Mycophenolic acid (MPA) is the most potent and specific inhibitor of inosine monophosphate dehydrogenase (IMPDH). This compound was reported to bind the NAD site of IMPDH and mimic the binding of nicotinamide moiety of nicotinamide adenine dinucleotide. We linked MPA derivatives with the adenine moiety of NAD through a methylenebis(phosphonate) bridge to form novel mycophenolic adenine dinucleotides (MADs) which resemble well the intact natural cofactor. The MAD analogues differ by the length of the side chain (linker) between the aromatic ring of mycophenolic derivative and the β- phosphorus atom of the adenosine bis(phosphonate) moiety. Regardless of the linker size, MADs were found to be potent inhibitors of human IMPDH type I and type II with K(i)'s = 0.25-0.52 μM, an order of magnitude less potent than MPA itself (K(i) = 0.01-0.04 μM). The growth of K562 cells was inhibited by MPA (IC50 = 0.3 μM) and the MAD analogues (IC50 = 0.1-1.5 μM) with a similar potency. Accordingly, a suppression of alloantigen- induced proliferation of human lymphocytes by the MAD analogues at concentration of 10-20 μM was equally effective as that observed for MPA. In contrast to MPA, MAD analogues were found to be resistant to glucuronidation in vitro. Since therapeutic potential of MPA is limited by its undesirable glucuronidation, the glucuronidation-resistant MAD analogues may be superior immunosuppressants if they are not glucuronidated in vivo.
|Original language||English (US)|
|Number of pages||6|
|Journal||Current medicinal chemistry|
|State||Published - Jul 24 1999|