Various D- and L-2',3'-unsaturated 3'-fluoro-4'-thionucleosides (D- and L-3'F-4'Sd4Ns) were synthesized for the studies of structure-activity relationships. The synthesized D-2',3'-unsaturated 3'-fluoro-4'-thionucleosides did not show any significant antiviral activity against HIV-1, while unnatural L-nucleosides such as cytosine 34 (EC(50) = 0.13 microM; EC(90) = 1.7 microM) and 5-fluorocytosine 35 (EC(50) = 0.031 microM; EC(90) = 0.35 microM) derivatives exhibited potent anti-HIV activity without significant toxicity. Molecular modeling study shows that the 3'-fluorine atom of the d-2',3'-unsaturated cytidine triphosphate (D-3'F-4'Sd4CTP) experiences unfavorable electrostatic interaction with its own triphosphate moiety, resulting in the decreased binding affinity to wild-type HIV-1 reverse transcriptase (RT), which may be one of the reasons for the insensitivity of HIV-1 RT to these compounds. On the other hand, L-3'F-4'Sd4CTP binds to the active site of wild-type HIV-1 RT without steric hindrance and there is a possible hydrogen bonding between the 3'-fluorine atom and Asp185, which correlates with its potent anti-HIV activity. However, L-3'F-4'Sd4C 34 and L-3'F-4'Sd4FC 35 showed high cross-resistance to 3TC-resistant mutant (M184V) RT. Like other unnatural L-nucleosides, the unfavorable steric hindrance of the sugar moiety of L-3'F-4'Sd4CTP with the side chain of Val184 explains its significant cross-resistance to the M184V mutant.
The effect of simultaneous gamma irradiation and optical bleaching on ^-center production in high-purity KC1 at room temperature has been investigated. It is found that for high gamma-ray intensities (^4X10 3 R/min) simultaneous irradiation and bleaching decreases the net F-center production rate compared with that characteristic of the same samples irradiated in the dark. This suppression of F centers is associated with the later stage of coloration and is a function of bleaching intensity and dose rate. When a sample is given the same total dose and amount of bleaching sequentially, there is a small net decrease in the ^-center concentration. However, this decrease is much less than the amount of suppression observed in crystals irradiated in light. The effect of simultaneous bleaching and irradiation on the late-stage coloration suggests that the charge state of the radiation-produced vacancies, e.g., whether F centers or a. centers are formed, is very important in the coloration process. In the case of low dose rates (^92 R/min) the F-center growth curves in dark-irradiated crystals consist of essentially only early-stage centers, whereas in samples simultaneously bleached and irradiated (light-irradiated), ^-center production was completely suppressed.
611
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.