Synthesis and Complement Inhibitory Activity of B/C/D-Ring Analogues of the Fungal Metabolite 6,7-Diformyl-3‘,4‘,4a‘,5‘,6‘,7‘,8‘,8a‘-octahydro-4,6‘,7‘-trihydroxy- 2‘,5‘,5‘,8a‘-tetramethylspiro[1‘(2‘H)-naphthalene-2(3H)-benzofuran]
| Autor: | Bruce R. Gaumond, Piotr Bartyzel, Teodoro S. Kaufman, Barton J. Bradbury, Marcelo J. Nieto, Susanne M. Scesney, Robert D. Sindelar, Henry C. Marsh |
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| Rok vydání: | 2003 |
| Předmět: |
Natural product
Hydroxamic acid Stereochemistry Complement C5a In Vitro Techniques Sesquiterpene Hemolysis Chemical synthesis In vitro Structure-Activity Relationship chemistry.chemical_compound chemistry Drug Discovery Complement C3a Animals Humans Molecular Medicine Rabbits Benzofuran Sesquiterpenes IC50 Derivative (chemistry) |
| Zdroj: | Journal of Medicinal Chemistry. 46:2697-2705 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm0204284 |
| Popis: | This paper reports the synthesis and the bioassay of 4-methoxy- and 4-hydroxyspiro[benzofuran-2(3H)-cyclohexane] partial analogues (5) of the complement inhibitory sesquiterpene fungal metabolite 6,7-diformyl-3',4',4a',5',6',7',8',8a'-octahydro-4,6',7'-trihydroxy-2',5',5',8a'-tetramethylspiro[1'(2'H)-naphthalene-2(3H)-benzofuran] (1a, K-76) and its silver oxide oxidized product (1b, K-76COOH). The described target compounds represent spirobenzofuran B/C/D-ring analogues lacking the A-ring component of the prototype structure. The target compounds were evaluated by the inhibition of total hemolytic complement activity in human serum. It was observed that the structurally simplified analogue 4-methoxyspiro[benzofuran-2(3H)-cyclohexane]-6-carboxylic acid (5a) exhibited an IC(50) = 0.53 mM similar to the IC(50) = 0.57 mM that was observed for the natural product derivative 1b. Exhibiting an IC(50) = 0.16 mM, the three-ringed partial structure 6-carboxy-7-formyl-4-methoxyspiro[benzofuran-2(3H)-cyclohexane] (5k)was found to be the most potent target compound. Like the natural product, 5k appears to inhibit primarily at the C5 activation step and inhibits both the classical and alternative human complement pathways. Several other analogues inhibited complement activation in vitro at concentrations similar to those required for inhibition by the natural product 1b. |
| Databáze: | OpenAIRE |
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