Synthesis of Novel AZA-Analogues of Tiazofurin with 2-[5,5-bis(Hydroxymethyl)Pyrrolidin-2-yl] Framework as Sugar Mimic

• Published in: Nucleosides, nucleotides & nucleic acids Vol. 31; no. 1; pp. 72 - 84
• Main Authors: Mironiuk-Puchalska, Ewa, Koszytkowska-Stawińska, Mariola, Sas, Wojciech, De Clercq, Erik, Naesens, Lieve
• Format: Journal Article
• Language: English
• Published: PHILADELPHIA Taylor & Francis Group 01.01.2012; Taylor & Francis
• Subjects: Animals; Antiviral Agents - chemical synthesis; Antiviral Agents - pharmacology; Aza Compounds - chemical synthesis; Aza Compounds - pharmacology; Biochemistry & Molecular Biology; Carbohydrates - chemical synthesis; Carbohydrates - pharmacology; Cercopithecus aethiops; Cysteine - analogs & derivatives; Cysteine - chemistry; DNA Viruses - drug effects; Fibroblasts - drug effects; Fibroblasts - virology; HeLa Cells; Humans; Life Sciences & Biomedicine; Molecular Mimicry; Pyrrolidine synthesis; Pyrrolidines - chemical synthesis; Pyrrolidines - pharmacology; Ribavirin - analogs & derivatives; Ribavirin - chemical synthesis; Ribavirin - pharmacology; RNA Viruses - drug effects; Science & Technology; thiazole synthesis; tiazofurin aza-analogues; Vero Cells; tiazofurin aza-analogues; C-NUCLEOSIDE ANALOGS; ANTIPROLIFERATIVE ACTIVITY; THIAZOLE; thiazole synthesis; DEHYDROGENASE; Pyrrolidine synthesis; IN-VITRO; BIOLOGICAL EVALUATION; CHEMISTRY; INHIBITORS; ANTIVIRAL DRUGS; DERIVATIVES
• ISSN: 1525-7770; 1532-2335
• DOI: 10.1080/15257770.2011.643848

The novel aza-analogues of tiazofurin (TZF) with 2-[5,5-bis(hydroxymethyl)pyrrolidin-2-yl] moiety, as sugar mimic, were synthesized from O,O-cyclohexylidene derivative of 4,4-bis(hydroxymethyl)-4-nitrobutanal in multi-gram scale. The synthetic route consisted of three stages: (i) the synthesis of corresponding derivative of 5,5-bis(hydroxymethyl)pyrrolidine-2-carbonitrile, (ii) the construction of ethyl thiazole-2-carboxylate part by the conversion of the pyrrolidine-2-carbonitrile into the N-trifluoroacetyl derivative followed by cyclocondensation with L-cysteine ethyl ester and then by dehydrogenation, and (iii) the final transformation of the ethyl thiazole-4-carboxylate into the aza-analogues of TZF. The TZF aza-analogues were evaluated for their antiviral activities in cell-culture-based assays.