Stereochemistries and Biological Properties of Oligomycin A Diels–Alder Adducts

Stereochemistries and Biological Properties of Oligomycin A Diels–Alder Adducts Научная публикация

Журнал

Journal of Organic Chemistry
ISSN: 1520-6904 , E-ISSN: 0022-3263

Вых. Данные

Год: 2021, Том: 86, Номер: 12, Страницы: 7975-7986 Страниц : 12 DOI: 10.1021/acs.joc.1c00296

Авторы

Omelchuk Olga A ¹ , Malyshev Vadim I ² , Medvedev Michael G ^2,3 , Lysenkova Lyudmila N ¹ , Belov Nikita M ¹ , Dezhenkova Lyubov G ¹ , Grammatikova Natalia E ¹ , Scherbakov Alexander M ⁴ , Shchekotikhin Andrey E ^5,1

Организации

1	Gause Institute of New Antibiotics, Moscow 119021, Russian Federation
2	N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky Prospect 47, Moscow 119991, Russian Federation
3	National Research University Higher School of Economics, Myasnitskaya Street 20, Moscow 101000, Russian Federation
4	Department of Experimental Tumor Biology, N. N. Blokhin National Medical Research Center of Oncology, Moscow 115522, Russian Federation
5	D. I. Mendeleev University of Chemical Technology of Russia, Moscow 125047, Russian Federation

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 1H 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.

Omelchuk O.A. , Malyshev V.I. , Medvedev M.G. , Lysenkova L.N. , Belov N.M. , Dezhenkova L.G. , Grammatikova N.E. , Scherbakov A.M. , Shchekotikhin A.E.
Stereochemistries and Biological Properties of Oligomycin A Diels–Alder Adducts
Journal of Organic Chemistry. 2021. V.86. N12. P.7975-7986. DOI: 10.1021/acs.joc.1c00296 WOS Scopus OpenAlex

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