LAUSR

Abstract Three new derivatives of a platinum–acridine hybrid anticancer agent were synthesized using nitrile–amine coupling (amidination) chemistry. In the new structures, the nonleaving group propane-1,3-diamine (pn) of a previously optimized analogue (hybrid 1) was replaced with 2,2-dimethylpropane-1,3-diamine (Me2pn, hybrid 2), (1R,2R)-1,2-diaminocyclohexane (R,R-dach, hybrid 3), or (1S,2S)-1,2-diaminocyclohexane (S,S-dach, hybrid 4). The cytotoxicity of the four compounds was determined in two non-small cell lung cancer (NSCLC) cell lines, NCI-H460 and A549. The IC50 values extracted from cell proliferation assays span a range of two orders of magnitude, with the highest activity established for compound 1 in NCI-H460 (8 nM) and the lowest for compound 4 in A549 (825 nM). Partitioning coefficients (log D, based on compound distribution in 1-octanol/saline) and levels of cellular accumulation (by inductively coupled plasma mass spectrometry, ICP-MS) were determined for the hybrids. The results suggest that efficient cellular uptake by an active transport mechanism, which depends on the nature of the nonleaving group, is a modulator of chemosensitivity and a prerequisite for the high nanomolar cytotoxicity observed for the most active platinum–acridines.