A ring-enlarged oxetanocin A analogue as an inhibitor of HIV infectivity.
Two ring-expanded analogues (compounds 2 and 3) of the anti-HIV fermentation product oxetanocin A (1) were synthesized from commercially available diacetone D-glucose. Antiviral testing against HIV in ATH8 cells revealed that the ring-expanded analogue 2 possessed a similar activity profile as oxetanocin A. Neither compound, however, was capable of providing full protection to the cells against HIV infection. The isomeric ring-expanded analogue 3 was totally devoid of anti-HIV activity. Molecular modeling suggested that while oxetanocin A and compounds 2 and 3 share a large common substructure with the potent anti-HIV drug, dideoxyadenosine (ddA), the extra hydroxymethyl substituent may contribute negatively to the binding of these molecules to a critical enzyme. The negative contribution may be less important in oxetanocin and isomer 2 than in isomer 3. From these studies it would appear that both oxetane and tetrahydrofuran rings are equivalent templates to support the adenine base in terms of anti-HIV activity.
Tseng
C K
CK
Laboratory of Medicinal Chemistry, National Cancer Institute, NIH, Bethesda, Maryland 20892.
Marquez
V E
VE
Milne
G W
GW
Wysocki
R J
RJ
Mitsuya
H
H
Shirasaki
T
T
Driscoll
J S
JS
D000225:Adenine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002460:Cell Line; D006678:HIV / Q000187:drug effects*; D006801:Humans; D007202:Indicators and Reagents; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D014961:X-Ray Diffraction
D000998:Antiviral Agents; D007202:Indicators and Reagents; C051061:oxetanocin; D000225:Adenine