Rhodium Complexes Targeting DNA Mismatches as a Basis for New Therapeutics in Cancers Deficient in Mismatch Repair

Abstract

Cancers with microsatellite instability (MSI), which include ≤20% of solid tumors, are characterized by resistance to chemotherapy due to deficiency in the DNA mismatch repair (MMR) pathway. Rhodium metalloinsertors make up a class of compounds that bind DNA mismatches with high specificity and show selective cytotoxicity in MSI cancer cells. We determined that rhodium complexes with an N∧O coordination showed significantly increased cell potency compared with that of N∧Ncoordinated compounds, and we identified [Rh(chrysi)(phen)-(PPO)] 2+ (RhPPO) as the most potent, selective compound in this class. Using matched cell lines that are MMR-deficient (HCT116O) and MMR-proficient (HCT116N), we demonstrated that RhPPO preferentially activates the DNA damage response and inhibits DNA replication and cell proliferation in HCT116O cells, leading to cell death by necrosis. Using a fluorescent conjugate of RhPPO, we established that the metalloinsertor localizes to DNA mismatches in the cell nucleus and causes DNA double-strand breaks at or near the mismatch sites. Evaluation of RhPPO across MMR-deficient and MMR-proficient cell lines confirmed the broad potential for RhPPO to target MSI cancers, with cell potency significantly higher than that of platinum complexes used broadly as chemotherapeutics. Moreover, in a mouse xenograft model of MSI cancer, RhPPO shows promising antitumor activity and increased survival. Thus, our studies indicate that RhPPO is a novel DNA-targeted therapy with improved potency and selectivity over standard-of-care platinum-based chemotherapy and, importantly, that DNA mismatches offer a critical new target in the design of chemotherapeutics for MSI cancers.

Fifty Shades of Phenanthroline: Synthesis Strategies to Functionalize 1,10-Phenanthroline in All Positions

“…Because isopropyl groups strengthen more efficiently the σ-donating character of phen than methyl groups, the steric and electronic effects here are opposing, thus resulting in the similar measured Cu−N distances for both complexes. In the case of [Cu (37) 2 ] + , the steric factor is prominent. On the other hand, the electronic factor is prominent in the case of [Cu (38) 2 ] + , where the phenyl groups are indeed electron-withdrawing and weaken the σ-donating character of 38 compared to 36 or 1 (however, stabilizing intramolecular π-interactions make [Cu (38) 2 ] + one of the most stable copper(I) complexes).…”

“…The strong complexing ability of the N^N cavity also makes phen a potent herbicide. − M x + –phen complexes (M = Pd, Pt, Rh, Re, Ru, Ir, Os, Cu, Ni, lanthanides, etc.) have been developed and used as drugs, − homogeneous catalysts, ,,− and photosensitizers with applications in photochemistry, − or luminescent probes and materials. − In other well-known examples, M x + –phen complexes have been used to design supramolecular architectures through the template effect. − Furthermore, the rigidity and hydrophobicity of phen have conferred to the corresponding M x + –phen complexes (with M x + = Cu 2+ and Ru 2+ mostly) ,− strong affinity for DNA and RNA strands, either by interactions with the minor or major groove or by intercalation between base pairs.…”

Cell nucleus localization and high anticancer activity of quinoline–benzopyran rhodium(iii) metal complexes as therapeutic and fluorescence imaging agents

“…In parallel, similar results were observed in Rh(III) and other metal complexes. [66][67][68][69][70][71][72] Effect on the cell cycle and the G2-phase checkpoint pathways…”

Ruthenium-Locked Helical Chirality: A Barrier of Inversion and Formation of an Asymmetric Macrocycle

“…The interaction between inorganic compounds and biomolecules such as proteins or nucleic acids has been widely studied − since the discovery of the anticancer properties of cisplatin. , Especially, the interaction with DNA has gathered wide attention , as more and more platinum-based analogues of cisplatin have been reported, with improved properties such as oxaliplatin or satraplatin . One method to generate specific interaction between inorganic compounds and DNA is to use chiral scaffolds.…”