Design and\nSynthesis of Mycophenolic Acid Analogues\nfor Osteosarcoma Cancer Treatment

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