Ester prodrugs of cyclic 1-(S)-[3-hydroxy-2-(phosphonomethoxy)propyl]-5-azacytosine: synthesis and antiviral activity.
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.
Krecmerová
Marcela
M
Gilead Sciences and IOCB Research Centre, Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic. marcela@uochb.cas.cz
Holý
Antonín
A
Pohl
Radek
R
Masojídková
Milena
M
Andrei
Graciela
G
Naesens
Lieve
L
Neyts
Johan
J
Balzarini
Jan
J
De Clercq
Erik
E
Snoeck
Robert
R
D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D003596:Cytosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004267:DNA Viruses / Q000187:drug effects*; D024882:Drug Resistance, Viral; D004952:Esters; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012328:RNA Viruses / Q000187:drug effects*; D012190:Retroviridae / Q000187:drug effects*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C525472:1-((2-hydroxy-2-oxido-1,4,2-dioxaphosphinan-5-yl)methyl)-5-azacytosine 2-(hexadecyloxy)ethyl ester; D000998:Antiviral Agents; D004952:Esters; D011355:Prodrugs; D003596:Cytosine