Piotr Januszczyk

5-Ethynyl-1-β-D-ribofuranosyl-1H-[1,2,3]triazole-4-carboxylic acid amide (ETCAR) and its analogues: synthesis and cytotoxic properties.

Efficient Pd(0)-catalysed synthesis of 5-alkynyl-1-β-D-ribofuranosyl-1H-[1,2,3]triazole-4-carboxylic acid amide depends on the presence of different protecting groups of the ribose moiety. Peracetylated 5-iodo substrate (15) couples with terminal alkynes or trimethyl-[(tributylstannyl)ethynyl]silane in 50-71% and 72% yield (ETCAR), respectively, although its hydrodehalogenation to 19 is noticeable. On the other hand, hydrodehalogenation of acetonide (16) predominates over coupling with terminal alkyne and slightly decreases a yield of cross-coupling reaction with trimethyl[(tributylstannyl)ethynyl]silane. Alternative conditions of reaction with terminal alkynes, to exclude so far identified hydride sources to produce hydridopalladium species, have been established for acetonide 16 and allowed to achieve 72% of coupling. Fluoromethyl derivative (42) was prepared from its 5-hydroxymethyl precursor by fluorination with DAST. Additionally, X-ray structural analysis of 42 was performed. All 1,2,3-triazolonucleosides and two synthesized cycloSal-pronucleotides were evaluated for cytotoxic activity against K562, HeLa and HUVEC cells.

Antivirally active ribavirin analogues--4,5-disubstituted 1,2,3-triazole nucleosides: biological evaluation against certain respiratory viruses and computational modelling.

Background: Ribavirin is a broad-spectrum antiviral agent that derives some of its activity from inhibition of cellular inosine monophosphate dehydrogenase (IMPDH), resulting in lower guanosine triphosphate (GTP) levels. Here we report the biological activities of three ribavirin analogues. Methods: Antiviral activities of test compounds were performed by in vitro cytopathic effect inhibition assays against influenza A (H1N1, H3N2 and H5N1), influenza B, measles, parainfluenza type 3 (PIV-3) and respiratory syncytial viruses. Compounds were modelled into the ribavirin 5‘-monophosphate binding site of the crystallographic structure of the human type II IMPDH (hIMPDH2) ternary complex. Effects of compounds on intracellular GTP levels were performed by strong anion exchange HPLC analysis. Results: Of the three compounds evaluated, the 5-ethynyl nucleoside (ETCAR) exhibited virus-inhibitory activities (at 1.2–20 μM, depending upon the virus) against most of the viruses, except for weak activity against PIV-3 (62 μM). Antiviral activity of ETCAR was similar to ribavirin; however, cytotoxicity of ETCAR was greater than ribavirin. Replacing the 5-ethynyl group with a 5-propynyl or bromo substituent (BrCAR) considerably reduced antiviral activity. Computational studies of ternary complexes of hIMPDH2 enzyme with 5‘-monophosphates of the compounds helped rationalize the observed differences in biological activity. All compounds suppressed GTP levels in cells; additionally, BrCAR suppressed adenosine triphosphate and elevated uridine triphosphate levels. Conclusions: Three compounds related to ribavirin inhibited IMPDH and had weak to moderate antiviral activity. Cytotoxicity adversely affected the antiviral selectivity of ETCAR. As with ribavirin, reduction in intracellular GTP may play a role in virus inhibition.

Bioactive fused heterocycles: Nucleoside analogs with an additional ring

The following mini-review summarizes the basic literature data regarding synthesis, biological activity, structure-activity relationship, and discussion of the mechanisms of action of two major classes of nucleoside analogs with fused heterocyclic rings: (i) the ethenonucleosides and their related derivatives of the 5,9-dihydro-3-glycosyl-6-alkyl-9-oxo-5H-imidazo[1,2-a]purine type; (ii) the bicyclic nucleosides of 6-alkyl-2,3-dihydrofurano[2,3-d]-pyrimidin-2(3H)-one and 6-alkyl-2,3-dihydropyrrolo[2,3-d]-pyrimidin-2(3H,7H)-one.

