Stereochemistries and Biological Properties of Oligomycin A Diels–Alder Adducts

Abstract

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.

Inverse α-Effect as the Ariadne’s Thread on the Way to Tricyclic Aminoperoxides: Avoiding Thermodynamic Traps in the Labyrinth of Possibilities

“…These conclusions enabled us to narrow the number of considered paths (see the Supporting Information) and to propose the mechanism shown in Scheme . This case is similar to how a combination of NMR and quantum chemical calculations was necessary to establish the product configuration in reactions of Oligomycin A with dienophiles …”

“…This case is similar to how a combination of NMR and quantum chemical calculations was necessary to establish the product configuration in reactions of Oligomycin A with dienophiles. 131 The reaction pathway was modeled for substrate 1e (R = CH 3 ) instead of 1a (R = CH 2 Ph) in order to simplify quantum chemical calculations by decreasing the number of atoms and conformational flexibility. The initial stages preceding the formation of I′ were excluded from consideration due to their low activation energies and lack of influence on the final products.…”

Alashanines A–C, Three Quinone-Terpenoid Alkaloids from Syringa pinnatifolia with Cytotoxic Potential by Activation of ERK

“…After a series of reactions such as cyclization, ring-opening reaction, amination, and esterification, intermediates i5 and i7 were generated . Particularly, a N atom could be introduced during the conversion of intermediate i2 to i3 under biotic and abiotic stresses. , Intermolecular Diels–Alder reaction between the intermediates i5 and i7 gives rise to intermediate i8 . , Alashanines A–C ( 1 – 3 ) are generated from intermediate i8 by following further dehydrogenation . On the basis of the comprehensive analysis, quinone–terpenoid alkaloids belong to pseudoalkaloids from the perspective of biotransformation.…”

“…36,37 Intermolecular Diels−Alder reaction between the intermediates i5 and i7 gives rise to intermediate i8. 38,39 Alashanines A− C (1−3) are generated from intermediate i8 by following further dehydrogenation. 40 On the basis of the comprehensive analysis, quinone−terpenoid alkaloids belong to pseudoalkaloids from the perspective of biotransformation.…”

Structures, Biosynthesis, and Bioactivity of Oligomycins from the Marine-Derived Streptomyces sp. FXY-T5

“…The members of oligomycins typically feature a 26-membered macrocyclic lactone fused to a 6,6spiroketal moiety, which was constructed by a typical modular type I polyketide synthase (PKS) biosynthetic system (Figure S1). 6 They have shown numerous potent biological properties, including antifungal, 8,9 cytotoxic, 10,11 immunosuppressive, 12 and insecticidal activities, 13 and have been classified as inhibitors of the mitochondrial F 0 F 1 -ATPase, 14 ABC transporter efflux pump P-glycoprotein, 15 and oncogenic K-Ras plasma membrane localization. 6 During our continuous search for marine-derived novel natural products with antiagricultural fungal pathogen activities, 16,17 a library of actinomycete strains was set up (Figure S2).…”