Platinum-acridine agents have been developed that show major advantages over traditional platinum-based anticancer therapies, resulting in a unique activity profile (NCI-60). For instance, the dicationic hybrid agents accumulate in cancer cells significantly higher levels and induce adducts in nuclear DNA at a faster rate than the oncology drug cisplatin. The 1000-fold higher potency observe for platinum-acridines relative to cisplatin is most likely the result of a combination of these mechanistic differences. In the current study, we introduced chirality and stereochemically constrained linkers that connect the acridine intercalator to the monofunctional platinum moiety. These modifications were introduced to determine if the chirality and entropic effects due to increased rigidity affect DNA platination and/or active, transporter-mediated cell uptake. The R and S isomers of our new chiral platinum-acridine drugs showed a dramatic difference in cytotoxicity when tested in non-small cell lung cancer cells (NSCLC) of approximately 100-fold. To rationalize this distinct difference, we have performed assays to determine total platinum concentrations in lung cancer cells and the level of platinum in extracted DNA. The results showed R had a significantly higher cellular accumulation than S by 4-fold, and the DNA adduct levels achieved by the R isomer were 50 times higher relative to those observed for the S isomer. In DNA unwinding assays, the R isomer was able to completely unwind plasmid DNA in less than 2 hours, whereas the same process with the S isomer took approximately 24 hours. Introducing additional non-rotatable linker components into these agents allowed us to probe the stereochemical requirements for the nanomolar anticancer activity that can be achieved with this pharmacophore. The structure activity relationship (SAR) delineated in this study provide an incentive for additional mechanistic work and further optimization of this class of agents.

Shenjie Zhang

Senior PhD candidate, Wake forest University

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