Frederick M. MacDonnell

The University of Texas at Arlington

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Nagham Alatrash

Southwestern Medical Center

Norma R. de Tacconi

The University of Texas at Arlington

Daniel W. Armstrong

The University of Texas at Arlington

Reynaldo O. Lezna

Instituto de Investigaciones Fisicoquímicas Teóricas y Aplicadas

Rama Konduri

The University of Texas at Arlington

Sebastiano Campagna

University of Messina

Brian H. Dennis

The University of Texas at Arlington

Krishnan Rajeshwar

The University of Texas at Arlington

David J. Boston

New Iridium (United States)

Joseph M. Aslan

The University of Texas at Arlington

Cooperative Institutions

The University of Texas at Arlington

Mississippi State University

Northwestern University

University of Messina

Friedrich Schiller University Jena

The University of Texas at Austin

Centre National de la Recherche Scientifique

University of North Carolina at Charlotte

Instituto de Investigaciones Fisicoquímicas Teóricas y Aplicadas

City of Hope

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Regression of Lung Cancer by Hypoxia-Sensitizing Ruthenium Polypyridyl Complexes

Molecular Cancer Therapeutics (2013)

Abhishek Yadav Thamara Janaratne Arthi Krishnan Sharad S. Singhal Sushma Yadav

The ruthenium (II) polypyridyl complexes (RPC), Δ-[(phen)2Ru(tatpp)]Cl2 (Δ-[3]Cl2) and ΔΔ-[(phen)2Ru(tatpp)Ru(phen)2]Cl4 (ΔΔ-[4]Cl4, are a new generation of metal-based antitumor agents. These RPCs bind DNA via intercalation of the tatpp ligand, which itself is redox-active and is easily reduced at biologically relevant potentials. We have previously shown that RPC 4(4+) cleaves DNA when reduced by glutathione to a radical species and that this DNA cleavage is potentiated under hypoxic conditions in vitro. Here, we show that 3(2+) also exhibits free radical-mediated DNA cleavage in vitro and that 3(2+) and 4(4+) both exhibit selective cytotoxicity toward cultured malignant cell lines and marked inhibition of tumor growth in vivo. The murine acute toxicity of RPCs 3(2+) and 4(4+) (maximum tolerable doses ~ 65 μmol/kg) is comparable with that for cisplatin (LD50 ~ 57 μmol/kg), but unlike cisplatin, RPCs are generally cleared from the body unchanged via renal excretion without appreciable metabolism or nephrotoxic side effects. RPCs 3(2+) and 4(4+) are shown to suppress growth of human non-small cell lung carcinoma (~83%), show potentiated cytotoxicity in vitro under hypoxic conditions, and induce apoptosis through both intrinsic and extrinsic pathways. The novel hypoxia-enhanced DNA cleavage activity and biologic activity suggest a promising new anticancer pharmacophore based on metal complexes with aromatic ligands that are easily reduced at biologically accessible potentials.

Cleavage (geology)

10.1158/1535-7163.mct-12-1130

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Citations (60)

Metal‐Catalyzed Hydride Transfer from Alcohols to Photoexcited Dipyridophenazine^†

Photochemistry and Photobiology (2021)

Joseph M. Aslan Melissa M. Reardon Nagham Alatrash Francesco Nastasi Frederick M. MacDonnell

Abstract Dipyridophenazine (dppz) is known to react with alcohols upon photoexcitation into an n‐π* transition at 378 nm to yield dihydrodipyridophenazine (dppzH 2 ). This process occurs via H‐atom abstraction from alcohols and subsequent disproportionation of the dppzH • radical species, to the final product. This reaction shows a primary kinetic isotope effect (KIE = 4.9) in methanol/perdeuteromethanol solvents, consistent with H‐atom transfer processes. Addition of excess Zn(II) ions to the dppz solution not only accelerates the rate of photoreduction, but also lowers the KIE to 1.7, indicating a change in reaction mechanism. We postulate that the coordination of the alcoholic solvent to Zn(II) activates the alcohol α C‐H bonds toward hydride transfer processes which would be consistent with the lowered KIE and faster overall reduction of the aromatic ligand. Interestingly, this appears to be an intramolecular process in which the Zn(II) is coordinated to both the dppz ligand and the reactive alcohol, as a sharp inflection in the overall rate increase is observed at a Zn:dppz ratio of 2:1. At this ratio, the dominant dppz species involves a Zn(II) bound to one dppz and several solvent molecules (methanol and water).

