Synthesis and biological evaluation of cruentaren A analogues.
The complex macrolide cruentaren A is a highly selective and potent inhibitor of F-ATPase (F-type adenosine triphosphatase). As it shows some resemblance to benzolactone enamides like apicularen A, it was of interest to perform some structure-activity studies to delineate the key functional groups that are responsible for the activity. Building upon our previously developed route to cruentaren A, which is based on a ring-closing alkyne metathesis reaction (RCAM), several cruentaren analogues were prepared. Replacement of the 3-hydroxy hexanoic part with acids that lack the hydroxy group function resulted in a significant drop in cytotoxicity and F-ATPase inhibition. Furthermore, two enamide analogues 23 and 50 were synthesized. However, these compounds were only cytotoxic in the micromolar range. Under the conditions for cleavage of the C3 aromatic methyl ether, the enamide function was transformed to the corresponding oxazinanone, resulting in analogues 25 and 52.
Vintonyak
Viktor V
VV
Institut für Organische Chemie, Universität Tübingen, Auf der Morgenstelle 18, 72076 Tübingen, Germany.
Calà
Marcellino
M
Lay
Frank
F
Kunze
Brigitte
B
Sasse
Florenz
F
Maier
Martin E
ME
D000818:Animals; D002417:Cattle; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006321:Heart / Q000187:drug effects; D020128:Inhibitory Concentration 50; D018942:Macrolides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D025261:Mitochondrial Proton-Translocating ATPases / Q000037:antagonists & inhibitors*; D008968:Molecular Conformation; D013237:Stereoisomerism
D018942:Macrolides; C516694:cruentaren A; D025261:Mitochondrial Proton-Translocating ATPases