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

Abstract

Cationic Mn(III) porphyrins (MnPs) are among the most efficacious SOD mimics. A lead MnP, BMX-001 is now in two Clinical Trials as a radioprotector of normal tissues with glioma and head&neck cancer patients. Due to the optimized catalytic properties, MnPs couple efficiently with ascorbate (Asc) thereby inflicting significant anticancer effects. The anticancer activity is due to the intratumoral H2O2 production arising from the MnP-driven catalysis of Asc oxidation. We have recently developed a new class of fluorinated MnPs. Herein we report the synthesis, characterization and redox activity of one member of a new class of fluorinated MnPs, Mn(III) meso-tetrakis(2-fluoroethylpyridinium-2-yl) por-phyrin, MnFE. It is a more potent SOD mimic (log kcat(O2•‒) = 7.91, E1/2 = +242 mV vs NHE) and more powerful catalyst for Asc oxidation (v0(Asc)ox = 543 nM s-1) than the previous lead analogs, MnTE-2-PyP5+ and BMX-001. MnFE accumulates more in tumor vs normal tissue, which is essential for the differential effects of MnP in tumor vs normal tissues. Further, MnFE does not cause dose-limiting hypotension-based acute toxicity seen with non-fluorinated MnPs. Finally, MnFE has excellent safety/toxicity profile. In combination with Asc, MnFE exerts stronger cytotoxicity to various cancer cell lines than the earlier lead MnPs. MnFE/Asc treatment significantly suppressed tumor growth in BalbC mice bearing triple negative 4T1 mammary flank tumor. Furthermore, MnFE/Asc system was also tested as an adjuvant to radiotherapy (RT) in a same tumor model. While single (MnFE, Asc, RT) and double (MnFE/Asc, MnFE/RT, Asc/RT) treatments exhibited strong anticancer effects, the triple combination (MnFE/Asc/RT) was superior in suppressing tumor growth. Our findings demonstrate that the fluorination of MnPs comprises major modification in the development of Mn porphyrin-based therapeutics. In the light of our results and the fact that Asc is already in Clinical Trials, the MnFE alone or in combination with Asc and/or RT carries outstanding therapeutic potential which warrants its clinical development.