Synthesis and antiviral activity of novel isonucleoside analogs.
A series of branched-chain sugar isonucleosides was synthesized and evaluated for antiviral activity against herpesviruses. The preparation of homochiral [3S-(3 alpha, 4 beta, 5 alpha)]-2-amino-1, 9-dihydro-9-[tetrahydro-4,5-bis(hydroxymethyl)-3-furanyl]-6H-purin-6-one (7, BMS-181,164) and related compounds was stereospecifically achieved starting from 1,2-isopropylidene-D-xylofuranose (10). An efficient two-step reduction of the anomeric center of bis-acetate 18 involved formation of the chloride intermediate 19, followed by diisobutylaluminum hydride reduction. Tosylation of the resulting alcohol 20 provided the key intermediate 21, which was coupled with a variety of nucleobase anions. Several members of this new class of compounds possess activity against herpes simplex virus types 1 and 2 (HSV-1 and -2), varicella-zoster virus (VZV), and human cytomegalovirus (HCMV). Compound 7 exhibits potent and selective activity against thymidine kinase encoding herpesviruses, in particular, HSV-1 and HSV-2. Evaluation of compound 7 for inhibition of WI-38 cell growth indicated an ID50 of > 700 microM. Although the antiherpetic activity in vitro of 7 is less than that of acyclovir (1), compound 7 displays superior efficacy in mouse model infections. The (bromovinyl)uridine analog 8 (BMS-181,165) also exhibits selective activity against HSV-1 and VZV, with no cytostatic effect on WI-38 cell growth at > 800 microM. Compound 8 is active against simian varicella virus and is efficacious in the corresponding monkey model.
Tino
J A
JA
Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000.
Clark
J M
JM
Field
A K
AK
Jacobs
G A
GA
Lis
K A
KA
Michalik
T L
TL
McGeever-Rubin
B
B
Slusarchyk
W A
WA
Spergel
S H
SH
Sundeen
J E
JE
D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis*; D002460:Cell Line; D002644:Chickenpox / Q000188:drug therapy; D003587:Cytomegalovirus / Q000187:drug effects; D005260:Female; D006151:Guanosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D006561:Herpes Simplex / Q000188:drug therapy; D006564:Herpesviridae / Q000187:drug effects* / Q000201:enzymology; D014645:Herpesvirus 3, Human / Q000187:drug effects; D051379:Mice; D015394:Molecular Structure; D018139:Simplexvirus / Q000187:drug effects; D013329:Structure-Activity Relationship; D013937:Thymidine Kinase / Q000037:antagonists & inhibitors; D014529:Uridine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D014616:Vaccinia virus / Q000187:drug effects; D010948:Viral Plaque Assay
D000998:Antiviral Agents; D006151:Guanosine; C081110:BMS 181164; C081111:BMS 181165; D013937:Thymidine Kinase; D014529:Uridine