Site-Selective Synthesis of C-17 Ester Derivatives of Natural Andrographolide for Evaluation as a Potential Anticancer Agent.

A library of 57 compounds of natural andrographolide was designed, synthesized, and screened for studies against four human cancer cell lines: A594, PC-3, MCF-7, and HCT-116. Most of the synthesized compounds displayed better cytotoxic profile against all tested cells compared to the parent andrographolide (). The tested semisynthetic derivatives of andrographolide were found to be more sensitive toward lung carcinoma (A594) and prostate carcinoma (PC-3) cell lines. Among the synthesized compounds, the C-17 -methoxy phenyl ester analog inhibited cell proliferation effectively in A549 (IC: 6.6 μM) and PC-3 (IC: 5.9 μM) cell variants, and compound exhibited the most potent activity against the A594 cell line, with an IC value of 3.5 μM. Further anticancer mechanistic investigation demonstrated that compound displayed nuclear morphological changes and increased reactive oxygen species (ROS) with disturbed mitochondrial membrane potential (MMP) that can lead to apoptosis. To know the exact structure confirmation of intermediate compounds and , single X-ray crystallography was performed, which supported the complete reaction design of this work.