Newer human inosine 5'-monophosphate dehydrogenase 2 (hIMPDH2) inhibitors as potential anticancer agents

Abstract

Human inosine 5'-monophosphate dehydrogenase 2 (hIMPDH2), being an age-old target, has attracted attention recently for anticancer drug development. Mycophenolic acid (MPA), a well-known immunosuppressant drug, was used a lead structure to design and develop modestly potent and selective analogues. The steep structure-activity relationship (SAR) requirements of the lead molecule left little scope to synthesise newer analogues. Here, newer MPA amides were designed, synthesised and evaluated for hIMPDH2 inhibition and cellular efficacy in breast, prostate and glioblastoma cell lines. Few title compounds exhibited cellular activity profile better than MPA itself. The observed differences in the overall biological profile could be attributed to improved structural and physicochemical properties of the analogues over MPA. This is the first report of the activity of MPA derivatives in glioblastoma, the most aggressive brain cancer.

Keywords: MTT; Mycophenolic acid; anticancer agents; de novo purine synthesis; hIMPDH2 inhibitors.

Figure 1.

Currently used IMPDH inhibitor drugs.

Figure 2.

Recently reported MPA analogues.

Scheme 1.

General scheme for synthesis of mycophenolic acid amides (14–28): Reagents and conditions: Method A: DMAP, EDCI.HCl, DMF, 0 °C 6 h, RT, 48–72 h; Method B: DIPEA, HATU, DMF, 0 °C 6 h, RT, 48–72 h.

Figure 3.

hIMPDH2 % inhibition of compounds 14–28.

Figure 4.

Cytotoxicity of MPA amide derivatives.