New Conjugates of 3'-Azido-3'-deoxythymidine and 2',3'-Dideoxy-3'-thiacytidine Based on 1,3-(Dipalmitoylamino)-propan-2-ol: Synthesis and Investigation of Anti-Hiv Activity on Model Cellular Systems

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Abstract

The development of prodrugs of antiviral nucleosides with isosteric derivatives of natural lipids makes it possible to increase the bioavailability of these drugs and modulate their effectiveness. In this work, new lipophilic prodrugs of 3'-azido-3'-deoxythymidine (AZT), 2', 3'-dideoxy-3'-thiacytidine (3TC) based on 1,3-(dipalmitoylamino)propane-2-ol were synthesized by using the H-phosphonate method, as well as phosphoramidate derivatives modified by the phosphorus center with various esters of L-α-alanine. The anti-HIV activity of the synthesized compounds against various HIV strains (HIV-1 MVP-899, HIV-1 RF) and cytotoxicity against MT-4 cells have been studied. H-phosphonate ester and phosphodiester conjugates showed lower anti-HIV activity than the original nucleosides (EC50 = 0.59–3.04 μM), their advantages include low cytotoxicity (CC50 > 100 μM), while the phosphodiester conjugate 3TC was inactive on this cellular model of the virus. The antiviral activity of phosphoramidate derivatives with L-α-alanine esters decreased in the range (tBu) > Me > (iPr) > Et, EC50 values were 0.46, 4.60, 8.97, and 12.55 μM, respectively, and these compounds exhibited cytotoxicity similar to AZT (CC50 > 50 μM). An additional advantage of such conjugates may be the possibility of targeted transport into HIV reservoirs due to enterocyte-mediated lymphatic transport, as well as the potential intracellular release of nucleoside monophosphate, which makes it possible to bypass the limiting stage of phosphorylation of nucleosides to their active triphosphate form. Therefore, the development of such prodrugs can serve as a basis for the search for drugs with high efficacy.

About the authors

E. S Darnotuk

MIREA – Russian Technological University (ITHT named after M.V. Lomonosov)

Email: Mslizirichi@yandex.ru
Moscow, Russia

A. E Sinyavin

Department of Epidemiology, Federal State Budget Institution “National Research Centre for Epidemiology and Microbiology Named After Honorary Academician N. F. Gamaleya” of the Ministry of Health of the Russian Federation

Moscow, Russia

M. N Chudina

MIREA – Russian Technological University (ITHT named after M.V. Lomonosov)

Moscow, Russia

N. S Shastina

MIREA – Russian Technological University (ITHT named after M.V. Lomonosov)

Moscow, Russia

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