PubMed · 11364106
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D Gilden, J Falkenberg, G Torres. 1997. Dethroning AZT.. https://pubmed.ncbi.nlm.nih.gov/11364106/
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Understanding the molecular mechanisms of HIV-1 reverse transcriptase (RT) action and drug inhibition is essential for designing effective antiretroviral therapies. Although comparisons of the different crystal forms of RT give insights into the flexibility of different domains, a direct computational assessment of the effect of inhibitor binding on the collective dynamics of RT is lacking. A structure-based approach is used here for exploring the dynamics of RT in unliganded and inhibitor-bound forms. Non-nucleoside RT inhibitors (NNRTI) are shown to interfere directly with the global hinge-bending mechanism that controls the cooperative motions of the p66 fingers and thumb subdomains. The net effect of nevirapine binding is to change the direction of domain movements rather than suppress their mobilities. The second generation NNRTI, efavirenz, on the other hand, shows the stronger effect of simultaneously reorienting domain motions and obstructing the p66 thumb fluctuations. A second hinge site controlling the global rotational reorientations of the RNase H domain is identified, which could serve as a target for potential inhibitors of RNase H activity.
Styrene is known to be both hepatotoxic and pneumotoxic in rodents. 4-Vinylphenol (4-VP) has been shown to be a minor metabolite of styrene in some studies and is a more potent toxicant in mice than either styrene or styrene oxide. 4-VP is metabolized primarily by CYP2E1 and CYP2F2 to an unknown metabolite. The purpose of this study was to use inhibitors of these cytochromes P450 to address the question of whether the parent compound or a metabolite is responsible for 4-VP induced toxicity. Rats as well as mice were found to be susceptible to the toxicity of 4-VP. Prior treatment with either diethyldithiocarbamate or 5-phenyl-1-pentyne as inhibitors of CYP2E1 and CYP2F2 prevented or greatly decreased the hepatotoxicity of 4-VP as assessed by measuring serum sorbitol dehydrogenase and its pneumotoxicity as determined by measurements of cells, protein and lactate dehydrogenase (LDH) activity in bronchoalveolar lavage fluid. Thus the hepatotoxicity and pneumotoxicity of 4-VP are due to a metabolite(s) and not the parent compound.
An efficient, convergent synthesis of the C1'-C11' side chain (3) of leucascandrolide A (1) has been achieved. The key bond connection is made through the use of a palladium(0)-catalyzed Sonogashira cross-coupling between trifloyl oxazole (4) and alkynylmetal species (5).