Document Report Card

ID: ALA1123434

Journal: J Med Chem

Title: Thiazole-4-carboxamide adenine dinucleotide (TAD). Analogues stable to phosphodiesterase hydrolysis.

Authors: Marquez VE, Tseng CK, Gebeyehu G, Cooney DA, Ahluwalia GS, Kelley JA, Dalal M, Fuller RW, Wilson YA, Johns DG.

Abstract: 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.

CiteXplore: 2875185

DOI: 10.1021/jm00159a027