Polypyridyl rhodium complexes bearing the sterically expansive chrysene diimine ligand are known to selectivity bind to mismatched-base pairs in duplex DNA through insertion via the minor groove.  These complexes are selectively cytotoxic to carcinomas bearing the microsatellite instability (MSI) phenotype, a marker for deficiencies in mismatch repair.  The MSI pehnotype has been found in a variety of carcinomas including hereditary nonpolyposis colorectal cancer, ovarian cancer, and treatment-related secondary leukemia.  The effects of tether length and functional group tolerance, including alcohols, carboxylic acids, and amines, on the cytotoxicity and cellular uptake properties in a carcinoma displaying the MSI phenotype were explored using a series of functionalized polypyridyl ligands.  The understanding gained from these rhodium metalloinsertors was incorporated into the design of new scaffolds for the development of peptide and antibody conjugates.  These new complexes aim to improve cellular uptake, localization, and ultimately differential cytotoxicity as a function of mismatch repair deficiency.

Rhodium metalloinsertors as scaffolds for bioconjugate development

243rd National Meeting (2012)

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