Design and Synthesis of Mycophenolic Acid Analogues for Osteosarcoma Cancer Treatment

  • ACS Bio Med Chem Au. 2024 Oct 17;5(1):106-118. doi: 10.1021/acsbiomedchemau.4c00079.
Patamawadee Silalai  1  2 ,  Pimpisa Teeyakasem  3  4 ,  Dumnoensun Pruksakorn  3  4  5 ,  Rungnapha Saeeng  1  2
Affiliations
  • 1. Department of Chemistry and Center for Innovation in Chemistry, Faculty of Science, Burapha University, Chonburi 20131, Thailand.
  • 2. The Research Unit in Synthetic Compounds and Synthetic Analogues from Natural Product for Drug Discovery (RSND), Burapha University, Chonburi 20131, Thailand.
  • 3. Musculoskeletal Science and Translational Research (MSTR) Center, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand.
  • 4. Center of Multidisciplinary Technology for Advanced Medicine (CMUTEAM), Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand.
  • 5. Department of Orthopedics, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand.
PMID: 39990949 DOI: 10.1021/acsbiomedchemau.4c00079
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.

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