Reaction of acylaminocyanoesters with 2,4-bis (4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide leading to substituted aminothiazoles. Crysta

Abstract 2-Acylamino-2-cyanoacetic acid ethyl esters 2a-c react with 2,4-bis (4-methoxyphenyl)-1, 3, 2, 4-dithiadiphosphetane 2,4-disulfide 1 in refluxing benzene with formation of 2-alkyl(aryl)-5-aminothiazole-4-carboxylic acid ethyl esters 3a-c . Structure 3 was established by spectroscopic means and an X ray crystallographic investigation of 3a . X-Ray analysis revealed that the thiazole ring, exocyclic nitrogen and carbonyl group forming a hydrogen-bonded cycle are nearly coplanar. A resonance interaction is manifested by distinctly shortened /1.447 (3)/ C(carbonyl)-C(thiazole) distance.

Synthesis and Antiviral Evaluation of 2′-C-Methyl Analogues of 5-Alkynyl- and 6-Alkylfurano- and Pyrrolo[2,3-d]Pyrimidine Ribonucleosides

A series of novel 2′-C-methylribonucleosides, involving 5-iodo and 5-alkynyl uridine analogues as well as related bicyclic furano- and pyrrolo[2,3-d]pyrimidinone compounds, has been synthesized and evaluated for their inhibitory effect on replication of the hepatitis C virus (HCV). The new nucleoside analogues did not show meaningful anti-HCV activity.

Base-Modified Nucleosides: Etheno Derivatives

This review presents synthesis and chemistry of nucleoside analogs, possessing an additional fused, heterocyclic ring of the “etheno” type, such as 1,N6-ethenoadenosine, 1,N4-ethenocytidine, 1,N2-ethenoguanosine, and other related derivatives. Formation of ethenonucleosides, in the presence of α-halocarbonyl reagents and their mechanism, stability, and degradation, reactions of substitution and transglycosylation, as well as their application in the nucleoside synthesis, have been described. Some of the discussed compounds may be applied as chemotherapeutic agents in antiviral and anticancer treatment, acting as pro-nucleosides of already known, biologically active nucleoside analogs.

An efficient route to novel 4,5-di- and 2,4,5-tri substituted imidazoles from imidazo[1,5-a]-1,3,5-triazine (5,8-diaza-7,9-dideazapurine) derivatives.

Two new types of imidazole derivatives: N‐(2‐R1‐5‐R2‐1H‐imidazol‐4‐yl) thioureas 7a–g and N‐(2‐R1‐5‐R2‐1H‐imidazol‐4‐yl) formamides 8b,c,g were obtained in high yields by the hydrolytic degradation of 6‐R1‐8‐R2‐2‐thioxo‐2,3‐dihydroimidazo[1,5‐a]‐1,3,5‐triazin‐4(1H)‐ones 5a–g and 6‐R1‐8‐R2‐imidazo[1,5‐a]‐1,3,5‐triazin‐4(3H)‐ones 6b,c,d, respectively. The tautomeric preferences of the new imidazoles were determined. †In honor and celebration of the 70th birthday of Professor Leroy B. Townsend.

Novel Analogues of Tiazofurin by Lawesson Reagent Effected Cyclization

Abstract 2-Benzylthiazole-4-carboxamide 4 and 5-(β-D-ribofuranosylamino) thiazole-4-carboxamide 10 were synthesized from phenylacetylamino- and formylamino cyanoacetic acid esters 1a and 1b, respectively. The ribosylation reaction leading to 10 gave rise also to its α anomer as a minor product.

Synthesis and fluorescent properties of the tricyclic analogues of acyclovir linked with nitrogen hetbrocyclic units.

Tricyclic (T, 3,9-dihydro-9-oxo-5H-imidazo[l,2-α]purine) analogues of acyclovir (ACV, 1), substituted in the 6 position with pyrid-4-yl, 4-(pyrid-4′-yl)Ph, 4-(pyrimidin-5′-yl)Ph and 4-(thiazol-2′-yl)Ph units were synthesized. For the synthesis ofthe heteroarylphenyl derivatives, a convenient general route was developed, i.e., Suzuki cross-coupling between protected 6-(4-dihydroxyborylphenyl) TACV and easily available bromoheterocycles. Fluorescent properties of newly synthesized TACV aoalogues strongly depend on the nature of a solvent. This sensitivity of fluorescence makes the compounds promising probes of H-bonding in the environment.