A comparative study of the hydrolysis pathways of substituted aryl phosphoramidate versus aryl thiophosphoramidate derivatives of stavudine.
A comparative study of aryl phosphoramidate and aryl thiophosphoramidate derivatives of 2',3'-didehydro-2',3'-dideoxythymidine (d4T) was performed. The study focused on the nature of the substituents and the influence of a thiophosphoramidate in the structure of these derivatives. The rate of alkaline hydrolysis of these two types of d4T derivatives indicated that replacement of oxygen with sulfur decreases the rate of hydrolysis by twofold. Additionally, the activation energy (E(a)) for the sulfur analogs is comparatively higher than that of the oxygen analogs. Notably, an intermediate was formed in the hydrolysis reaction of the sulfur analogs of d4T that was absent in the case of the oxygen analog, and the tentative structure of the intermediate was proposed based on LC/mass spectroscopy data. Using both HPLC and (31)P-NMR techniques, we identified the hydrolysis product of the phosphoramidate derivatives and were able to show in in vitro studies that porcine liver esterase can hydrolyze the methyl ester portion of the phosphoramidate derivatives. Aryl phosphoramidate derivatives of d4T were 1000-fold more active than the corresponding aryl thiophosphoramidate derivatives, indicating that the energy of activation of hydrolysis of these phosphoramidate derivatives plays a significant role in their biological potency.
Department of Chemistry, Parker Hughes Institute, 2699 Patton Road, Roseville, MN 55113, USA.
T K
TK
Venkatachalam
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G
Yu
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P
Samuel
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S
Qazi
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Pendergrass
F M
FM
Uckun
D000577:Amides / Q000737:chemistry* / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D006801:Humans; D006868:Hydrolysis; D010710:Phosphates / Q000737:chemistry* / Q000378:metabolism*; D010756:Phosphoric Acids / Q000737:chemistry* / Q000378:metabolism*; D018119:Stavudine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism*; D013552:Swine
D000577:Amides; D010710:Phosphates; D010756:Phosphoric Acids; C011067:phosphoramidic acid; D018119:Stavudine; C035638:thiophosphoric acid