Synthesis of photoactivatable acyclic analogues of the lobatamides.
[structure: see text] 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.
Shen
Ruichao
R
Department of Chemistry and Center for Chemical Methodology and Library Development, Boston University, 590 Commonwealth Avenue, Boston, Massachusetts 02215, USA.
Inoue
Takao
T
Forgac
Michael
M
Porco
John A
JA
D000818:Animals; D001665:Binding Sites; D002384:Catalysis; D002417:Cattle; D004791:Enzyme Inhibitors / Q000032:analysis / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D007202:Indicators and Reagents; D020128:Inhibitory Concentration 50; D018942:Macrolides / Q000032:analysis / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015394:Molecular Structure; D010777:Photochemistry; D012459:Salicylates / Q000032:analysis / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D025262:Vacuolar Proton-Translocating ATPases / Q000037:antagonists & inhibitors
D004791:Enzyme Inhibitors; D007202:Indicators and Reagents; D018942:Macrolides; D012459:Salicylates; C460781:lobatamide C; D025262:Vacuolar Proton-Translocating ATPases