Combinatorial synthesis can be applied for developing a library of compounds to be rapidly screened for biological activity. Using microwave-assisted combinatorial chemistry, 80 rhenium(I) tricarbonyl complexes were synthesized and screened for anticancer activity in a panel of cancer cell lines, leading to the identification of three lead structures, Re-9B, Re-9C, and Re-9D. These complexes were synthesized independently and fully characterized by NMR spectroscopy, mass spectrometry, elemental analysis, and X-ray crystallography. The most potent compound, Re-9D, was further explored to understand its mechanism of action. Re-9D is equally effective in both wild-type and cisplatin-resistant A2780 ovarian cancer cells, indicating that it circumvents cisplatin resistance. This compound was also shown to possess promising activity against ovarian cancer tumor spheroids. Additionally, flow cytometry showed that Re-9D does not induce cell cycle arrest or flipping of phosphatidylserine to the outer cell membrane. Analysis of the morphological changes of cancer cells treated with Re-9D revealed that this compound gives rise to rapid plasma membrane rupture. Collectively, these data suggest that Re-9D induces necrosis in cancer cells. Additionally, in vivo biodistribution and metabolite analysis of the radioactive 99mTc analogue of Re-9D, 99mTc-9D(H2O), displayed a distinct biodistribution profile and high metabolic stability. This research demonstrates that combinatorial synthesis is an effective approach for the development of new rhenium anticancer agents with advantageous biological properties.

Combinatorial synthesis to identify a potent, necrosis-inducing rhenium anticancer agent

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.