Platinum-[benz]acridines are a potent class of DNA-targeted hybrid anticancer agents with a unique spectrum of activity distinct from that of cisplatin, which was most recently confirmed in the NCI-60 screen by the NCI Developmental Therapeutics Program (DTP). The goal of this study was to develop a new generation of these agents as functionalized intracellular mechanistic probes and as cytotoxic warheads in macromolecular drug delivery systems. As demonstrated in a recent toxicity study, platinum-[benz]acridine P3B1 emerges as a less genotoxic, more tolerable and potentially more target-selective hybrid agent than platinum-acridine P8A1 (Figure 1). In an effort to gain a more detailed understanding of their molecular mechanism of action, synthetic methodology was developed that allows functionalization of the parent structures with clickable azide linkers. In a proof-of-concept study, we installed two chemically robust linkers in two alternative locations using amide and carbamate coupling chemistry (Figure 1). The azide moieties were introduced to allow detection of the platinum-[benz]acridines and their targeted gene sequences in cancer cells. In another application of this technology, platinum-[benz]acridines can be attached to biomolecular vectors to improve the biodistribution of the drugs and allow their target-selective delivery. We demonstrate that it is possible to attach a platinum-acridine agent to human serum albumin (HSA) and deliver the payload into cancer cells where the (non-cleavable) conjugate accumulates in the lysosomes. To determine the sites of modification with platinum in HSA, the conjugate was studied by heteronuclear [1H-15N] HSQC NMR spectroscopy, ESI-ToF (whole protein) mass spectrometry, as well as LC-ESI-MS analysis of tryptic digests.

Design, synthesis and characterization of multifunctional platinum-[benz]acridine agents

253rd National Meeting (2017)

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