Thiazole-4-carboxamide adenine dinucleotide (TAD), the active metabolite of the oncolytic C-
nucleoside tiazofurin (TR), is susceptible to phosphodiesteratic breakdown by a unique
phosphodiesterase present at high levels in TR-resistant
tumors. Since accumulation of TAD, as regulated by its synthetic and degradative
enzymes, appears to be an important determinant for sensitivity to the
drug, a series of hydrolytically resistant
phosphonate analogues of TAD were synthesized with the intent of producing more stable compounds with an ability to inhibit
IMP dehydrogenase equivalent to TAD itself. Isosteric
phosphonic acid analogues of TR and
adenosine nucleotides were coupled with activated forms of
AMP and TR monophosphate to give dinucleotides 2 and 4. Coupling of protected
adenosine 5'-(alpha, beta-methylene)diphosphate with
isopropylidene-TR in the presence of DCC afforded compound 3 after deprotection. These compounds are more resistant than TAD toward hydrolysis and still retain potent activity against
IMP dehydrogenase in vitro.
beta-Methylene-TAD (3), the most stable of the TAD
phosphonate analogues, produced a depletion of
guanine nucleotide pools in an experimentally induced TR-resistant P388
tumor variant that was superior to that obtained with TR in the corresponding sensitive line.