Kinetic isotope effect

Photoexcitation

10.1111/php.13437

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CCDC 2045351: Experimental Crystal Structure Determination

The Cambridge Structural Database (2020)

Nagham Alatrash Frederick M. MacDonnell

10.5517/ccdc.csd.cc26nc2b

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CCDC 2049829: Experimental Crystal Structure Determination

The Cambridge Structural Database (2020)

Melissa M. Reardon Frederick M. MacDonnell

10.5517/ccdc.csd.cc26t0jl

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Altered profiles and metabolism of l- and d-amino acids in cultured human breast cancer cells vs. non-tumorigenic human breast epithelial cells

Journal of Pharmaceutical and Biomedical Analysis (2018)

Siqi Du Yadi Wang Nagham Alatrash Choyce A. Weatherly Daipayan Roy

10.1016/j.jpba.2018.10.047

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Citations (51)

Design, synthesis and biological evaluation of Ruthenium (II) polypyridyl complexes with redox active ligands.

Cancer Research (2008)

Abhishek Yadav Sanjay Awasthi Frederick M. MacDonnell

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA LB-191 Purpose: Tumor cells under hypoxic stress are among the most resistant to radiotherapy and chemotherapy and are also most susceptible toward metastasis, making this subpopulation a particularly attractive chemotherapeutic target. We are interested in the development, toxicology and pharmacology of a new class of redox-active drugs that show potentiated DNA- cleavage activity under hypoxic conditions. These drugs are all based on a tetraazapentacene heterocycle which is the pharmacophore. Metal complexation of the drug provides solubility and imparts a cationic charge that helps the drug to tightly bind to DNA (Kb ~ 109 M-1) and this DNA damage is enhanced in presence of common cellular reductants like glutathione. The present paper presents structural design, studies in cultured malignant and normal cells, as well as animal toxicity and antitumor studies of this new pharmacophore. Experimental Design: A structure-activity relationship for a series of Ru(II) complexes has been established by synthesizing and screening them for its biological activity. Cytotoxicity studies were performed to determine the IC50 using a standard MTT drug sensitivity assay on non-small cell lung cancer (NSCLC) H358 and H226. The control experiments for this were also carried out in normal healthy cells HUVEC and HAVSMC. An initial animal toxicity screen was determined in a dose ranging study by intraperitoneal injection in C57BL/6NTac mice to calculate the maximum tolerable dose (MTD). The animals were also autopsied after interval of 0, 24 and 48 hr and the organs liver, spleen, intestine, kidney, heart, lung and brain collected and analyzed for studying the pharmacokinetics of the complex using Atomic Absorption Spectroscopy. The in vivo antitumor activities of the most promising complexes were performed using an orthotopic syngeneic mouse melanoma model. For each complex 4 male C57BL/6NTac mice were injected with 1 million B16 mouse melanoma cells subcutaneously. The tumor volume and regression was monitored for the group. Results: The results of the drug sensitivity assay were determined for a total of 17 complexes (racemic/chiral). The most antipromising activity was shown by complex with a longer bridging redox active ligand tatpp with an IC50 value of about 10 μM, very rare for this class. The complex also showed low animal toxicity in the screen with MTD as high as 100 mg/Kg. Also we found that the complex had a measurable inhibitory effect on tumor growth as measured by the tumor volume. Conclusions: We report synthesis and biological activity of a novel molecule with anticancer properties that support a potential clinical utility for advanced human cancer. Supported by National Cancer Institute grant CA 113747

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Multielectron Photoreduction of a Bridged Ruthenium Dimer, [(phen)₂Ru(tatpp)Ru(phen)₂][PF₆]₄: Aqueous Reactivity and Chemical and Spectroelectrochemical Identification of the Photoproducts

Journal of the American Chemical Society (2004)

Rama Konduri Norma R. de Tacconi Krishnan Rajeshwar Frederick M. MacDonnell

The dinuclear ruthenium(II) complex [(phen)(2)Ru(tatpp)Ru(phen)(2)][PF(6)](4) (P) (where phen is 1,10-phenanthroline and tatpp is 9,11,20,22-tetraazatetrapyrido[3,2-a:2'3'-c:3' ',2' '-l:2' ",3' "]pentacene) is shown to accept up to four electrons and two protons on the central tatpp bridging ligand via a combination of stoichiometric chemical reductions and protonations and spectroelectrochemistry (SEC) in acetonitrile. The absorption spectra of seven distinct species related by reduction and/or protonation of the central tatpp ligand were obtained and the two sequential photoproducts obtained from visible irradiation of P in acetonitrile (with 0.25 M triethylamine (TEA)) thus identified as P(-) (singly reduced, nonprotonated P) and HP(-) (doubly reduced, monoprotonated P), respectively. Importantly, the photochemical activity is maintained in mixed water-acetonitrile (1:4) solutions under basic conditions, and the protonation state of the photoproducts is readily controlled by varying the solution pH between 8 and 12. Absorption spectra obtained by SEC under similar solvent conditions were virtually identical to those obtained photochemically, and thus the doubly reduced photoproducts were identified as P(2)(-) (pH 12), HP(-) (pH 10), and H(2)()P (pH 8). This last photoproduct, H(2)()P, is particularly promising with respect to solar hydrogen production in that it can be produced in the presence of water and its dehydrogenation under appropriate conditions could yield H(2) and regenerate P. A qualitative MO diagram is presented as a framework for understanding the observed optical transitions as a function of oxidation and protonation state.

