical found in the seeds of Syzygium nervosum, exhibiting anticancer activity in various cells through multiple pathways. Herein, the bioactivity of DMC (1) was enhanced by chemical modification through esterification, attaching fatty acid and amino acid moieties to yield 27 semi-synthetic derivatives. These compounds were evaluated for their in vitro cytotoxicity against three main types of cervical cancer cells, including SiHa, HeLa, and C-33A. As a result, the amino acid DMC derivative, 4´-(L-tyrosinyloxy)-DMC (7j), exhibited potent cytotoxicity against SiHa cells, which was approximately two-fold greater than that of 1. Further investigation into the mechanism of action of 7j was conducted, revealing its ability to induce cell cycle arrest and apoptosis. Gene expression analysis showed the downregulation of CDK2 and upregulation of the BAX/BCL2 ratio. Atomistic insight was studied on HPV 16 E6 via molecular dynamics simulation, revealing key interactions between tyrosinyl portion and C51 residue.