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Open AccessArticle

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

Shaw Department of Chemistry, Duke University, Durham, NC 27708, USA
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Author to whom correspondence should be addressed.
Academic Editor: Ramon Eritja
Molecules 2015, 20(10), 18808-18826; https://doi.org/10.3390/molecules201018808
Received: 16 August 2015 / Revised: 15 September 2015 / Accepted: 21 September 2015 / Published: 16 October 2015
(This article belongs to the Special Issue Frontiers in Nucleic Acid Chemistry)
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
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MDPI and ACS Style

Xu, Z.; Shaw, B.R. Synthesis, Hydrolysis, and Protonation-Promoted Intramolecular Reductive Breakdown of Potential NRTIs: Stavudine α-P-Borano-γ-P-N-l-tryptophanyltriphosphates. Molecules 2015, 20, 18808-18826. https://doi.org/10.3390/molecules201018808

AMA Style

Xu Z, Shaw BR. Synthesis, Hydrolysis, and Protonation-Promoted Intramolecular Reductive Breakdown of Potential NRTIs: Stavudine α-P-Borano-γ-P-N-l-tryptophanyltriphosphates. Molecules. 2015; 20(10):18808-18826. https://doi.org/10.3390/molecules201018808

Chicago/Turabian Style

Xu, Zhihong; Shaw, Barbara R. 2015. "Synthesis, Hydrolysis, and Protonation-Promoted Intramolecular Reductive Breakdown of Potential NRTIs: Stavudine α-P-Borano-γ-P-N-l-tryptophanyltriphosphates" Molecules 20, no. 10: 18808-18826. https://doi.org/10.3390/molecules201018808

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