68245-92-1

Upstream product

• 20187-82-0 2'-fluorodeoxyadenosine 
• 20187-82-0 9-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)adenine 

Relevant academic research and scientific papers

C-nucleoside isostere of nicotinamide adenine dinucleotide, analogs thereof and use as anti-cancer agent

This invention provides a compound having the structure: STR1 wherein each R1, R2, R3, and R4 is independently fluorine, OH or H; Z is O, CH2 or CF2 ; each Y is independently OH or F; X7 is N or CH, X8 is NH, S or Se; and W is C or N, wherein when W is C, the dashed line (---) represents a double bond and X9 is N or CH, and wherein when W is N, the dashed line (---) represents a single bond and X9 is S or Se, or the dashed line (---) represents a double bond and X9 is N or CH. This invention also provides a pharmaceutical composition comprising the compounds and methods of treating a mammal having an inosine monophosphate dehydrogenase associated disorder.

Potent inhibitors of human inosine monophosphate dehydrogenase type II. Fluorine-substituted analogues of thiazole-4-carboxamide adenine dinucleotide

Three analogues of thiazole-4-carboxamide adenine dinucleotide (TAD) (1- 3) containing a fluorine atom at the C2' of the adenine nucleoside (in the ribo and arabino configuration) and at the C3' (in the ribo configuration) were synthesized in high yield from the corresponding 5'-monophosphates of 2'-deoxy-2'-fluoroadenosine (9), 9-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)- adenine (17), and 3'-deoxy-3'-fluoroadenosine (14), respectively. Pure 2',3'- O-isopropylidene-tiazofurin 5'-phosphorimidazolide (8) was obtained by phosphorylation of the protected tiazofurin followed by treatment with carbonyldiimidazole and HPLC purification. Reaction of 8 with 9 in DMF-d7 (monitored by 1H and 31P NMR) afforded the desired dinucleotide 12, which after deisopropylidenation gave 1 in 82% yield. Small amounts of symmetrical dinucleotides AppA (10, 7.2%) and TRppTR (11, 8.0%) were also isolated during HPLC purification of the major product 12. In a similar manner, compounds 2 and 3 were obtained by coupling of 8 with 14 and 17 in 80% and 76% yield, respectively. All newly prepared fluoro-substituted compounds as well as β- CF2-TAD, earlier synthesized by us, showed good inhibitory activity against inosine monophosphate dehydrogenase type II, the isozyme which is predominant in neoplastic cells. Binding of 1 (K(is) = 0.5 μM), 2 (K(is) = 0.7 μM), and 3 (K(is) = 2.9 μM) was comparable to that of TAD (K(i) = 0.2 μM). The difluoromethylene bisphosphonate analogue, β-CF2-TAD (K(i) = 0.17 μM), was found to be equally effective as the best cofactor-type inhibitor, β-CH2- TAD (K(i) = 0.11 μM). Interestingly, the level of inhibition of horse liver alcohol dehydrogenase by these compounds was found to be much lower (0.1 mM for 1 and 2 and no inhibition up to 10 mM for 3). These findings show that inhibition of tumor-induced inosine monophosphate dehydrogenase type II is selective and may be of therapeutic interest.