Triethylamine

10.1021/ja047931l

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Citations (84)

Spectroelectrochemistry of [(bpy)2Ru(tatpp)]Cl2, a Photocatalyst for Hydrogen Generation

Meeting abstracts/Meeting abstracts (Electrochemical Society. CD-ROM) (2007)

Reynaldo O. Lezna Norma R. de Tacconi Frederick M. MacDonnell

Abstract not Available.

10.1149/ma2007-02/31/1495

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Photodriven Multi‐electron Storage in Disubstituted Ru^IIDppz Analogues

Chemistry - A European Journal (2015)

Joseph M. Aslan David J. Boston Frederick M. MacDonnell

Abstract Four derivatives of the laminate acceptor ligand dipyrido‐[3,2‐a:2′,3′‐c]phenazine (dppz) and their corresponding ruthenium complexes, [Ru(phen) 2 (dppzX 2 )] 2+ , were prepared and characterized by NMR spectroscopy, ESI‐MS, and elemental analysis. The new ligands, generically denoted dppzX 2 , were symmetrically disubstituted on the distal benzene ring to give 10,13‐dibromodppz (dppz‐ p ‐Br), 11,12‐dibromodppz (dppz‐ o ‐Br), 10,13‐dicyanodppz (dppz‐ p ‐CN), 11,12‐dicyanodppz (dppz‐ o ‐CN). Solvated ground state MO calculations of the ruthenium complexes reveal that these electron‐withdrawing substituents not only lower the LUMO of the dppz ligand (dppz(CN) 2 <dppzBr 2 <dppz), but that the para disubstitution results in a lower LUMO than the ortho disubstitution (dppz‐ p ‐CN<(dppz‐ o ‐CN), and dppz‐ p ‐Br<dppz‐ o ‐Br). The validity of the calculations was confirmed experimentally using cyclic voltammetry. Of the complexes evaluated in this study, only the dicyanodppz complexes showed multiple dppz‐based reductions prior to reduction of the phen ligands. The capacity to form singly and doubly reduced dppz‐based anions at modest reduction potentials was confirmed using a combination of spectroelectrochemical and chemical titration methods. When subjected to photolysis with visible light in the presence of a sacrificial donor, such as triethylamine, both cyano complexes showed multi‐electron reduction. The other complexes only show a single reduction.

Phenazine

HOMO/LUMO

Quinoxaline

Triethylamine

Electron acceptor

10.1002/chem.201502607

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Citations (27)

Primary Photoinduced Processes in Bimetallic Dyads with Extended Aromatic Bridges. Tetraazatetrapyridopentacene Complexes of Ruthenium(II) and Osmium(II)

Inorganic Chemistry (2005)

Claudio Chiorboli Sandro Fracasso Marcella Ravaglia Franco Scandola Sebastiano Campagna

The photophysics of the binuclear complexes [(phen)2M(tatpp)M(phen)2]4+, where M = Ru or Os, phen = 1,10-phenanthroline, and tatpp = 9,11,20,22-tetraazatetrapyrido[3,2-a:2'3'-c:3'',2''-l:2''',3''']pentacene, has been studied in acetonitrile and dichloromethane by femtosecond and nanosecond time-resolved techniques. The results demonstrate that complexes of different metals have different types of lowest excited state: a tatpp ligand-centered (LC) triplet in the case of Ru(II); a metal-to-ligand charge-transfer (MLCT) triplet state in the case of Os(II). The excited-state kinetics is strongly solvent-dependent. In the Ru(II) system, the formation and decay of the LC state take place, respectively, in 25 ps and ca. 5 ns in CH3CN and in 0.5 ps and 1.3 micros in CH2Cl2. These solvent effects can be rationalized on the basis of a thermally activated decay of the LC state through the upper MLCT state. In the Os(II) system, the formation and decay of the MLCT state take place, respectively, in 3.8 and 60 ps in CH3CN and in 0.5 and 4 ps in CH2Cl2. These effects are consistent with the solvent sensitivity of the MLCT energy, in terms of driving force and energy-gap law arguments. The relevance of these results for the use of ladder-type aromatic bridges as potential molecular wires is discussed.

Osmium

Flash photolysis

Bimetallic strip

Dichloromethane

10.1021/ic051062z

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Citations (37)