Targeted Chemotherapy with Metal Complexes

Weidmann, Alyson G.; Komor, Alexis C.; Barton, Jacqueline K.

doi:10.1080/02603594.2014.890099

Cited by 35 publications

(35 citation statements)

References 36 publications

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“…On the basis of the binding constant of [Rh(bpy) 2 (chrysi)] 3+ , the binding constants of all subsequent complexes are then determined by solving simultaneous equilibria at the inflection point of the photocleavage titration curve. The results, along with those of all previously reported compounds, 22,30 are shown in Figure 1. Interestingly, despite the variance in both the ancillary ligands and number of hydrogen-bond donors, all compounds (except the extremely bulky [Rh(DIP) 2 (chrysi)] 3+ ) exhibit binding affinities within essentially the same order of magnitude, varying from 2.3 × 10 6 M −1 to 4.4 × 10 7 M −1 .…”

Section: Resultssupporting

confidence: 62%

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Cell-Selective Biological Activity of Rhodium Metalloinsertors Correlates with Subcellular Localization

et al. 2012

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Deficiencies in the mismatch repair (MMR) pathway are associated with several types of cancers, as well as resistance to commonly used chemotherapeutics. Rhodium metalloinsertors have been found to bind DNA mismatches with high affinity and specificity in vitro, and also exhibit cell-selective cytotoxicity, targeting MMR-deficient cells over MMR-proficient cells. Ten distinct metalloinsertors with varying lipophilicities have been synthesized and their mismatch binding affinities and biological activities determined. Although DNA photocleavage experiments demonstrate that their binding affinities are quite similar, their cell-selective antiproliferative and cytotoxic activities vary significantly. Inductively coupled plasma mass spectrometry (ICP-MS) experiments have uncovered a relationship between the subcellular distribution of these metalloinsertors and their biological activities. Specifically, we find that all of our metalloinsertors localize in the nucleus at sufficient concentrations for binding to DNA mismatches. However, the metalloinsertors with high rhodium localization in the mitochondria show toxicity that is not selective for MMR-deficient cells, whereas metalloinsertors with less mitochondrial rhodium show activity that is highly selective for MMR-deficient versus proficient cells. This work supports the notion that specific targeting of the metalloinsertors to nuclear DNA gives rise to their cell-selective cytotoxic and antiproliferative activities. The selectivity in cellular targeting depends upon binding to mismatches in genomic DNA.

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Section: Resultssupporting

confidence: 62%

“…22,29,30 [Rh(chrysi)(phen)(NH 3 ) 2 ]Cl 3 was prepared from [Rh(phen)(NH 3 ) 4 ]OTf 3 and 5,6-chrysenequinone following the methods described by Mürner et. al.…”

Section: Methodsmentioning

confidence: 99%

Cell-Selective Biological Activity of Rhodium Metalloinsertors Correlates with Subcellular Localization

et al. 2012

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“…10–16 Although many complexes are derived from [Ru(bpy) 3 ] 2+ (bpy = 2,2′-bipyridine) (Figure 1a), 17 these applications often have different demands. For example, the excited-state redox potential is crucial in solar energy schemes and charge transfer reactions, which often require long-lived triplet metal-to-ligand charge transfer ( 3 MLCT) excited states, whereas strong luminescence and sensitivity to the environment have been important in sensor applications.…”

Section: Introductionmentioning

confidence: 99%

New Ru(II) Complexes for Dual Photoreactivity: Ligand Exchange and ¹O₂ Generation

