Novel fluorinated Mn porphyrin as a powerful SOD mimic and catalyst for ascorbate-coupled anticancer therapy

H2O2‐Driven Anticancer Activity of Mn Porphyrins and the Underlying Molecular Pathways

“…Such strategy gave rise to Mn(III) meso-tetrakis(N-trifluoropentylpyridinium-2yl)porphyrin MnTF 3 Pen-2-PyP 5+ (BMX-003). As anticipated, both compounds have increased lipophilicity and reduced toxicity relative to nonfluorinated analogs as assessed in an E. coli assay [23,24]. Another example of the reduced toxicity relates to the blood pressure drop, which imposes a limitation to the dosing of MnPs.…”

“…Aqueous chemistry data suggest improved safety/toxicity and efficacy profiles of fluorinated vs. nonfluorinated analogs. Initial studies confirmed their potency in radioprotecting normal tissue and radio-and chemosensitizing the 4T1 mouse breast cancer cell line in cellular and animal models [23,24]. Below each of the structures, the metal-centered reduction potential for the Mn(III)/Mn(II) redox couple and log k cat ðO 2…”

“…Also, MnTF 3 Pen-2-PyP 5+ /ascorbate proved efficacious in the radioprotection of prostate and erectile function. Their efficacy is comparable to the efficacy of earlier analogs, which warrants their progression to the clinic [23,24].…”

“…We have most frequently utilized a 4T1, triple negative, metastatic mouse breast cancer cell line for therapeutic and mechanistic purposes in cellular studies and in the immunocompetent balb/c mouse. We have tested a variety of Mn porphyrins (MnTE-2-PyP 5+ , MnTnHex-2-PyP 5+ , MnTnBuOE-2-PyP 5+ , MnTFE-2-PyP 5+ , and MnTF 3 Pen-2-PyP 5+ ), in combination with ascorbate and radiation (RT), on the impact of their different redox and bioavailability properties on anticancer efficacies [4,12,23,43]. The chemistry behind such efficacies is elaborated under "Reactivity of Mn Porphyrins towards Protein Cysteines -Thiol Signaling," and briefly summarized below.…”

Thiol regulation by Mn porphyrins, commonly known as SOD mimics

“…We recently modified Mn porphyrins by introducing fluorine atoms instead of hydrogen atoms into the alkyl chains. Two molecules, monofluorinated ethyl-, MnTFE-2-PyP 5+ , and the trifluorinated pentyl analog, MnTF 3 Pen-2-PyP 5+ , have been fully characterized and tested as radioprotectors and tumor radiosensitizers [18]. In efficacy studies where MnP analogs have been compared, those compounds that are the best performers with regards to all reactions thus far studied are exhibiting the best therapeutic potential in preclinical models [8], [19], [20].…”