Stereochemistries and Biological Properties of Oligomycin A Diels–Alder Adducts

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.