The Squalestatins: Synthesis and Biological Activity of Some C3-Modified Analogs; Replacement of a Carboxylic Acid or Methyl Ester with an Isoelectronic Heterocyclic Functionality
| Autor: | B. E. Kirk, A P Craven, Michael George Lester, D Green, Panayiotis Alexandrou Procopiou, Chuen Chan, R A Henson, Brian Dymock, M J Bamford, Michael A. Snowden |
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| Rok vydání: | 1995 |
| Předmět: |
Models
Molecular Stereochemistry Carboxylic acid Chemical synthesis Bridged Bicyclo Compounds Structure-Activity Relationship chemistry.chemical_compound Drug Discovery Animals Structure–activity relationship chemistry.chemical_classification Farnesyl-diphosphate farnesyltransferase biology Bicyclic molecule Tricarboxylic Acids Esters Biological activity Bridged Bicyclo Compounds Heterocyclic Rats Farnesyl-Diphosphate Farnesyltransferase chemistry Enzyme inhibitor biology.protein Molecular Medicine Mitosporic Fungi Derivative (chemistry) |
| Zdroj: | Journal of Medicinal Chemistry. 38:3502-3513 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm00018a010 |
| Popis: | A series of squalestatins modified at the C3-position with a heterocyclic functionality was prepared and evaluated in vitro as inhibitors of squalene synthase (SQS). Structure-activity relationships for compounds with the 4,6-dimethyloctenoate at C6(S1 analogues) were different from those for analogues lacking the C6 ester (H1 analogues), with a greater dependence on the nature of the C3-substituent for the H1 series. Potent SQS inhibitory activity equivalent to that of H1 is retained by a C3-(tetrazol-5-yl) analogue, i.e., a carboxylic acid mimetic. The C3-methyl ester derivative is 10-fold less active than H1, and SQS inhibitory activity similar to that of the methyl ester was retained only in those C3-heterocycle-substituted H1 analogues for which electrostatic potential maps of the C3-substituent were closely similar to that of a methyl ester. |
| Databáze: | OpenAIRE |
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