Synthesis and in vitro evaluation of antiviral and cytostatic properties of novel 8-triazolyl acyclovir derivatives

• Published in: Nucleosides, nucleotides & nucleic acids Vol. 37; no. 7; pp. 397 - 414
• Main Authors: Saftić, Dijana, Žinić, Biserka, Glavaš-Obrovac, Ljubica, Studzińska, Mirosława, Paradowska, Edyta, Leśnikowski, Zbigniew J.
• Format: Journal Article
• Language: English
• Published: PHILADELPHIA Taylor & Francis 01.01.2018; Taylor & Francis Ltd
• Subjects: 1,4-disubstituted 1,2,3-triazole; 8-Triazolyl acyclovir; Acyclovir; Antiviral activity; Biochemistry & Molecular Biology; cytotoxic activity; DNA viruses; Guanosine; Hydrazine; Life Sciences & Biomedicine; RNA viruses; Science & Technology; Tumor cell lines; AZIDES; ANALOGS; 8-Triazolyl acyclovir; 3-triazole; antiviral activity; ANTITUMOR-ACTIVITY; ALKYNES; ACYCLONUCLEOSIDES; 4-disubstituted 1; 1; CYCLOADDITION; NUCLEOSIDE; 2; RING; DRUGS; BIOLOGICAL EVALUATION; cytotoxic activity; 1,4-disubstituted 1,2,3-triazole
• ISSN: 1525-7770; 1532-2335
• DOI: 10.1080/15257770.2018.1485932

As a part of the research aimed on identification of new nucleobase derivatives with improved biological properties, a series of novel 8-substituted acyclovir derivatives were synthesized. The 8-azidoguanosine 4 and novel 8-azidoacyclovir 9 were synthesized from commercially available guanosine 1 and acyclovir 6 which were transformed into 8-bromopurine derivatives 2 and 7 and hydrazine derivatives 3 and 8, respectively. 8-Triazolylguanosine 5 and 8-triazolylacyclovir analogs 10-12 were successfully synthesized via the Cu(I) catalyzed 1,3-dipolar cycloaddition reaction of azides 4 and 9 with propargyl alcohol, 4-pentyn-1-ol and 5-hexyn-1-ol. The novel 1,4-disubstituted 1,2,3-triazolyl compounds 5, 10-12 were evaluated for antiviral activity against selected DNA and RNA viruses and cytostatic activity against normal Madine Darby canine kidney (MDCK I) cells, and seven tumor cell lines (HeLa, CaCo-2, NCI-H358, Jurkat, K562, Raji and HuT78). While tested compounds exerted no antiviral activity at nontoxic concentrations, the 8-triazolyl acyclovir derivative 10, with the shortest alkyl substituent at the C-4 of triazole ring, was found to be the most active against the CaCo-2 cell line.