Exploring structure-activity relationship around the phosphomannose isomerase inhibitor AF14049 via combinatorial synthesis

Bioorganic and Medicinal Chemistry Letters

Volumn 8, Issue 17, 1998, Pages 2303-2308

  Bhandari, Ashok ^a   Jones, David G ^a   Schullek, John R ^a,b   Vo, Kham ^a   Schunk, Caryn A ^a   Tamanaha, Lisa L ^a   Chen, Dawn ^a,c   Yuan, Zhengyu ^a,c   Needels, Michael C ^a   Gallop, Mark A ^a  

^a AFFYMAX RESEARCH INSTITUTE   (United States)

^b MetaXen   (United States)

^c Versicor Inc   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

AF 14049; AF 15394; FRUCTOSE 6 PHOSPHATE; INDAN DERIVATIVE; MANNOSE 6 PHOSPHATE; MANNOSE PHOSPHATE ISOMERASE; METALLOPROTEIN; UNCLASSIFIED DRUG;

ANTIFUNGAL ACTIVITY; ARTICLE; CANDIDA ALBICANS; CELL WALL; CHEMICAL MODIFICATION; DRUG STRUCTURE; ENZYME MECHANISM; MINIMUM INHIBITORY CONCENTRATION; MYCOSIS; NONHUMAN; SACCHAROMYCES CEREVISIAE; SOLID PHASE EXTRACTION; STRUCTURE ACTIVITY RELATION;

AMIDES; ANIMALS; BINDING SITES; CANDIDA ALBICANS; CELL WALL; DATABASES; DRUG DESIGN; ENZYME INHIBITORS; HUMANS; INDANS; INDICATORS AND REAGENTS; KINETICS; MANNOSE-6-PHOSPHATE ISOMERASE; MOLECULAR STRUCTURE; SACCHAROMYCES CEREVISIAE; STRUCTURE-ACTIVITY RELATIONSHIP; SWINE;

CANDIDA ALBICANS; SACCHAROMYCES CEREVISIAE;

EID: 0032497345     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(98)00417-X     Document Type: Article

References (15)

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10. 11. Inhibition of CaPMI was determined in a coupled enzyme assay using phosphoglucose isomerase (0.3 U/mL) and glucose-6-phosphate dehydrogenase (0.3 U/mL) as coupling enzymes. PMI (1,6 nM) was preincubated with inhibitor and coupling enzymes in 50 mM Tris buffer, pH 8.0, for 30 min. at ambient temperature prior to the addition of mannose-6-phosphate as substrate to 0.2 mM. Formation of the coupled product NADPH was monitored over time using a SpectraMax 250 microtiter platereader. Putative PMI inhibitors were checked for inhibition of the coupling enzymes in control incubations.
11. i = 27 μM was obtained for 1. For routine screening, a 30 min preincubation of PMI and inhibitor was found to generate significant and reproducible levels of enzyme inhibition and these conditions were typically used to compare the activities of different compounds.
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15. 16. We gratefully acknowledge Dr. T. N. C. Wells (Geneva Biomedical Research Institute) and Dr. J. J. Martin (Glaxo-Wellcome, Tres Cantos, Madrid) for reagents and helpful discussions.