Novel mycophenolic adenine bis(phosphonate)s as potential immunosuppressants

Mycophenolic acid (MPA) is the most potent and specific inhibitor of inosin e monophosphate dehydrogenase (IMPDH). This compound was reported to bind t he NAD site of IMPDH and mimic the binding of nicotinamide moiety of nicoti namide adenine dinucleotide. We linked MPA derivatives with the adenine moi ety of NAD through a methylenebis(phosphonate) bridge to form novel mycophe nolic adenine dinucleotides (MADs) which resemble well the intact natural c ofactor. The MAD analogues differ by the length of the side chain (linker) between the aromatic ring of mycophenolic derivative and the P-phosphorus a tom 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 = 0.25-0.52 mu M, an order of magnitude less potent than MPA itse lf (K-i = 0.01-0.04 mu M). The growth of K562 cells was inhibited by MPA (I C50 = 0.3 mu M) and the MAD analogues (IC50 = 0.1-1.5 mu M) with a similar potency. Accordingly, a suppression of alloantigen-induced proliferation of human lymphocytes by the MAD analogues at concentration of 10-20 mu M was equally effective as that observed for MPA. In contrast to MPA, MAD analogu es were found to be resistant to glucuronidation in vitro. Since therapeuti c potential of MPA is limited by its undesirable glucuronidation, the glucu ronidation-resistant MAD analogues may be superior immunosuppressants if th ey are not glucuronidated in vivo.