Structure-Activity Relationships of Tiazofurin Analogs: Synthesis and Computational Studies of 4′-Thio Derivatives of Thiophenfurin and Furanfurin

Abstract

The synthesis and computational studies of 5-(4-thio-β-D-ribofuranosyl)-furan-3-carboxamide (furanthiofurin) and 5-(4-thio-β-D-ribofuranosyl)thiophene-3-carboxamide (thiophenthiofurin) are reported.     

Synthesis and Antitumor Activity of a Heterodinucleotide of BVDU and Gemcitabine

A heterodinucleotide comprising BVDU and Gemcitabine bound together by a 5′,5′-pyrophospate bridge (BVDUp₂dFdC) has been synthesized and evaluated as antitumor agent against AH13 rat sarcoma cells. BVDUp₂dFdC showed a cytotoxicity similar to that of Gemcitabine.     

A New Facile Synthesis and Antiviral Activity of Oxazofurin

Abstract

A new, more facile synthesis of oxazofurin, a structural analogue of tiazofurin, selenazofurin and ribavirin, has been carried out by rhodium catalyzed reaction of ethyl α-formyl-diazoacetate with 2,3, 5-tri-O-benzoyl-β-D-ribofu-ranosyl cyanide. When evaluated against DNA and RNA viruses, HIV-1 inclu-ded, oxazofurin was found inactive. It was also ineffective in potentiating the anti-HIV activity of 2′, 3′-dideoxyadenosine.     

A new tiazofurin pronucleotide: synthesis and biological evaluation of cyclosaligenyl-tiazofurin monophosphate

Synthesis and biological activities of cyclosaligenyl-tiazofurin monophosphate (CycloSal-TRMP), a new tiazofurin pronucleotide, are reported. CycloSal-TRMP proved to be active in vitro against human myelogenous leukemia K562 cell line and as A1 adenosine receptor agonist.     

C-nucleoside analogues of furanfurin as ligands to A1 adenosine receptors

Furanfurin (2-beta-D-ribofuranosylfuran-4-carboxamide) derivatives and analogues were synthesized and their affinity for adenosine receptors was determined. The agonistic behavior of furanfurin against A1 receptors is preserved only when the furan ring is substituted with isosteric pentatomic ring systems such as oxazole, thiazole or thiophene, and the carboxamide group is unsubstituted. Replacement of the hydrogen atoms of the carboxamide group with alkyl, cycloalkyl or arylalkyl groups generates compounds endowed with moderate antagonistic activity.     

Ribose-modified Mizoribine Analogues: Synthesis and Biological Evaluation

Synthesis, conformational analysis and antitumor evaluation of 2′- and 3′-C-methyl analogues of mizoribine (bredinine, 4-carbamoyl-1-β-D-ribofuranosylimidazole-5-olate) are reported.     

Synthesis, conformational analysis, and biological activity of new analogues of thiazole-4-carboxamide adenine dinucleotide (TAD) as IMP dehydrogenase inhibitors

Thiazole-4-carboxamide adenine dinucleotide (TAD) analogues T-2'-MeAD (1) and T-3'-MeAD (2) containing, respectively, a methyl group at the ribose 2'-C-, and 3'-C-position of the adenosine moiety, were prepared as potential selective human inosine monophosphate dehydrogenase (IMPDH) type II inhibitors. The synthesis of heterodinucleotides was carried out by CDI-catalyzed coupling reaction of unprotected 2'-C-methyl- or 3'-C-methyl-adenosine 5'-monophosphate with 2',3'-O-isopropylidene-tiazofurin 5'-monophosphate, and then deisopropylidenation. Biological evaluation of dinucleotides 1 and 2 as inhibitors of recombinant human IMPDH type I and type II resulted in a good activity. Inhibition of both isoenzymes by T-2'-MeAD and T-3'-MeAD was noncompetitive with respect to NAD substrate. Binding of T-3'-MeAD was comparable to that of parent compound TAD, while T-2'-MeAD proved to be a weaker inhibitor. However, no significant difference was found in inhibition of the IMPDH isoenzymes. T-2'-MeAD and T-3'-MeAD were found to inhibit the growth of K562 cells (IC(50) 30.7 and 65.0muM, respectively).     

Effect of acyclic nucleoside phosphonates on the HIV-1 integrase in vitro.

Integrase (IN) is an essential enzyme in the human immunodeficiency virus type-1 (HIV-1) replication cycle and, thus, a potential target for chemotherapeutic agents. Because various nucleotide analogues have been reported to inhibit IN in vitro, we investigated the effect of acyclic nucleoside phosphonates. Both unphosphorylated and diphosphorylated derivatives were inhibitory to IN at concentrations ranging between 60 and 800 microM, with diphosphorylated derivatives being 5- to 8-fold more potent than unphosphorylated counterparts.