Synthesis and Biological Activity of 2,3,16,17,18,19-Hexahydrooligomycin A

Omelchuk, Olga A.; Belov, Nikita M.; Цветков, В. Б.; Grammatikova, Natalia E.; Lysenkova, Lyudmila N.; Королев, А. М.; Bekker, Olga B.; Даниленко, В. Н.; Shchekotikhin, Andrey E.

doi:10.6060/mhc160964o

Cited by 3 publications

(1 citation statement)

References 12 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The structure of Oligomycin A ( 1 ) contains a 26-membered lactone core that is fused to a spiroketal moiety with a hydroxypropyl side chain. There are three possible directions for the chemical modification of Oligomycin’s structure: (1) hydroxypropyl side chain, − (2) double C–C bonds, , and (3) carbonyl groups. , Currently, the modification of diene fragment is a poorly studied area of Oligomycin’s transformations.…”

Section: Introductionmentioning

confidence: 99%

Stereochemistries and Biological Properties of Oligomycin A Diels–Alder Adducts

et al. 2021

Self Cite

View full text Add to dashboard Cite

Oligomycin A is a potent antibiotic and antitumor agent. However, its applications are restricted by its high toxicity and low bioavailability. In this study, we obtained Oligomycin A Diels− Alder adducts with benzoquinone and N-benzylmaleimide and determined their absolute configurations by combining 1 H and ROESY NMR data with molecular mechanics conformational analysis and quantum chemical reaction modeling. The latter showed that adduct stereochemistry is controlled by hydrogen bonding of the Oligomycin A side-chain isopropanol moiety with the carbonyl group of the dienophile. Biological studies showed that the Diels−Alder modification of the Oligomycin A diene system resulted in a complex antiproliferative potential pattern. The synthesized adducts were determined to be more active against the triple-negative (ERα, PR, and HER2 negative) breast cancer cell line MDA-MB-231 and lung carcinoma cell line A-549 compared to Oligomycin A. Meanwhile, Oligomycin A was more potent against myeloid leukemia cell line K-562 and breast carcinoma cell line MCF-7 than its derivatives. Thus, modification of the diene moiety of Oligomycin A is a promising strategy for developing novel antitumor agents based on its scaffold.

show abstract

Section: Introductionmentioning

confidence: 99%

Stereochemistries and Biological Properties of Oligomycin A Diels–Alder Adducts

et al. 2021

Self Cite

View full text Add to dashboard Cite

show abstract

Verification of oligomycin A structure: synthesis and biological evaluation of 33-dehydrooligomycin A

et al. 2017

View full text Add to dashboard Cite

Although, the structure of oligomycin A (1) was confirmed by spectroscopic and chemical evaluations, some crystallographic data cast doubt on the originally adopted structure of the side 2-hydroxypropyl moiety of this antibiotic. It was suggested that the side chain of the oligomycin is enol-related (2-hydroxy-1-propenyl). To clarify this matter we synthesized and evaluated 33-dehydrooligomycin A (2) prepared by the Kornblum oxidation of 33-O-mesyloligomycin A (3) by dimethyl sulfoxide. NMR data for 33-dehydrooligomycin (2) and results of quantum chemical calculations have shown that this derivative exists in the keto rather than in the enol tautomer 2a. The in vitro antimicrobial activity of 2 was approximately two times weaker in comparison with oligomycin A against Streptomyces fradiae ATCC-19609 and reference Candida spp. strains and similar activity against certain filamentous fungi. The docking binding estimate of 2 with FFATP synthase showed a slight decrease in binding affinity for 2 when compared with oligomycin A; that correlated with its activity against S. fradiae ATCC 19609 that is supersensitive to oligomycin A. The in vitro antiproliferative activities of 2 are also discussed.

show abstract