Abstract
Platinum–acridine anticancer agents (PAs) containing acyclic (1 and 3) and heterocyclic (R)-3-aminopiperidine (2) and 2-iminopyrrolidine (4) based linker moieties were studied. Similar to 1, rigidified 2 shows a strong positive correlation between potency and SLC47A1 (multi-drug and toxin extrusion protein 1, MATE1) gene expression levels across the NCI-60 panel of cancer cell lines. All derivatives show nanomolar activity in HepG2 (liver), NCI-H460 (lung), and MDA-MB-436 (breast), which express high levels of SLC47A1 (Cancer Cell Line Encyclopedia, CCLE). The PAs are up to 350-fold more potent than cisplatin. In a MATE1 inhibition assay, a significant reduction in activity is observed in the three cancer cell lines (4000-fold lower for HepG2). Molecular docking experiments provide insight into the compatibility of a structurally diverse set of PAs with MATE1-mediated transport. MATE1 is a predictive marker and actionable target that sensitizes cancer cells regardless of tissue of origin to PAs.
Supplementary materials
Title
Supporting Info
Description
Experimental details, synthetic procedures and details of compound characterization and purity (1H NMR and 13C NMR spectra, MS data, and HPLC traces), 2-D NMR solution and X-ray crystallographic characterization of compound 4, additional molecular docking results, and figures/tables summarizing cytotoxicity and SLC47A1 expression data.
Actions
Title
CIF file
Description
CIF file for crystal structure of compound 4
Actions