An Unusual Ligand Coordination Gives Rise to a New Family of Rhodium Metalloinsertors with Improved Selectivity and Potency

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 structure
of the complex without DNA support this assignment. Remarkably, all
members of this new family of compounds have significantly increased
potency in a range of cellular assays; indeed, all are more potent
than 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 levels
of selective cytotoxicity for MMR-deficient versus proficient colorectal
cancer cells.