Potent Inhibitors of Human Inosine Monophosphate Dehydrogenase Type II. Fluorine-Substituted Analogs of Thiazole-4-carboxamide Adenine Dinucleotide

Abstract

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-beta-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 beta-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 (Kis = 0.5 microM), 2 (Kis = 0.7 microM), and 3 (Kis = 2.9 microM) was comparable to that of TAD (Ki = 0.2 microM). The difluoromethylene bisphosphonate analogue, beta-CF2-TAD (Ki = 0.17 microM), was found to be equally effective as the best cofactor-type inhibitor, beta-CH2-TAD (Ki = 0.11 microM). 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.

Straightforward Ball‐Milling Access to Dinucleoside 5′,5′‐Polyphosphates via Phosphorimidazolide Intermediates

“…Moreover, MS analysis indicated the carbonation of the 2′ and 3′ position of the glycosyl moiety, corresponding to compound 3 a . This result is consistent with the carbonation of ribonucleotides by CDI in solution‐phase reactions . We assume that the acid form of UMP (p K a values of 1.6 and 6.6) allows for the protonation of the imidazole of CDI and, therefore, facilitates its substitution by the phosphate monoester.…”

“…[d] 460 0100 4UMP [d] 445 15 85 5UMP [d] 360 36 64 6CMP [d] 460 0100 7AMP [d] 460 0100 compound 3a.T his result is consistentw ith the carbonation of ribonucleotides by CDI in solution-phaser eactions. [24] We assume that the acid form of UMP (pK a values of 1.6 and 6.6) allows for the protonation of the imidazole of CDI and, therefore, facilitates its substitution by the phosphate monoester. Considering that only 50 %c onversion could be obtained under these conditions, acetonitrile (0.3 mLmg À1 )w as added as al iquid assistant for grinding.…”

Diadenosine and Diuridine Poly(borano)phosphate Analogues: Synthesis, Chemical and Enzymatic Stability, and Activity at P2Y1 and P2Y2 Receptors

“…21 Phosphoroimidazolides may be generated in situ or isolated by use of carbonyl diimidazole (CDI) prior to the reaction with the corresponding nucleotides. 22 Additional nucleotide coupling procedures include the use of dicyclohexylcarbodiimide (DCC) 23 or N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (EDC). 24 By implementation of these procedures, dinucleoside polyphosphates with a phosphate linker ranging from 2 to 6 phosphates have been synthesized.…”

A Novel Insulin Secretagogue Based on a Dinucleoside Polyphosphate Scaffold

“…Dinucleoside polyphosphates are conventionally prepared via the activation of the 5′ terminal phosphate of a nucleotide with carbonyl diimidazole (CDI), 32 thereby forming a phosphoryl donor (P-donor) that reacts with a nonactivated nucleotide (i.e., phosphoryl (P-acceptor)). We attempted two different approaches to synthesize analogues 8–10 .…”