Synthesis and conformational analysis of a locked analogue of carbovir built on a bicyclo[3.1.0]hex-2-enyl template.
The synthesis and biological evaluation of a carbovir analogue (5) built on a bicyclo[3.1.0]hex-2-enyl template is described. A conformational analysis using density functional theory at the B3LYP/6-31G* level has been carried out on the rigid pseudosugar template of 5, the cyclopentene moiety of carbovir and the bicyclo[3.1.0]hex-2-yl pseudosugars of two isomeric carbonucleosides (12 and 13) containing exo- and endo-fused cyclopropane rings. The results show that while the planar configuration of the fused cyclopentane ring of compound 5 helps retain weak anti-HIV activity, the ability of the cyclopentene ring of carbovir to easily adopt a planar or puckered conformation with little energy penalty may prove to be a crucial advantage. The bicyclo[3.1.0]hex-2-yl nucleosides 12 and 13 that were inactive against HIV exhibited stiffer resistance to having a planar, fused cyclopentane moiety.
Choi
Yongseok
Y
Laboratory of Medicinal Chemistry, Center for Cancer Research, NCI-Frederick, NIH, Frederick, Maryland 21702, USA.
Sun
Guangyu
G
George
Clifford
C
Nicklaus
Marc C
MC
Kelley
James A
JA
Marquez
Victor E
VE
D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D003517:Cyclopentanes / Q000737:chemistry; D003521:Cyclopropanes / Q000737:chemistry; D015224:Dideoxynucleosides / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D006151:Guanosine / Q000031:analogs & derivatives*; D015497:HIV-1 / Q000187:drug effects; D015498:HIV-2 / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D008826:Microbial Sensitivity Tests; D008968:Molecular Conformation; D015394:Molecular Structure; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000821:virology; D013816:Thermodynamics
D019380:Anti-HIV Agents; D003517:Cyclopentanes; D003521:Cyclopropanes; D015224:Dideoxynucleosides; C057503:carbovir; D006151:Guanosine; C030797:cyclopropane