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

Abstract

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 (R¹ = TPS, R² = H) exhibited good cytotoxic activity against all osteosarcoma cancer cell lines with IC₅₀ values ranging from 0.64 to 2.27 μM and showing low cytotoxicity against normal cells. Further investigations revealed that compound 2d (R¹ = TPS, R² = 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 (R¹ = TPS, R² = 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.