Texaphyrins: Tumor Localizing Redox Active Expanded Porphyrins

Arambula, Jonathan F.; Preihs, Christian; Borthwick, Derric; Magda, Darren; Sessler, Jonathan L.

doi:10.2174/187152011795255894

Cited by 29 publications

(20 citation statements)

References 71 publications

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“…Peroxynitrite is a strong oxidant and can oxidize even those metalloporphyrins whose metal center is not very electron-deficient and thus not eager to bind electron-donating ligands such as ONOO − . The role of this and other anionic and neutral porphyrins, as well as modified porphyrins (corroles and texaphyrins [see review in ref 18,98,99]) with respect to peroxynitrite scavenging, may require further thermodynamic and kinetic considerations. Aside from ONOO − - related reactivity, their differential accumulation in tissues and subcellular compartments is critical to their actions and must be accounted for.…”

Section: Mn Porphyrins and Reactive Oxygen And Nitrogen Speciesmentioning

confidence: 99%

Diverse functions of cationic Mn(III) N-substituted pyridylporphyrins, recognized as SOD mimics

Batinić‐Haberle

Rajić

Tovmasyan

et al. 2011

Free Radical Biology and Medicine

130

201

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Oxidative stress, a redox imbalance between the endogenous reactive species and antioxidant systems, is common to numerous pathological conditions such as cancer, central nervous system injuries, radiation injury, diabetes etc. Therefore, compounds able to reduce oxidative stress have been actively sought for over 3 decades. Superoxide is the major species involved in oxidative stress either in its own right or through its progeny, such as ONOO−, H2O2, ·OH, CO3·−, and ·NO2. Therefore, the very first compounds developed in the late 1970-ies were the superoxide dismutase (SOD) mimics. Thus far the most potent mimics have been the cationic meso Mn(III) N-substituted pyridylporphyrins and N,N′-disubstituted imidazolylporphyrins (MnPs), some of them with kcat(O2·−) similar to the kcat of SOD enzymes. Most frequently studied are ortho isomers MnTE-2-PyP5+, MnTnHex-2-PyP5+, and MnTDE-2-ImP5+. The ability to disproportionate O2·− parallels their ability to remove the other major oxidizing species, peroxynitrite, ONOO−. The same structural feature that gives rise to the high kcat (O2·−) and kred (ONOO−), allows MnPs to strongly impact the activation of the redox-sensitive transcription factors, HIF-1α, NF-κB, AP-1, and SP-1, and therefore modify the excessive inflammatory and immune responses. Coupling with cellular reductants and other redox-active endogenous proteins seems to be involved in the actions of Mn porphyrins. While hydrophilic analogues, such as MnTE-2-PyP5+ and MnTDE-2-ImP5+ are potent in numerous animal models of diseases, the lipophilic analogues were developed to cross blood brain barrier and target central nervous system and critical cellular compartment, mitochondria. The modification of its structure, aimed to preserve the SOD-like potency and lipophilicity, and diminish the toxicity, has presently been pursued. The pulmonary radioprotection by MnTnHex-2-PyP5+ was the first efficacy study performed successfully with non-human primates. The Phase I toxicity clinical trials were done on amyotrophic lateral sclerosis patients with N,N′-diethylimidazolium analogue, MnTDE-2-ImP5+ (AEOL10150). Its aggressive development as a wide spectrum radioprotector by Aeolus Pharmaceuticals has been supported by USA Federal government. The latest generation of compounds, bearing oxygens in pyridyl substituents is presently under aggressive development for cancer and CNS injuries at Duke University and is supported by Duke Translational Research Institute, The Wallace H. Coulter Translational Partners Grant Program, Preston Robert Tisch Brain Tumor Center at Duke, and National Institute of Allergy and Infectious Diseases. Metal center of cationic manganese porphyrins easily accepts and donates electrons as exemplified in the catalysis of O2·− dismutation. Thus such compounds may be equally good anti- and pro-oxidants; in either case the beneficial therapeutic effects may be observed. Moreover, while the in vivo effects may appear antioxidative, the mechanism of action of MnPs that produced such effects may be pro-oxidat...

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Section: Mn Porphyrins and Reactive Oxygen And Nitrogen Speciesmentioning

confidence: 99%

Diverse functions of cationic Mn(III) N-substituted pyridylporphyrins, recognized as SOD mimics

Batinić‐Haberle

Rajić

Tovmasyan

et al. 2011

Free Radical Biology and Medicine

130

201

View full text Add to dashboard Cite

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“…Due to the abundance of oxygen relative to the levels of other species, Mn II P may prefer reducing O 2 to O 2 – · which will eventually dismute to H 2 O 2 . The normal cell has the abundance of peroxide-removing enzymes, thus the contribution of Fenton chemistry leading to a deleterious – OH radical may be negligible [203,204,205,206,207,208,209,210,211]. Cancer cells are frequently deprived of H 2 O 2 -removing enzymes, thus excessive amounts of peroxide will be formed.…”

Section: Figmentioning

confidence: 99%

Design, Mechanism of Action, Bioavailability and Therapeutic Effects of Mn Porphyrin-Based Redox Modulators

