Design and Synthesis of Mycophenolic Acid Analogues for Osteosarcoma Cancer Treatment.

Mycophenolic acid (MPA), a natural compound, was modified to new MPA analogues via the classical method of silylation and esterification. Their cytotoxicity was evaluated in vitro on four osteosarcoma cancer cell lines (MNNG/HOS, U2OS, 143B, and SaOS-2) and human normal cells (hFOB 1.19). The most potent silicon-containing compound 2d (R(1) = TPS, R(2) = H) exhibited good cytotoxic activity against all osteosarcoma cancer cell lines with IC(50) values ranging from 0.64 to 2.27 μM and showing low cytotoxicity against normal cells. Further investigations revealed that compound 2d (R(1) = TPS, R(2) = H) displayed significant inhibition of IMPDH2 with K (i) (app) 1.8 μM. Furthermore, molecular modeling studies were performed to investigate the binding affinity of 2d (R(1) = TPS, R(2) = H) which can effectively bind to critical amino acids of three proteins (vascular endothelial growth factor receptor 2; VEGFR-2, cyclin-dependent kinase 2; CDK2, inosine-5'-monophosphate dehydrogenase; IMPDH) involved in cancer therapy. This finding suggests that triphenylsilyl-MPA (TPS-MPA) analogue could serve as a promising starting point for developing new anticancer drugs for osteosarcoma.