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
摘要
Objective: Currently, various drugs have been developed and are being used in practice for the treatment of HIV infection, however, the emergence of multidrug resistance to the drugs used is still a serious problem in anti-HIV therapy. Limitations in the use of existing nucleoside reverse transcriptase inhibitors (NRTIs) have led to the development of strategies for creating prodrugs based on them. 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 efficiency. Methods: In this work, new lipophilic prodrugs of 3′-azido-3′-deoxythymidine (AZT), 2′,3′-dideoxy-3′-thiacytidine (3TC) based on 1,3-(dipalmitoylamino)propan-2-ol were synthesized using the H-phosphonate method. Phosphoramidate derivatives with various esters of L-α-alanine have also been obtained. Results and Discussion: The anti-HIV activity of the synthesized compounds against various HIV strains (HIV-1 MVP-899; HIV-1 RF) and cytotoxicity in relation to MT-4 cells were studied.The H-phosphonatediester and phosphodiester conjugates showed anti-HIV activity inferior to the parent nucleosides, and their advantages include low cytotoxicity (CC50 >100 µM). The phosphodiester conjugate 3TC was inactive in this virus cell system. The antiviral activity of phosphoamidates with L-α-alanine esters decreased in the range (tBu) >Me > (iPr) > Et. Thus, compounds with methyl, ethyl and isopropyl ether residues showed a similar level of anti-HIV activity (IC50 = 4.60–12.55 µM), the derivative containing the residue of tert-butyl ether of L-α-alanine (IC50 = 0.46 µM) showed the greatest activity. These compounds showed cytotoxicity similar to AZT (CC50 >50 µM). Conclusions: The new lipophilic derivatives of AZT and 3TC synthesized in the work have low toxicity and exhibit antiviral activity against various clinical isolates of HIV-1. Although they are inferior in effectiveness to the parent anti-HIV nucleosides in cellular models, their cytotoxicity is lower, the advantages of such conjugates include the possibility of increasing the bioavailability of drugs due to enterocyte-mediated lymphatic transport, potential intracellular release of nucleoside monophosphate, which additionally bypasses the limiting stage of primary phosphorylation of nucleosides. Therefore, the design of such prodrugs can serve as the basis for the search for drugs with high efficacy.