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Mn Porphyrin-Based Redox-Active Drugs: Differential Effects as Cancer Therapeutics and Protectors of Normal Tissue Against Oxidative Injury.

ABSTRACT: SIGNIFICANCE:After approximatelty three decades of research, two Mn(III) porphyrins (MnPs), MnTE-2-PyP5+ (BMX-010, AEOL10113) and MnTnBuOE-2-PyP5+ (BMX-001), have progressed to five clinical trials. In parallel, another similarly potent metal-based superoxide dismutase (SOD) mimic-Mn(II)pentaaza macrocycle, GC4419-has been tested in clinical trial on application, identical to that of MnTnBuOE-2-PyP5+-radioprotection of normal tissue in head and neck cancer patients. This clearly indicates that Mn complexes that target cellular redox environment have reached sufficient maturity for clinical applications. Recent Advances: While originally developed as SOD mimics, MnPs undergo intricate interactions with numerous redox-sensitive pathways, such as those involving nuclear factor ?B (NF-?B) and nuclear factor E2-related factor 2 (Nrf2), thereby impacting cellular transcriptional activity. An increasing amount of data support the notion that MnP/H2O2/glutathione (GSH)-driven catalysis of S-glutathionylation of protein cysteine, associated with modification of protein function, is a major action of MnPs on molecular level. CRITICAL ISSUES:Differential effects of MnPs on normal versus tumor cells/tissues, which support their translation into clinic, arise from differences in their accumulation and redox environment of such tissues. This in turn results in different yields of MnP-driven modifications of proteins. Thus far, direct evidence for such modification of NF-?B, mitogen-activated protein kinases (MAPK), phosphatases, Nrf2, and endogenous antioxidative defenses was provided in tumor, while indirect evidence shows the modification of NF-?B and Nrf2 translational activities by MnPs in normal tissue. FUTURE DIRECTIONS:Studies that simultaneously explore differential effects in same animal are lacking, while they are essential for understanding of extremely intricate interactions of metal-based drugs with complex cellular networks of normal and cancer cells/tissues.

SUBMITTER: Batinic-Haberle I

PROVIDER: S-EPMC6207162 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Mn Porphyrin-Based Redox-Active Drugs: Differential Effects as Cancer Therapeutics and Protectors of Normal Tissue Against Oxidative Injury.

Batinic-Haberle Ines I Tovmasyan Artak A Spasojevic Ivan I

Antioxidants & redox signaling 20180828 16

<h4>Significance</h4>After approximatelty three decades of research, two Mn(III) porphyrins (MnPs), MnTE-2-PyP<sup>5+</sup> (BMX-010, AEOL10113) and MnTnBuOE-2-PyP<sup>5+</sup> (BMX-001), have progressed to five clinical trials. In parallel, another similarly potent metal-based superoxide dismutase (SOD) mimic-Mn(II)pentaaza macrocycle, GC4419-has been tested in clinical trial on application, identical to that of MnTnBuOE-2-PyP<sup>5+</sup>-radioprotection of normal tissue in head and neck cance ...[more]

PMID: 29926755

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Project description:Cationic Mn porphyrins are among the most potent catalytic antioxidants and/or cellular redox modulators. Mn(III) meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin chloride (MnTE-2-PyPCl(5)) is the Mn porphyrin most studied in vivo and has successfully rescued animal models of a variety of oxidative stress-related diseases. The stability of an authentic MnTE-2-PyPCl(5) sample was investigated hereon by thermogravimetric, derivative thermogravimetric, and differential thermal analyses (TG/DTG/DTA), under dynamic air, followed by studies at selected temperatures to evaluate the decomposition path and appropriate conditions for storage and handling of these materials. All residues were analyzed by thin-layer chromatography (TLC) and UV-vis spectroscopy. Three thermal processes were observed by TG/DTG. The first event (endothermic) corresponded to dehydration, and did not alter the MnTE-2-PyPCl(5) moiety. The second event (endothermic) corresponded to the loss of EtCl (dealkylation), which was characterized by gas chromatography-mass spectrometry. The residue at 279°C had UV-vis and TLC data consistent with those of the authentic, completely dealkylated analog, MnT-2-PyPCl. The final, multi-step event corresponded to the loss of the remaining organic matter to yield Mn(3)O(4) which was characterized by IR spectroscopy. Isothermal treatment at 188°C under static air for 3h yielded a mixture of partially dealkylated MnPs and traces of the free-base, dealkylated ligand, H(2)T-2-PyP, which reveals that dealkylation is accompanied by thermal demetallation under static air conditions. Dealkylation was not observed if the sample was heated as a solid or in aqueous solution up to ?100°C. Whereas moderate heating changes sample composition by loss of H(2)O, the dehydrated sample is indistinguishable from the original sample upon dissolution in water, which indicates that catalytic activity (on Mn basis) remains unaltered. Evidently, dealkylation at high temperature compromises sample activity.

Dataset Information

Mn Porphyrin-Based Redox-Active Drugs: Differential Effects as Cancer Therapeutics and Protectors of Normal Tissue Against Oxidative Injury.

Publications

Mn Porphyrin-Based Redox-Active Drugs: Differential Effects as Cancer Therapeutics and Protectors of Normal Tissue Against Oxidative Injury.

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