Platinum-acridines (PAs) show potent activity at low-nanomolar concentrations in various solid tumors but show suboptimal pharmacological properties in vivo.  In this study we wanted to answer the question whether these agents can be turned into prodrug-payloads for targeted antigen-specific delivery to tumor tissue.  Chemically robust, azide-modified Pt(IV) analogues of PAs were designed that are compatible with efficient azide-strained alkyne click chemistry, which was monitored by LC-MS, and allow the introduction of thiol-reactive linkers.  Several payloads of the most cytotoxic analog, [PtCl(pn)(N-(2-(acridin-9-ylamino)ethyl)-N-methylacetimidamide](NO<sub>3</sub>)<sub>2</sub> (compound 1, pn = 1,3-diaminopropane) were synthesized and fully characterized.  In pH neutral aqueous media, the conjugates are highly stable but undergo rapid reduction (less than 30 minutes) in the presence of ascorbate to release the intact, active Pt(II) form of the prodrug.  Preliminary data from model reactions is presented demonstrating that the payloads are compatible with thiol-directed bioconjugation.  PA prodrug-payloads may open new strategies for targeting aggressive cancers susceptible of the unique DNA damage caused by PAs.

Designing ADC payloads for platinum acridine anticancer agents

ACS Fall 2021

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