Synthesis, antimicrobial and antiproliferative properties of epi-oligomycin A, the (33S)-diastereomer of oligomycin A

abstract

We describe the synthesis of epi-oligomycin A, a (33S)-diastereomer of the antibiotic oligomycin A. The structure of (33S)-oligomycin A was determined by elemental analysis, spectroscopic studies, including 1D and 2D NMR spectroscopy, and mass spectrometry. Isomerization of C33 hydroxyl group led to minor changes in the potency against Aspergillus niger, Candida spp., and filamentous fungi whereas the activity against Streptomyces fradiae decreased by approximately 20-fold compared to oligomycin A. We observed that 33-epi-oligomycin A had the same activity on the human leukemia cell line K562 as oligomycin A but was more potent for the multidrug resistant subline K562/4. Non-malignant cells were less sensitive to both oligomycin isomers. Finally, our results pointed at the dependence of the cytotoxicity of oligomycins on oxygen supply.

Graphical Abstract

Keywords:

• Oligomycin A
• 33-O-mesyloligomycin
• epimers
• (33S)-oligomycin A
• mitochondrial F₁F_O ATP-synthase
• cytotoxicity
• antimicrobial activity

Additional information

Funding

This work was partly supported by the Russian Science Foundation, Grant number 15-15-00141-П. Experiments with breast cancer and non-malignant mammary gland cells were funded by the Russian Foundation for Basic Research, grant number 18-29-09017. The authors thank N.M. Maliutina for HPLC, E.N. Bychkova (Gause Institute of New Antibiotics) for IR and UV analyses, A.V. Shunayev and E.I. Mikhaevich for assistance in study on the antiproliferative activity, D.N. Kaluzhny for performing of the ECD spectra and Dr. S.E. Semina (Blokhin National Medical Research Center of Oncology) for assistance in development and characterization of MCF-7/TR subline.