Synthesis, Hydrolysis, and Protonation-Promoted Intramolecular Reductive Breakdown of Potential NRTIs: Stavudine α-P-Borano-γ-P-N-l-tryptophanyltriphosphatesReportar como inadecuado




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Shaw Department of Chemistry, Duke University, Durham, NC 27708, USA





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Academic Editor: Ramon Eritja

Abstract Phosphorus-modified prodrugs of dideoxynucleoside triphosphates ddNTPs have shown promise as pronucleotide strategies for improving antiviral activity compared to their parent dideoxynucleosides. Borane modified NTPs offer a promising choice as nucleoside-nucleotide reverse transcriptase inhibitors NRTIs. However, the availability of α-P-borano-γ-P-substituted NTP analogs remains limited due to challenges with synthesis and purification. Here, we report the chemical synthesis and stability of a new potential class of NRTI prodrugs: stavudine d4T 5′-α-P-borano-γ-P-N-L-tryptophanyltriphosphates. One-pot synthesis of these compounds was achieved via a modified cyclic trimetaphosphate approach. Pure Rp and Sp diastereomers were obtained after HPLC separation. Based on LC-MS analysis, we report degradation pathways, half-lives 5–36 days and mechanisms arising from structural differences to generate the corresponding borano tri- and di-phosphates, and H-phosphonate, via several parallel routes in buffer at physiologically relevant pH and temperature. Here, the major hydrolysis products, d4T α-P-boranotriphosphate Rp and Sp isomers, were isolated by HPLC and identified with spectral data. We first propose that one of the major degradation products, d4T H-phosphonate, was generated from the d4T pronucleotides via a protonation-promoted intramolecular reduction followed by a second step nucleophilic attack. This report could provide valuable information for pronucleotide-based drug design in terms of selective release of target nucleotides. View Full-Text

Keywords: boron chemistry; pronucleotide; d4T boranotriphosphate analog; stability; mechanism; intramolecular reduction boron chemistry; pronucleotide; d4T boranotriphosphate analog; stability; mechanism; intramolecular reduction





Autor: Zhihong Xu * and Barbara Ramsay Shaw

Fuente: http://mdpi.com/



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