A Divergent Approach for the Synthesis of d- and l-4′-Ethynyl Dioxolane Nucleosides with Potent Anti-HIV Activity

Abstract

Novel 4′-C-ethynyl isomeric dioxolane nucleoside analogues (β-D, α-D, β-L, and α-L, respectively) are successfully synthesized via a divergent strategy from the common starting material, (Z)-but-2-ene-1,4-diol, and are characterized and evaluated for their anti-HIV-1 and anti-HIV-2 activities. The β-D and β-L products display potent in vitro activities against HIV-1 (IIIB) with EC 50 values of 0.75 and 0.87 μM, respectively, and against HIV-2 (ROD) with EC 50 values of 0.75 and 0.35 μM, respectively, being better in comparison with 3TC [EC 50 , 5.27 μM (HIV-1) and 1.30 μM (HIV-2)]. The β-D and β-L nucleosides also potently inhibit different drug-resistant strains of the HIV-1 virus (L100I, K103N, Y181C, and V106A). The selectivity indices and cytotoxic profiles of the β-D and β-L nucleosides are much better than those of the standard drugs AZT and d4T.

Pyrrolo[2,1-f][1,2,4]triazine: a promising fused heterocycle to target kinases in cancer therapy

“…It is an integral part of avapritinib recently approved for adults with unresectable or metastatic gastrointestinal stromal tumor harboring a platelet-derived growth factor receptor alpha exon 18 mutation, including D842V mutations [ 45 ]. Pyrrolo[2,1-f][1,2,4]triazine is also a part of nucleoside [ 46 , 47 ] drug remdesivir used to treat broad-spectrum viral infections including SARS COVID-19 [ 48 ]. Various synthetic strategies have been developed to synthesize pyrrolo[2,1-f][1,2,4]triazine either starting from triazine or pyrrole [ 48 ].…”