A ring-enlarged oxetanocin A analog as an inhibitor HIV infectivity

• Published in: Journal of medicinal chemistry 1991-01, Vol.34 (1), p.343-349
• Main Authors: Tseng, Christopher K. H, Marquez, Victor E, Milne, George W. A, Wysocki, Ronald J, Mitsuya, Hiroaki, Shirasaki, Takuma, Driscoll, John S
• Format: Article
• Language: English
• Subjects: Adenine - analogs & derivatives; Adenine - chemical synthesis; Adenine - chemistry; Adenine - pharmacology; AIDS/HIV; Antiviral Agents - chemical synthesis; Antiviral Agents - pharmacology; Bacillus megaterium; Carbohydrates. Nucleosides and nucleotides; Cell Line; Chemistry; Exact sciences and technology; HIV - drug effects; Humans; Indicators and Reagents; Models, Molecular; Molecular Conformation; Molecular Structure; Nucleosides, nucleotides and oligonucleotides; Organic chemistry; Preparations and properties; Structure-Activity Relationship; X-Ray Diffraction
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00105a054

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.