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Redox-Active Therapeutics pp 165–212Cite as

Mn Porphyrin-Based Redox-Active Therapeutics

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Abstract

Twenty-five years of development gave rise to several lead Mn porphyrins (MnPs) that proved of remarkable efficacy in animal models and are developed towards Clinic. The one, MnTE-2-PyP5+, is already in Canadian Clinical Trials on protection of islets during transplants, while the other one, MnTnBuOE-2-PyP5+, has entered Phase I/II Clinical Trial at Duke University as a radioprotecor of normal brain with glioma patients. The Phase I/II Clinical Trial on radioprotection of salivary glands and mouth mucosa with head and neck cancer patients will start later in 2016.

MnPs were originally developed as mimics of superoxide dismutases (SOD). MnP showed efficacy in different diseases that have oxidative stress in common. Such are cancer, radiation injury, central nervous system injuries (stroke, subarachnoid hemorrhage, spinal cord injury), neurological disorders (ALS, Alzheimer’s), diabetes, and ischemia/reperfusion injuries of liver and kidney. Based on their ability to mimic kinetics and thermodynamics of the catalysis of superoxide (O2 •−) dismutation, the cationic ortho Mn(III) N-substituted pyridylporphyrins (MnPs) were identified as the most powerful mimics. Over years the general knowledge on cell biology, and in particular oxidative stress, has grown. It has been accompanied by the awareness of the ability of Mn porphyrins to interact with numerous small and large reactive species thereby affecting cellular transcription and in turn cell metabolism. The importance of the interactions of MnPs with cellular reductants, such as ascorbate and thiols, was realized early on. Yet the possible therapeutic application of such interactions became obvious only recently. Our studies provided evidence that the ability of MnPs to catalyze O2 •− dismutation parallels their ability to react with other species, such as peroxynitrite (ONOO−) and ascorbate, and correlates well with the magnitude of their therapeutic effects. MnPs couple with numerous species they encounter, acting either as prooxidant (such as oxidation of O2 •−, ascorbate, or thiols) or as antioxidant (reduction of O2 •− or ONOO−). Recently, the reactivities of SOD mimics towards different thiols (simple thiols such as glutathione and protein thiols such as p50 and p65 subunits of NF-κB) in GPx- and cysteine oxidase-fashion have been extensively studied. It appears that such actions likely predominate in vivo controlling the therapeutic effects of MnPs. Preliminary data suggest also the involvement of Nrf2 in actions of MnPs. The type and the magnitude of the actions of MnPs would ultimately depend upon their concentration, concentration of reactive species they would encounter, and their co-localization at high enough concentrations. Other classes of redox-active drugs are also addressed, yet in part only.

In order to further clarify the nature of in vivo actions of MnPs and other SOD mimics one must keep in mind that with a powerful mimic of SOD enzyme, the reduction potential of Mn site needs to be such that it facilitates equally well both steps of dismutation process, i.e., allow for the equal ability of Mn porphyrin to reduce and oxidize O2 •−. That indicates that SOD mimics, alike SOD enzymes, act as both oxidants (oxidizing O2 •− to oxygen, O2) and antioxidants (reducing O2 •− to peroxide, H2O2). If H2O2 formed during O2 •− reduction step gets removed by enzymatic systems (such as GPx, catalase and peroxiredoxins) as is the case with normal cell, SOD enzyme and its mimic function as antioxidative defense systems. However, such as frequently happens with cancer (or gravely ill cell), the H2O2 removing enzymes become dysfunctional. In turn H2O2 accumulates inside cell and SOD and its mimic cease to function as antioxidative defenses.

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Acknowledgements

Over years multiple funding mechanisms have supported development of SOD mimics; only few are listed here. IBH, AT, and IS acknowledge NIH 1R03-NS082704-01, NIH U19AI067798, DTRI, Wallace H. Coulter Foundation, BioMimetix JVLLC (USA), and NC Biotechnology BIG Award (#2016-BIG-6518). AT acknowledges mini-fellowship award from SFRBM. IS is grateful for the support of NIH Core Grant, 5-P30-CA14236-29 that enabled the synthetic and pharmacokinetic studies. IBH also acknowledges the financial help from joint Benov/Batinić-Haberle Kuwait grants (MB02/12, YM04/14 and SRUL02/13), and joint Reboucas/Batinić-Haberle Brazilian CNPq and CAPES grants. IBH and IS are consultants with BioMimetix JVLLC and hold equities in BioMimetix JVLLC. IBH, IS, and Duke University have patent rights and have licensed technologies to BioMimetix JVLLC.

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Authors and Affiliations

  1. Department of Radiation Oncology, Duke University School of Medicine, Research Drive, 281b/285 MSRB I, Box 3455, Durham, NC, 27710, USA

    Ines Batinić-Haberle & Artak Tovmasyan

  2. Department of Medicine and Duke Cancer Institute, Pharmaceutical Research Shared Resource, PK/PD Core Laboratory, Duke University School of Medicine, Duke Hospital South, 5317 Orange Zone, Trent Drive, Durham, NC, 27710, USA

    Ivan Spasojević

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  1. Ines Batinić-Haberle
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  2. Artak Tovmasyan
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  3. Ivan Spasojević
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Correspondence to Ines Batinić-Haberle .

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  1. Duke University School of Medicine, Durham, North Carolina, USA

    Ines Batinić-Haberle

  2. Universidade Federal da Paraíba, João Pessoa, Paraíba, Brazil

    Júlio S. Rebouças

  3. Duke University School of Medicine, Durham, North Carolina, USA

    Ivan Spasojević

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Batinić-Haberle, I., Tovmasyan, A., Spasojević, I. (2016). Mn Porphyrin-Based Redox-Active Therapeutics. In: Batinić-Haberle, I., Rebouças, J., Spasojević, I. (eds) Redox-Active Therapeutics. Oxidative Stress in Applied Basic Research and Clinical Practice. Springer, Cham. https://doi.org/10.1007/978-3-319-30705-3_8

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