A RING-ENLARGED OXETANOCIN-A ANALOG AS AN INHIBITOR OF HIV INFECTIVITY

被引:72
作者
TSENG, CKH
MARQUEZ, VE
MILNE, GWA
WYSOCKI, RJ
MITSUYA, H
SHIRASAKI, T
DRISCOLL, JS
机构
[1] NCI,DIV CANC TREATMENT,DEV THERAPEUT PROGRAM,MED CHEM LAB,BETHESDA,MD 20892
[2] NCI,DIV CANC TREATMENT,CLIN ONCOL PROGRAM,BETHESDA,MD 20892
关键词
D O I
10.1021/jm00105a054
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
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.
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页码:343 / 349
页数:7
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