Synthesis and evaluation of sulfonylethyl-containing phosphotriesters of 3'-azido-3'-deoxythymidine as anticancer prodrugs.

Abstract

A series of bis(sulfonylethyl) and mono(sulfonylethyl) phenyl phosphotriesters of zidovudine (3'-azido-3'-deoxythymidine, AZT) were synthesized as potential anticancer prodrugs that liberate AZT monophosphate via nonenzymatic β-elimination mechanism. Stability studies demonstrated that all the synthesized prodrugs spontaneously liberate AZT monophosphate with half-lives in the range of 0.07-278.8h under model physiological conditions in 0.1M phosphate buffer at pH 7.4 and 37 °C. Analogous to aldophosphamide, the elimination rates were accelerated in the presence of reconstituted human plasma under the same conditions. Among the compounds, 3, 4, 8, and 10 were comparable or superior to AZT against five established human cancerous cell lines in vitro. Moreover, the selected compounds were equally sensitive to both the wild-type osteosarcoma 143 B and the thymidine kinase-deficient 143 B/TK(-) cell lines. The findings are consistent with that these compounds deliver AZT monophosphate intracellularly.

• Authors: Jiang Wang, Yi-Jun Wang, Zhe-Sheng Chen, Chul-Hoon Kwon
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 22 Issue 21 Pg. 5747-56 (Nov 01 2014) ISSN: 1464-3391 [Electronic] England
• PMID: 25440502 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents
• Esters
• Phosphoramide Mustards
• Prodrugs
• Sulfones
• Zidovudine
• aldophosphamide

Topics

• Antineoplastic Agents (chemical synthesis, pharmacokinetics, pharmacology)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Esters
• Half-Life
• Humans
• MCF-7 Cells
• Phosphoramide Mustards (chemistry)
• Prodrugs (chemical synthesis, pharmacokinetics, pharmacology)
• Sulfones (chemistry)
• Zidovudine (chemistry, pharmacokinetics, pharmacology)