Platinum-acridines are an example of highly potent, DNA-damaging anticancer drugs superior to previous clinical platinum drugs, such as cisplatin. To minimize the compounds’ toxicity in non-cancerous cells, one goal is to improve the specificity and selectivity by designing platinum-based molecules with advantages in uptake and activity in cancerous cells. Modifications to the structure of the previous platinum-acridine molecules may allow more efficient uptake into cells and possibly higher reactivity with genomic DNA. Due to the chirality of the right-handed DNA double helix as well as that of many other proteins within cells, modification of an active platinum drug with chiral carrier ligands may be beneficial in terms of (i) transporter-dependent uptake into the cell, (ii) rate of reaction with target DNA, and (iii) enantioselective repair of the DNA adducts formed by these agents. Using bulky and chiral diamine non-leaving groups, a pair of enantiomers were synthesized from chiral monofunctional platinum precursors and linker-modified acridines. Characterization and purity were assessed via proton NMR, carbon NMR, and LCMS; following characterization, cell proliferation assays were performed and differential activity for the enantiomers was measured. In conclusion, four platinum derivatives were successfully synthesized including one pair of enantiomers. Results from the cell proliferation assay showed chiral discrimination in a cancer cell line concluding chiral non-leaving groups are a critical modulator of biological activity within the cells. This mechanistic difference can be further investigated in future experiments involving chiral carrier ligands.

Effects of oln-leaving group structure and chirality on the biological activity of platinum-acridine anticancer agents

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.