- A new cyclic phosphoramidate d4t prodrug approach cfcl0amb-d4t-phosphoramidates
-
A new potential phosphoramidate prodrug approach for d4T 1 is described. In hydrolyses studies the cycloAmb-d4T-phosphoramidates 2 and 3 proved to deliver d4TMP following a tandem reaction. Copyright 1999 by Marcel Dekker, Inc.
- Lorey, Martina,Meier, Chris
-
-
Read Online
- Cyclic saligenyl phosphotriesters of 2',3'-dideoxy-2',3'-didehydrothymidine (d4T) - A new pro-nucleotide approach
-
The synthesis of a new pro-nucleotide approach for d4TMP 2 based on cycloSal-4TMP 3a-d is described. Phosphotriesters 3 release d4TMP 2 selectively by a controlled, chemically induced tandem reaction. CycloSal-phosphotriesters 3 exhibited high biological activity against HIV-1/ HIV-2 in CEM cells which was retained in CEM TK- cells.
- Meier, Chris,Lorey, Martina,De Clercq,Balzarini, Jan
-
-
Read Online
- 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 (Ea) 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 31P-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.
- Venkatachalam,Yu,Samuel,Qazi,Pendergrass,Uckun
-
p. 665 - 683
(2007/10/03)
-
- 2-Nucleos-5'-O-yl-4H-1,3,2-benzodioxaphosphinin-2-oxide - ein neues Konzept fuer lipophile, potentielle Prodrugs biologisch aktiver Nucleosidmonophosphate
-
Keywords: AIDS; Chemotherapie; Phosphotriester-Prodrugs; Prodrugs; Thymidinderivate
- Meier, Chris
-
-