Synthesis of Photoactivatable Acyclic Analogues of the Lobatamides

The lobatamides and related salicylate enamide natural products are potent mammalian V-ATPase inhibitors. To probe details of binding of the lobatamides to mammalian V-ATPase, three photoactivatable analogues bearing benzophenone photoaffinity labels have been prepared. The analogues were designed o...

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Bibliographic Details
Published in:Journal of organic chemistry 2005-04, Vol.70 (9), p.3686-3692
Main Authors: Shen, Ruichao, Inoue, Takao, Forgac, Michael, Porco, John A
Format: Article
Language:English
Subjects:
Animals
Binding Sites
Catalysis
Cattle
Chemistry
Enzyme Inhibitors - analysis
Enzyme Inhibitors - chemical synthesis
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
Exact sciences and technology
Indicators and Reagents
Inhibitory Concentration 50
Macrolides - analysis
Macrolides - chemical synthesis
Macrolides - chemistry
Macrolides - pharmacology
Molecular Structure
Noncondensed benzenic compounds
Organic chemistry
Photochemistry
Preparations and properties
Salicylates - analysis
Salicylates - chemical synthesis
Salicylates - chemistry
Salicylates - pharmacology
Structure-Activity Relationship
Vacuolar Proton-Translocating ATPases - antagonists & inhibitors
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Summary:The lobatamides and related salicylate enamide natural products are potent mammalian V-ATPase inhibitors. To probe details of binding of the lobatamides to mammalian V-ATPase, three photoactivatable analogues bearing benzophenone photoaffinity labels have been prepared. The analogues were designed on the basis of a simplified acyclic analogue 2. Late-stage installation of the enamide side chain and tandem deallylation/amidation were employed in synthetic routes to these derivatives. Simplified analogue 2 showed strong inhibition against bovine clathrin-coated vesicle V-ATPase (10 nM). Analogues 3−5 were also evaluated for inhibition of bovine V-ATPase in order to select a suitable candidate for future photoaffinity labeling studies.
ISSN:0022-3263
1520-6904
DOI:10.1021/jo0477751