Rhodium metalloinsertors are a unique set of metal complexes that bind specifically to DNA base pair mismatches in vitro and kill mismatch repair (MMR)-deficient cells at lower concentrations than their MMR-proficient counterparts. A family of metalloinsertors containing rhodium-oxygen ligand coordination, termed “Rh–O” metalloinsertors, has been prepared and shown to have a significant increase in both overall potency and selectivity towards MMR-deficient cells regardless of structural changes in the ancillary ligands. Here we describe DNA-binding and cellular studies with the second generation of Rh–O metalloinsertors in which an ancillary ligand is varied in both steric bulk and lipophilicity. These complexes, of the form [Rh(L)(chrysi)(PPO)]2+, all include the O-containing PPO ligand (PPO = 2-(pyridine-2-yl)propan-2-ol) and the aromatic inserting ligand chrysi (5,6-chrysene quinone diimine) but differ in the identity of their ancillary ligand L, where L is a phenanthroline or bipyridyl derivative. The Rh–O metalloinsertors in this family all show micromolar binding affinities for a 29-mer DNA hairpin containing a single CC mismatch. The complexes display comparable lipophilic tendencies and pKa values of 8.1–9.1 for dissociation of an imine proton on the chrysi ligand. In cellular proliferation and cytotoxicity assays with MMR-deficient cells (HCT116O) and MMR-proficient cells (HCT116N), the complexes containing the phenanthroline-derived ligands show highly selective cytotoxic preference for the MMR-deficient cells at nanomolar concentrations. Using mass spectral analyses, it is shown that the complexes are taken into cells through a passive mechanism and exhibit low accumulation in mitochondria, an off-target organelle that, when targeted by parent metalloinsertors, can lead to non-selective cytotoxicity. Overall, these Rh–O metalloinsertors have distinct and improved behavior compared to previous generations of parent metalloinsertors, making them ideal candidates for further therapeutic assessment.
Defects in DNA mismatchrepair (MMR) are commonly found in various cancers, especially in colorectal cancers. Despite the high prevalence of MMR-deficient cancers, mismatch-targeted therapeuticsa re limited and diagnostic tools are indirect. Here, we examine the cytotoxic properties of ar hodiummetalloinsertor, [Rh(phen)(chrysi)(PPO)] 2 + (RhPPO)i n2 7d iversec olorectal cancer cell lines. Despite the low frequency of genomic mismatches and the non-covalentn ature of the RhPPO-DNA lesion, RhPPO is on average five times more potent than cisplatin. Importantly,t he biological target and profile for RhPPO differs from that of cisplatin. Af luorescent metalloinsertor, RhCy3,w as used to demonstrate that the cellulart arget of RhPPO is the DNA mismatch. RhCy3 representsadirect probe for MMR-deficiency and correlates directlyw ith the cytotoxicity of RhPPO across different cell lines. Overall, our studies clearly indicate that RhPPO and RhCy3 are promising anticancer and diagnostic probes for MMR-deficient cancers, respectively.
DNA has been exploited as a biological target of chemotherapeutics since the 1940s. Traditional chemotherapeutics, such as cisplatin and DNA-alkylating agents, rely primarily on increased uptake by rapidly proliferating cancer cells for therapeutic effects, but this strategy can result in off-target toxicity in healthy tissue. Recently, research interests have shifted towards targeted chemotherapeutics, in which a drug targets a specific biological signature of cancer, resulting in selective toxicity towards cancerous cells. Here, we review a family of complexes, termed rhodium metalloinsertors, that selectively target DNA base pair mismatches, a hallmark of mismatch-repair (MMR) deficient cancers. These rhodium metalloinsertors, bind DNA mismatches with high specificity and display high selectively in killing MMR-deficient versus MMR-proficient cells. This cell selectivity is unique for small molecules that bind DNA. Current generations of rhodium metalloinsertors have shown nanomolar potency along with high selectivity towards MMR-deficient cells, and show promise as a foundation for a new family of chemotherapeutics for MMR-deficient cancers.
DNA base pair mismatches occur naturally in cells as a result of incorporation errors and damage. Most cells are able to identify and correct these mistakes before replication, allowing for high genome fidelity between cellular generations. In some forms of cancer, however, proteins involved in the machinery of mismatch repair (MMR) undergo mutation, making those cells unable to correct mismatches and leading to an increase in mutations. Since higher mismatch frequency serves as an early indicator of cancer progression, for many researchers mismatches have provided a novel target for the design of organic and inorganic small-molecule therapeutics. In particular, transition metal complexes have shown great promise in this context owing to their valuable spectroscopic and photophysical properties and flexibility with respect to modification of their coordination spheres. Thus far, experimental designs have ranged from targeting the thermodynamic destabilization of mismatched sites to the hydrogen-bonding pattern of specific mismatched base pairs. Here, we review the diversity, practical application, and evolution of mismatch-targeting small molecules, with an emphasis on rhodium metalloinsertors and luminescent ruthenium compounds. Importantly, we highlight the discovery of metalloinsertion, a noncovalent DNA binding mode that is specific towards destabilized sites, such as mismatches, within the DNA duplex.
A pentadentate ligand platform, bis[2-(diispropylphosphino-methylamino)phenyl]ether (1), abbreviated as H 2 (PNONP), is introduced that enables the isolation of homodinuclear chromium complexes. In a one-step metalation using Cr(III) and Cr(II) chloride reagents, the bimetallic compounds, [Cr(μ−Cl)(PNONP)] 2 (2) and [Cr(PNONP)] 2 (3), respectively, were synthesized. These complexes have been characterized by X-ray diffraction, NMR spectroscopy, cyclic voltammetry, magnetometry, UV−vis−NIR spectroscopy, combustion analysis, and computational methods. Complex 3 has a reasonably short Cr−Cr bond length of 2.1342(5) Å. Quantum chemical calculations support a diradical singlet ground-state with a formal triple bond between the chromium centers. By cyclic voltammetry, 3 exhibits two reversible oxidations at E ½ = −472 and −753 mV versus FeCp 2 0/+. The one-and two-electron oxidized analogues, 3 + and 3 2+ , were generated in situ via chemical oxidation using ferrocenium. Based on in situ characterization of 3 + and 3 2+ , we hypothesize the oxidations are metal-based to yield Cr 2 5+ and Cr 2 6+ cores, respectively.
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