2′,3′-Didehydro-3′-deoxy-4′-ethynylthymidine (4′-Ed4T) has been identified as a novel nucleoside analog with potent and selective anti-human immunodeficiency virus type 1 (HIV-1) activity and weak cytotoxicity in cell cultures. 4′-Ed4T proved to be 5- to 10-fold more active than its structurally related compound, stavudine (d4T). However, the drug resistance profile of 4′-Ed4T was different from those of d4T and other existing HIV-1 nucleoside reverse transcriptase inhibitors (NRTIs). Approximately 6- to 11-fold decreases in susceptibility to 4′-Ed4T were observed for HIV-1 carrying NRTI-associated mutations (D67N, K70R, T215F, and K219Q) or the lamivudine (3TC)-resistant mutation M184V. In contrast, the susceptibility of the virus carrying the K65R mutation or the multidrug-resistant mutation with the Q151M complex (A62V, V75I, F77L, F116Y, and Q151M) was not altered. Furthermore, the activity of 4′-Ed4T appeared to be enhanced in the presence of K103N, a major nonnucleoside reverse transcriptase inhibitor-resistant mutation. Although 4′-Ed4T was 4.5- to 17.5-fold less active against multidrug-resistant clinical isolates than against a reference strain isolated from a treatment-naive patient, it was still inhibitory to these isolates at low concentrations. Analysis of 4′-Ed4T-resistant HIV-1 obtained through in vitro selection revealed that the virus was also resistant to 3TC and had two amino acid mutations (P119S and T165A) in addition to the M184V mutation. Since 4′-Ed4T has increased anti-HIV-1 activity, decreased cytotoxicity, and a different resistance profile, it should be considered for further development as a new member of NRTIs.

Anti-Human Immunodeficiency Virus Type 1 Activity and Resistance Profile of 2′,3′-Didehydro-3′-Deoxy-4′-Ethynylthymidine In Vitro

Extensive efforts have been made to identify nucleoside reverse transcriptase inhibitors (NRTIs). Eight NRTIs have now been approved for clinical use; however, variants of HIV-1 resistant to these antiviral agents have emerged in patients even when they are treated with combinations [highly active antiretroviral therapy (HAART)]. Thus, the development of novel compounds that are active against drug-resistant HIV-1 variants and that prevent or delay the emergence of resistant HIV-1 variants is urgently needed. Previously, 4'-C-substituted nucleosides (4'-SNs) were designed as new types of NRTIs. They were synthesized and examined as potential therapeutic agents against HIV infection. Among them, several 4'-substituted-2'-deoxynucleosides (4'-SdNs), especially those that bear an ethynyl group, were shown to be active against various laboratory and clinical HIV-1 strains including known drug-resistant variants. These results were recently reported by our collaborators. In this review, we summarize the design, synthesis and demonstrations of the anti-HIV activity of 4'-SNs, and then consider 4'-SNs as potential therapeutic agents for HIV-1.

https://journals.sagepub.com/doi/pdf/10.1177/095632020401500401

Potential of 4′-C-Substituted Nucleosides for the Treatment of HIV-1

Motivated by our recent finding that 4‘-ethynylstavudine (4) is a promising anti-human immunodeficiency virus type 1 (HIV-1) agent, we synthesized its 4‘-thio analogue, as well as other 4‘-thiostavudines having a carbon substituent at the 4‘-position, as racemates in this study. Methyl 3-oxo-tetrahydrothiophen-2-carboxylate (5) was used as a starting material to construct the requisite 4-thiofuranoid glycal (13). Introduction of a thymine base was carried out by an electrophilic addition reaction to 13 using N-iodosuccinimide (NIS) and bis(trimethylsilyl)thymine. The desired β-anomer (16β) obtained as a major product in this reaction underwent ready elimination with activated Zn to give the 4‘-carbomethoxy derivative (18). By using 18 as a common intermediate, 4‘-carbon-substituted (CH2OH, CO2Me, CONH2, CHCH2, CN, and C⋮CH) 4‘-thiostavudines were prepared. Among these six compounds, 4‘-cyano (28) and 4‘-ethynyl (29) analogues were found to show inhibitory activity against HIV-1 with ED50 values of 7.6 and...

Synthesis and anti-human immunodeficiency virus activity of 4'-branched (+/-)-4'-thiostavudines.

A compound which has excellent anti-HIV activity, is effective also against polypharmacy-resistant HIV strains having resistance to two or more anti-HIV drugs, especially AZT, DDI, DDC, D4T, 3TC, etc., is lowly cytotoxic, and has resistance to deactivation by adenosine deaminase. It is a 4'-C-substituted 2-haloadenosine derivative represented by the following formula [I], [II], or [III]. Also provided is a medicinal composition comprising the derivative and a pharmaceutically acceptable support. [Chemical formula 1] (In the formulae, X represents halogeno; R1 represents ethynyl or cyano; and R2 represents hydrogen or the atoms of a residue of phosphoric acid or a derivative thereof.)

4'-c-substituted-2-haloadenosine derivative

Synthesis of 4′-aryl-2′,3′-dideoxynucleoside analogues

A new anti‐HIV agent 4′‐cyano‐2′,3′‐didehydro‐3′‐deoxythymidine (9) was synthesized by allylic substitution of the 3′,4′‐unsaturated nucleoside 14, having a leaving group at the 2′‐position, with cyanotrimethylsilane in the presence of SnCl4. Evaluation of the anti‐HIV activity of 9 showed that this compound is much less potent than the recently reported 2′,3′‐didehydro‐3′‐deoxy‐4′‐(ethynyl)thymidine (1).

Synthesis and anti-HIV activity of 4'-cyano-2',3'-didehydro-3'-deoxythymidine.

Synthesis and anti-HIV Activity of 4′-Cyano-2′,3′-didehydro-3′-deoxythymidine.

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Synthesis and anti-HIV activity of 4'-cyano-2',3'-didehydro-3'-deoxythymidine.

Synthesis and anti-HIV Activity of 4′-Cyano-2′,3′-didehydro-3′-deoxythymidine.