Synthesis, and in vitro Enzymatic and Antiviral Evaluation of d4T Polyphosphate Derivatives as Chain Terminators

Abstract

A series of d4T di- or triphosphate derivatives have been synthesized and evaluated as effective substrates for HIV-1 RT, and also tested for their in vitro anti-HIV activity. The steady-state kinetic study of compounds 1-4 in an enzymatic incorporation assay by HIV-1 RT follows Michaelis-Menten profile. In addition, compounds 2-4 are able to inhibit HIV-1 replication to the same extent as d4T and d4TMP in MT-4 cells, as well as in CEM/0 cells and CEM/TK(-) cells. The data suggests that these d4T polyphosphate derivatives are hydrolyzed to d4T and rephosphorylated to d4TTP before exerting their antiviral activity.

Evaluation of the Antiviral Activity of Drugs from the Group of Polymer Electrolyte Derivatives against a Wide Range of Viruses

“…Также описаны противовирусные свойства серосодержащих полимеров в отношении нескольких оболочечных вирусов, включая вирус гриппа [16]. Различные фосфатсодержащие полимеры обладают противовирусной активностью в отношении SARS-CoV-2 и ВИЧ [17,18].…”

Synthesis of <i>P</i>¹-Stavudine-<i>P</i>²-Zidovudine-5′,5′-Diphosphate

“…Another approach for the preparation of symmetrical dinucleoside 5′,5′-polyphosphates is to react a NMP (the acceptor), with another activated phosphate such as phosphorimidazolide (the donor). [10] Recently, we developed a one-pot protocol for the synthesis of the homodinucleotides of AZT, d4T, and acyclovir from the corresponding nucleoside 5′-H-phosphonates. [11][12][13] The direct coupling method typically generates complicated polyphosphate byproducts while other approaches are plagued by laborious procedures.…”

Facile Synthesis of Symmetrical Homonucleotides of Antiviral Nucleosides

“…As shown in Figure 1, zidovudine (AZT) and stavudine (d4T) have been widely used for treatment of HIV/AIDS infection [5,6]. To overcome the clinical limitations of NRTIs-induced decrease in nucleoside kinase activity, homodimers of AZT and d4T 5′-diphosphates (AZTp 2 AZT, d4Tp 2 d4T) have been synthesized and identified as effective substrates for HIV reverse transcriptase [7][8][9][10].…”

“…Mauro et al reported a method for the synthesis of AZTp 2 AZT starting from P 1 -AZT-5′-P 2 -diphenyl pyrophosphate in low yield [7]. Herdewijn and co-workers synthesized d4Tp 2 d4T from d4T 5′-phosphorimidazolide in 41% yield [9]. Recently, a novel synthesis of homodinucleotides of AZT and d4T from the corresponding nucleoside 5′-H-phosphonates has been developed [11].…”