Synthesis and conformational analysis of a locked analogue of carbovir built on a bicyclo[3.1.0]hex-2-enyl template |
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Authors: | Choi Yongseok Sun Guangyu George Clifford Nicklaus Marc C Kelley James A Marquez Victor E |
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Institution: | Laboratory of Medicinal Chemistry, Center for Cancer Research, NCI-Frederick, NIH, Frederick, Maryland 21702, USA. |
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Abstract: | The synthesis and biological evaluation of a carbovir analogue (5) built on a bicyclo3.1.0]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 bicyclo3.1.0]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 bicyclo3.1.0]hex-2-yl nucleosides 12 and 13 that were inactive against HIV exhibited stiffer resistance to having a planar, fused cyclopentane moiety. |
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