NDLI: Bis(carbamoyloxymethyl) Esters of 2′,3′-Dideoxyuridine 5′-monophosphate (ddUMP) as Potential ddUMP Prodrugs

Content Provider	Springer Nature Link
Author	Khan, Saeed R. Kumar, Srinivas K. Farquhar, David
Copyright Year	2005
Abstract	We previously reported the synthesis of bis(pivaloyloxymethyl) 2′,3′-dideoxyuridine 5′-monophosphate (POM$_{2}$-ddUMP) (1a) as a membrane-transport prodrug formulation of the free parent nucleotide, ddUMP. Although successful at delivering ddUMP into cells in culture, POM$_{2}$-ddUMP was rapidly degraded by plasma carboxylate esterases after intravenous administration to experimental animals, and therefore has limited therapeutic potential as a systemically administered prodrug. We now report the synthesis of bis(N,N′-dimethylcarbamoyloxymethyl)- and bis(N-piperidinocarbamoyloxymethyl) 2′,3′-dideoxyuridine 5′-m onophosphate [DM$_{2}$-ddUMP (1b) and DP$_{2}$-ddUMP (1c), respectively], analogues of POM$_{2}$-ddUMP that were designed to be more resistant to degradation by plasma esterases..After entering cell by passive diffusion, it was anticipated that loss of one of the carbamoyloxymethyl groups of 1b and 1c would occur by spontaneous chemical hydrolysis to give the intermediate phosphodiesters, 2b and 2c. Cleavage of the remaining carbamoyloxymethyl groups by cellular phosphodiesterase I would generate ddUMP. 1b and 1c were prepared by condensation of 2′,3′-dideoxyuridine (ddU) with the appropriate bis(N-alkylcarbamoyloxymethyl) phosphate in DMA in the presence of triphenylphosphine and diethyl azodicarboxylate (the Mitsunobo reagent).The half-lives of 1b and 1c when incubated at a concentration of 10$^{−4}$ M in human plasma at 37°C were 3.5 h and 3.7 h, respectively, similar to the half-lives observed under the same temperature conditions in 0.05 M aqueous phosphate buffer, pH 7.4. By contrast, the half-life of the POM$_{2}$ prodrug, 1a, in plasma was only 5 min. The initial products of degradation of 1b and 1c were the phosphodiesters 2b and 2c. The latter compounds gave rise to ddUMP when incubated with snake venom phosphodiesterase I.These findings support the premise inherent in the design of 1b and 1c, namely that the carbamate prodrugs are far more resistant to hydrolysis by plasma carboxylate esterases than their POM counterparts and can revert to the free parent 5′-mononucletides by successive chemical and enzymatic hydrolysis. Further studies of 1b and 1c as membrane-permeable prodrugs of ddUMP are in progress.
Starting Page	390
Ending Page	396
Page Count	7
File Format	PDF
ISSN	07248741
Journal	Pharmaceutical Research
Volume Number	22
Issue Number	3
e-ISSN	1573904X
Language	English
Publisher	Kluwer Academic Publishers-Plenum Publishers
Publisher Date	2005-03-21
Publisher Place	New York
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	nanticancer 2′,3′-dideoxyuridine 5′-monophosphate membrane-permeable prodrugs Pharmacology/Toxicology Pharmacy Biochemistry Medical Law Biomedical Engineering
Content Type	Text
Resource Type	Article
Subject	Organic Chemistry Pharmacology Molecular Medicine Pharmacology (medical) Biotechnology Pharmaceutical Science

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