Sheng²,

et al. 2012

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Based on aqueous redox chemistry and simple in vivo models of oxidative stress, Escherichia coli and Saccharomyces cerevisiae, the cationic Mn(III) N-substituted pyridylporphyrins (MnPs) have been identified as the most potent cellular redox modulators within the porphyrin class of drugs; their efficacy in animal models of diseases that have oxidative stress in common is based on their high ability to catalytically remove superoxide, peroxynitrite, carbonate anion radical, hypochlorite, nitric oxide, lipid peroxyl and alkoxyl radicals, thus suppressing the primary oxidative event. While doing so MnPs could couple with cellular reductants and redox-active proteins. Reactive species are widely accepted as regulators of cellular transcriptional activity: minute, nanomolar levels are essential for normal cell function, while submicromolar or micromolar levels impose oxidative stress, which is evidenced in increased inflammatory and immune responses. By removing reactive species, MnPs affect redox-based cellular transcriptional activity and consequently secondary oxidative stress, and in turn inflammatory processes. The equal ability to reduce and oxidize superoxide during the dismutation process and recently accumulated results suggest that pro-oxidative actions of MnPs may also contribute to their therapeutic effects. All our data identify the superoxide dismutase-like activity, estimated by log k_cat(O₂^–), as a good measure for the therapeutic efficacy of MnPs. Their accumulation in mitochondria and their ability to cross the blood-brain barrier contribute to their remarkable efficacy. We summarize herein the therapeutic effects of MnPs in cancer, central nervous system injuries, diabetes, their radioprotective action and potential for imaging. Few of the most potent modulators of cellular redox-based pathways, MnTE2-PyP⁵⁺, MnTDE-2-ImP⁵⁺, MnTnHex-2-PyP⁵⁺ and MnTnBuOE-2-PyP⁵⁺, are under preclinical and clinical development.

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“…Over the last 20 years, more than 1,200 types of porphyrin derivatives have been synthesized. Modifications of their structures, affinities for tumor tissues, and mechanisms of action have been studied with the ultimate goal to develop them for use in cancer diagnosis and treatment [8–15]. The mechanism of photodynamic therapy is a pro-oxidative one, where killing occurs via enhanced production of reactive species.…”

Section: Introductionmentioning

confidence: 99%

Cellular Redox Modulator, ortho Mn(III) meso-tetrakis(N-n-Hexylpyridinium-2-yl)porphyrin, MnTnHex-2-PyP5+ in the Treatment of Brain Tumors

Keir¹,

Dewhirst²,

Kirkpatrick³

et al. 2011

ACAMC

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Despite intensive efforts to improve multimodal treatment of brain tumors, survival remains limited. Current therapy consists of a combination of surgery, irradiation and chemotherapy with predisposition to long-term complications. Identifying novel targeted therapies is therefore at the forefront of brain tumor research. This study explores the utility of a manganese porphyrin in a brain tumor model. The compound used is ortho isomer, manganese(III) meso-tetrakis(N-n-hexylpyridinium-2-yl)porphyrin, MnTnHex-2-PyP5+. It is a powerful SOD mimic and peroxynitrite scavenger and a potent modulator of redox-based cellular transcriptional activity, able to suppress excessive immune and inflammatory responses and in turn proliferative pathways. It is further one of the most lipophilic compounds among cationic Mn(III) N-alkylpyridylporphyrins, and thus accumulates predominantly in mitochondria relative to cytosol. In mitochondria, MnTnHex-2-PyP5+ could mimic our key antioxidant system, mitochondrial superoxide dismutase, MnSOD, whose overexpression has been widely shown to suppress tumor growth. Importantly, MnTnHex-2-PyP5+ crosses blood brain barrier in sufficient amounts to demonstrate efficacy in treating CNS injuries. For those reasons we elected to test its effects in inhibiting brain tumor growth. This study is the first report of the antitumor properties of MnTnHex-2-PyP5+ as a single agent in adult and pediatric glioblastoma multiforme (D-54 MG, D-245 MG, D-256 MG, D-456 MG) and pediatric medulloblastoma (D-341 MED), and is the first case where a redox-able metal complex has been used in glioma therapy. When given subcutaneously to mice bearing subcutaneous and intracranial xenografts, MnTnHex-2-PyP5+ caused a significant (P ≤ 0.001) growth delay in D-245 MG, D-256 MG, D-341 MED, and D-456 MG tumors. Growth delay for mice bearing subcutaneous xenografts ranged from 3 days in D-54 MG to 34 days in D-341 MED. With mice bearing intracranial xenografts, MnTnHex-2-PyP5+ increases median survival by 33% in adult glioblastoma multiforme (D-256 MG; P ≤ 0.001) and 173% in pediatric medulloblastoma (D-341 MED, ≤0.001). The beneficial effects of MnTnHex-2-PyP5+ are presumably achieved either (1) indirectly via elimination of signaling reactive oxygen and nitrogen species (in particular superoxide and peroxynitrite) which in turn would prevent activation of transcription factors; or (2) directly by coupling with cellular reductants and redox-sensitive signaling proteins. The former action is antioxidative while the latter action is presumably pro-oxidative in nature. Our findings suggest that the use of Mn porphyrin-based SOD mimics, and in particular lipophilic analogues such as MnTnHex-2-PyP5+, is a promising approach for brain tumor therapy.

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Texaphyrins: Tumor Localizing Redox Active Expanded Porphyrins

Cited by 29 publications

References 71 publications

Diverse functions of cationic Mn(III) N-substituted pyridylporphyrins, recognized as SOD mimics

Diverse functions of cationic Mn(III) N-substituted pyridylporphyrins, recognized as SOD mimics

Design, Mechanism of Action, Bioavailability and Therapeutic Effects of Mn Porphyrin-Based Redox Modulators

Cellular Redox Modulator, ortho Mn(III) meso-tetrakis(N-n-Hexylpyridinium-2-yl)porphyrin, MnTnHex-2-PyP5+ in the Treatment of Brain Tumors

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