An UnusualLigand Coordination Gives Rise to a NewFamily of Rhodium Metalloinsertors with Improved Selectivity and Potency

摘要

Rhodium metalloinsertors are octahedral complexes that bind DNA mismatches with high affinity and specificity and exhibit unique cell-selective cytotoxicity, targeting mismatch repair (MMR)-deficient cells over MMR-proficient cells. Here we describe a new generation of metalloinsertors with enhanced biological potency and selectivity, in which the complexes show Rh–O coordination. In particular, it has been found that both Δ- and Λ-[Rh(chrysi)(phen)(DPE)]²⁺ (where chrysi =5,6 chrysenequinone diimmine, phen =1,10-phenanthroline, and DPE = 1,1-di(pyridine-2-yl)ethan-1-ol) bind to DNA containing a single CC mismatch with similar affinities and without racemization. This is in direct contrast with previous metalloinsertors and suggests a possible different binding disposition for these complexes in the mismatch site. We ascribe this difference to the higher pKa of the coordinated immine of the chrysi ligand in these complexes, so that the complexes must insert into the DNA helix with the inserting ligand in a buckled orientation; spectroscopic studies in the presence and absence of DNA along with the crystal structureof the complex without DNA support this assignment. Remarkably, allmembers of this new family of compounds have significantly increasedpotency in a range of cellular assays; indeed, all are more potentthan cisplatin and N-methyl-N′-nitro-nitrosoguanidine(MNNG, a common DNA-alkylating chemotherapeutic agent). Moreover,the activities of the new metalloinsertors are coupled with high levelsof selective cytotoxicity for MMR-deficient versus proficient colorectalcancer cells.