Synthesis of potent inhibitors of histidinol dehydrogenase

Bioorganic and Medicinal Chemistry Letters

Volumn 6, Issue 17, 1996, Pages 2131-2136

  Dancer, Jane E ^b   Ford, Mark J ^a   Hamilton, Kenneth ^b   Kilkelly, Michael ^b   Lindell, Stephen D ^b   O'Mahony, Mary J ^b   Saville Stones, Elizabeth A ^b  

^a AgrEvo UK Limited   (United Kingdom)

^b AgrEvo UK Limited   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

ENZYME INHIBITOR; HISTIDINOL DEHYDROGENASE; KETONE;

ARTICLE; DRUG SYNTHESIS; ENZYME BINDING; ENZYME INHIBITION; LIPOPHILICITY; PLANT; QUANTITATIVE STRUCTURE ACTIVITY RELATION;

EID: 0030567858     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/0960-894X(96)00384-8     Document Type: Article

References (24)

1. This work represents an ongoing interest within AgrEvo in using biochemical reasoning to generate leads for the discovery of new agrochemicals. For other recent examples see reference 3 and references therein.
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21. We have also prepared several compounds which could potentially trap an enzymic nucleophile upon oxidation at the active site of HDH, for example structures 22 - 24. These compounds were very poor inhibitors of HDH. However, as far as we were able to determine they were not enzyme substrates and so were not transformed into the active species (i.e. the ketones). (equation presented)
22. m app histidinol = 8 μM) was cloned from cDNA by PCR using primers designed to the mature form of the protein predicted by Nagai et al. (
23. + 2 mM. Each value represents the mean of five individual assays with varying inhibitor concentrations.
24. We have found that the TFA is significantly more efficient than HCl at removing the trityl group. However, the resultant TFA salts are usually gums so they were converted into the more easily handled HCl salts which were amorphous powders. In the case of compound 6 the protecting groups were removed by treating with anhydrous HCl in EtOAc for 4.5 hours at room temperature.