Mycophenolic acid (MPA) is a fungally-derived inhibitor of inosine 5′-monophosphate dehydrogenase (IMPDH). MPA binds IMPDH at the nicotinamide sub-site of the NAD cofactor binding domain leaving the adenosine sub-site empty. In order to improve the binding affinity we synthesized MPA analogs by linking adenosine 5′-methylenebis(phosphonate) with mycophenolic alcohols containing 2-, 4-, and 6-carbon atoms in their aliphatic side chain. Adenine dinucleotide analogs of tiazofurin, selenazofurin and benzamide riboside were synthesized as P1, P2-disubstituted pyrophosphates. Cytotoxicity of each analog was examined in human colon adenocarcinoma HT-29 and erythroleukemia K562 cells, and induction of differentiation in K562 cells by these agents was determined. Mycophenolic acid is currently used as an immunosuppressant but its anticancer action is limited by inactivation due to rapid glucuronidation. The new analogs show resistance to metabolism to inactive species and exhibit enhanced cytotoxicity in tumor cell lines, and therefore could be useful as anticancer agents.
Bibliographical noteFunding Information:
This work was supported by the IU School of Medicine Cancer Biology Training Program Fellowship (JAY) and NIH Small Business in Research (SBIR) grant #1R43CA84828 (HNJ and KWP).
Copyright 2008 Elsevier B.V., All rights reserved.
- Cancer chemotherapy
- Mycophenolic acid