2015

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CONSPECTUS Uncovering the factors that govern the electronic structure of Ru(II)–polypyridyl complexes is critical in designing new compounds for desired photochemical reactions, and strategies to tune excited states for ligand dissociation and 1O2 production are discussed herein. The generally accepted mechanism for photoinduced ligand dissociation proposes that population of the dissociative triplet ligand field (3LF) state proceeds through thermal population from the vibrationally cooled triplet metal-to-ligand charge transfer (3MLCT) state; however, temperature-dependent emission spectroscopy provides varied activation energies using the emission and ligand exchange quantum yields for [Ru(bpy)2(L)2]2+ (bpy = 2,2′-bipyridine; L = CH3CN or py). This suggests that population of the 3LF state proceeds from the vibrationally excited 3MLCT state. Because the quantum yield of ligand dissociation for nitriles is much more efficient than that for py, steric bulk was introduced into the ligand set to distort the pseudo-octahedral geometry and lower the energy of the 3LF state. The py dissociation quantum yield with 500 nm irradiation in a series of [Ru(tpy)(NN)(py)]2+ complexes (tpy = 2,2′:6′,2″-terpyridine; NN = bpy, 6,6′-dimethyl-2,2′-bipyridine (Me2bpy), 2,2′-biquinoline (biq)) increases by 2–3 orders of magnitude with the sterically bulky Me2bpy and biq ligands relative to bpy. Ultrafast transient absorption spectroscopy reveals population of the 3LF state within 3–7 ps when NN is bulky, and density functional theory calculations support stabilized 3LF states. Dual activity via ligand dissociation and 1O2 production can be achieved by careful selection of the ligand set to tune the excited-state dynamics. Incorporation of an extended π system in Ru(II) complexes such as [Ru(bpy)(dppn)(CH3CN)2]2+ (dppn = benzo[i]dipyrido[3,2-a:2′,3′-c]phenazine) and [Ru(tpy)(Me2dppn)(py)]2+ (Me2dppn = 3,6-dimethylbenzo[i]dipyrido[3,2-a:2′,3′-c]phenazine) introduces low-lying, long-lived dppn/Me2dppn 3ππ* excited states that generate 1O2. Similar to [Ru(bpy)2(CH3CN)2]2+, photodissociation of CH3CN occurs upon irradiation of [Ru(bpy)(dppn)(CH3CN)2]2+, although with lower efficiency because of the presence of the 3ππ* state. The steric bulk in [Ru(tpy)(Me2dppn)(py)]2+ is critical in facilitating the photoinduced py dissociation, as the analogous complex [Ru(tpy)(dppn)(py)]2+ produces 1O2 with near-unit efficiency. The ability to tune the relative energies of the excited states provides a means to design potentially more active drugs for photochemotherapy because the photorelease of drugs can be coupled to the therapeutic action of reactive oxygen species, effecting cell death via two different mechanisms. The lessons learned about tuning of the excited-state properties can be applied to the use of Ru(II)–polypyridyl compounds in a variety of applications, such as solar energy conversion, sensors and switches, and molecular machines.

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“…Targeted therapy, in which a specific biological signature of cancer drives preferential drug action on cancerous cells over healthy cells, is a clear alternative to these non-specific chemotherapeutics. For example, proteins that are upregulated or expressed exclusively in cancer cells may be exploited as cancer-selective targets [27]. For such protein targets, kinase inhibitors and monoclonal antibodies have found clinical use in the treatment of a variety of cancers [28,29].…”

Section: Introductionmentioning

confidence: 99%

Targeting DNA mismatches with rhodium metalloinsertors

Boyle

Barton

2016

Inorganica Chimica Acta

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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.

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Targeted Chemotherapy with Metal Complexes

Cited by 35 publications

References 36 publications

Cell-Selective Biological Activity of Rhodium Metalloinsertors Correlates with Subcellular Localization

Cell-Selective Biological Activity of Rhodium Metalloinsertors Correlates with Subcellular Localization

New Ru(II) Complexes for Dual Photoreactivity: Ligand Exchange and ¹O₂ Generation

Targeting DNA mismatches with rhodium metalloinsertors

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Targeted Chemotherapy with Metal Complexes

Cited by 35 publications

References 36 publications

Cell-Selective Biological Activity of Rhodium Metalloinsertors Correlates with Subcellular Localization

Cell-Selective Biological Activity of Rhodium Metalloinsertors Correlates with Subcellular Localization

New Ru(II) Complexes for Dual Photoreactivity: Ligand Exchange and 1O2 Generation

Targeting DNA mismatches with rhodium metalloinsertors

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New Ru(II) Complexes for Dual Photoreactivity: Ligand Exchange and ¹O₂ Generation