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

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journal contribution
posted on 2018-11-17, 12:31 authored by Dijana Saftić, Biserka Žinić, Ljubica Glavaš-Obrovac, Mirosława Studzińska, Edyta Paradowska, Zbigniew J. Leśnikowski

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 1012 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, 1012 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.

Funding

The authors gratefully acknowledge financial support from the Ministry of Science, Education and Sport of Croatia (grants 098-0982914-2935, 219-0982914-2176); Croatian Science Foundation (grant HRZZ-1477); National Science Center, Poland (grant 2015/16/W/ST5/00413); J. J. Strossmayer University of Osijek supporting grant to Lj. Glavaš-Obrovac (IZIP-2016) and VIF2015-MEFOS-2. Additionally, contributions from the Statutory Fund of IMB PAS are also gratefully acknowledged.

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