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Ester Prodrugs of Cyclic 1-(S)-[3-hydroxy-2-(phosphonomethoxy)propyl]-5-azacytosine: Synthesis and Antiviral Activity

Ester Prodrugs of Cyclic 1-(S)-[3-hydroxy-2-(phosphonomethoxy)propyl]-5-azacytosine: Synthesis and Antiviral Activity

Marcela Krecmerová, Antonín Holý, Radek Pohl, Milena Masojídková, Graciela Andrei, Lieve Naesens, Johan Neyts, Jan Balzarini, Erik De Clercq, Robert Snoeck

J Med Chem. 2007 Nov 15;50(23):5765-72.

PMID: 17948980

Abstract:

Reaction of 1-(S)-[3-hydroxy-2-(phosphonomethoxy)propyl]-5-azacytosine (1) with dicyclohexylcarbodiimide and N,N,-dicyclohexyl-4-morpholinocarboxamidine in dimethylformamide at elevated temperature afforded the corresponding cyclic phosphonate 2, that is, 1-{[(5S)-2-hydroxy-2-oxido-1,4,2-dioxaphosphinan-5-yl]methyl}-5-azacytosine. Compound 2 exerts strong in vitro activity against DNA viruses, comparable with activity of parent compound 1. Transformation of 2 to its tetrabutylammonium salt followed by reaction with alkyl or acyloxyalkyl halogenides enabled us to prepare a series of structurally diverse ester prodrugs: alkyl (octadecyl), alkenyl (erucyl), alkoxyalkyl (hexadecyloxyethyl), and acyloxyalkyl (pivaloyloxymethyl) (3-6). The introduction of an alkyl, alkoxyalkyl, or acyloxyalkyl ester group to the molecule resulted in an increase of antiviral activity; the most active compound was found to be the hexadecyloxyethyl ester 5. The relative configuration of the diastereoisomer trans-6 was determined using H,H-NOESY NMR.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP4938721	2,4,5-T-2-methylpropyl ester		4938-72-1	Price

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