Study on retroaldol degradation products of antibiotic oligomycin A

Abstract

Studies of reactivity of antibiotic oligomycin A in various alkaline conditions showed that the compound easily undergoes retroaldol degradation in β-hydroxy ketone fragments positioned in the C7-C13 moiety of the antibiotic molecule. Depending on reaction conditions, the retroaldol fragmentation of the 8,9 or 12,13 bonds or formation of a product through double retroaldol degradation, when the fragment C9-C12 was detached, took place followed by further transformations of the intermediate aldehydes formed. The structures of the obtained non-cyclic derivatives of oligomycin A were supported by NMR and MS methods. NMR parameters demonstrate the striking similarity of the geometry (conformation) of the fragment C20-C34 in the non-cyclic products of retroaldol degradation and the starting antibiotic 1. The compounds obtained had lower cytototoxic properties than oligomycin A for human leukemia cells K-562 and colon cancer cells HCT-116 and lower activity against growth inhibition of model object Streptomyces fradiae. It cannot be excluded that the products of retroaldol degradation participate in the biological effects of antibiotic oligomycin A.

Synthesis and Biological Activity of 7(7,11)-Hydroderivatives of Oligomycin A

“…Низкий выход производного 3 связан с длительным выдерживанием реакционной смеси в слабощелочных условиях, в которых исходный антибиотик довольно лабилен из-за ретро-альдольного расщепления β-гидроксикарбонильных фрагментов. [14] Образование син-аддукта в этой реакции восстановления объясняется, вероятно, тем, что переходное состояние соответствует модели Фелкина, в которой положение С12 выполняет роль объемного заместителя, а присоединение гидрид-иона осуществляется со стерически менее затрудненной стороны -снизу от плоскости макроцикла.…”

“…Reaction proceeds with acceptable stereoselectivity and gives tetrahydro derivative 3, but in low yield (35 %), which associated with low stability of oligomycins in basic conditions. [14]…”

Draft Genome Sequence of Streptomyces fradiae olg1-1, a Strain Resistant to Nitrone-Oligomycin

“…Macrolide antibiotic oligomycin A produces an antibacterial effect on pathogenic actinobacteria, causing actinomycosis, as well as on nonpathogenic strains of S. fradiae ( 1 ). A series of derivatives of oligomycin A was obtained ( 1 , 2 ), including nitrone-oligomycin ( 3 ), for further research into new anticancer drugs ( 4 ) and drugs for the treatment of actinomycosis. There is evidence that the mechanism of action for oligomycin A is based on a chemical interaction with the C-subunit of F 0 F 1 -ATP synthase ( 5 ).…”

Synthesis and Anti-Actinomycotic Activity of the Oligomycin A Thiocyanato Derivative Modified at 2-Oxypropyl Side Chain

“…Oligomycins belong to the class of macrolide antibiotics which have highly functionalized molecules with keto-and hydroxyl groups, lactone and spiro moieties, and double bonds. The complexity of oligomycin and its lability in basic conditions [3] significantly impede drug modification and applicability. These challenges have prompted us to develop preparative ways to diversify the oligomycin scaffold.…”