{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T04:25:21Z","timestamp":1760243121444,"version":"build-2065373602"},"reference-count":43,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2015,10,16]],"date-time":"2015-10-16T00:00:00Z","timestamp":1444953600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["R01-AI-52061 and 2R01-GM-57693"],"award-info":[{"award-number":["R01-AI-52061 and 2R01-GM-57693"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>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 \u03b1-P-borano-\u03b3-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\u2032-\u03b1-P-borano-\u03b3-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\u201336 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 \u03b1-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.<\/jats:p>","DOI":"10.3390\/molecules201018808","type":"journal-article","created":{"date-parts":[[2015,10,16]],"date-time":"2015-10-16T14:46:27Z","timestamp":1445006787000},"page":"18808-18826","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Synthesis, Hydrolysis, and Protonation-Promoted Intramolecular Reductive Breakdown of Potential NRTIs: Stavudine \u03b1-P-Borano-\u03b3-P-N-l-tryptophanyltriphosphates"],"prefix":"10.3390","volume":"20","author":[{"given":"Zhihong","family":"Xu","sequence":"first","affiliation":[{"name":"Shaw Department of Chemistry, Duke University, Durham, NC 27708, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Barbara","family":"Shaw","sequence":"additional","affiliation":[{"name":"Shaw Department of Chemistry, Duke University, Durham, NC 27708, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2015,10,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1002\/1098-1128(200011)20:6<417::AID-MED1>3.0.CO;2-Z","article-title":"Pronucleotides: Toward the in vivo delivery of antiviral and anticancer nucleotides","volume":"20","author":"Wagner","year":"2000","journal-title":"Med. 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