Synthesis of thioether andrographolide derivatives and their inhibitory effect against cancer cells.

A series of novel thioether andrographolide derivatives were synthesized by incorporating various aromatic (or heteroaromatic) substituents into C-12 or 14-OH. A total of 38 andrographolide derivatives were prepared and evaluated for their inhibitory activity against cancer cells. All the derivatives exhibited better activity against prostate cancer cells (PC-3) than the parent compound. Among these, compounds , , , , , , and demonstrated good activity. These compounds were further evaluated for their anticancer activities against other cancer cell lines including MCF-7, MDA-MB-231, and A549. Compounds and showed excellent activity against MCF-7 with an IC value of 0.7 and 0.6 μM, respectively. The absolute configuration of was determined single-crystal X-ray diffraction. The activity of (12), which was the precursor of , was better than that of the diastereoisomer (12). Moreover, the preliminary structure-activity relationship has been summarized. The results obtained herein are very important for further optimization of andrographolide.