Synthesis and antiviral activity of enantiomeric forms of cyclobutyl nucleoside analogues.
The syntheses of the enantiomeric cyclobutyl guanine nucleoside analogues [1R-1 alpha, 2 beta, 3 alpha]- and [1S-1 alpha, 2 beta, 3 alpha]-2- amino-9-[2,3-bis(hydroxymethyl)cyclobutyl]-6H-purin-6-one (7 and 8, respectively) and the enantiomeric cyclobutyl adenine analogues [1R-1 alpha, 2 beta, 3 alpha]- and [1S-1 alpha, 2 beta, 3 alpha]-6-amino-9-[2,3-bis(hydroxymethyl) cyclobutyl]purine (9 and 10, respectively) are described. trans-3,3-Diethoxy-1,2-cyclobutanedicarboxylic acid (14) was coupled with R-(-)-2-phenylglycinol to provide a mixture of diastereomeric bis-amides, 15a and 15b, which was readily separated by crystallization. Conversion of each bis-amide to the corresponding diol enantiomer, 16a and 16b, respectively, was effected by a facile three-step sequence in high overall yield. Homochiral diol 16a was converted in a straightforward manner to 7 and 9, and homochiral diol 16b was similarly converted to the corresponding optical isomers 8 and 10. Compounds 7 and 9, which mimic the absolute configuration of natural nucleosides, are highly active against a range of herpesviruses in vitro while the isomers of opposite configuration, 8 and 10, are devoid of antiherpes activity. The corresponding triphosphates of 7 and 8 (7-TP and 8-TP) were prepared enzymatically. Compound 7-TP selectively inhibits HSV-1 DNA polymerase, compared to human (HeLa) DNA polymerase, while 8-TP is much less inhibitory than 7-TP against both types of enzymes. Compounds 7 and 9 are efficacious in a mouse cytomegalovirus model infection.
Bisacchi
G S
GS
Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08540.
Braitman
A
A
Cianci
C W
CW
Clark
J M
JM
Field
A K
AK
Hagen
M E
ME
Hockstein
D R
DR
Malley
M F
MF
Mitt
T
T
Slusarchyk
W A
WA
D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003586:Cytomegalovirus Infections / Q000188:drug therapy; D006147:Guanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D009705:Nucleosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018139:Simplexvirus / Q000187:drug effects; D013329:Structure-Activity Relationship; D014780:Viruses / Q000187:drug effects
D000998:Antiviral Agents; D007202:Indicators and Reagents; D009705:Nucleosides; D006147:Guanine