25 years of development of Mn porphyrins-from mimics of superoxide dismutase enzymes to thiol signaling to clinical trials: The story of our life in the USA

We have developed Mn porphyrins (MnPs) initially as mimics of superoxide dismutase (SOD) enzymes based on structure-activity relationships. Several cationic Mn porphyrins, being substituted with cationic ortho N-alkyl-or alkoxyalkylpyridyl groups in meso positions of the porphyrin ring, have been identified as potential therapeutics based on their high SOD-like activity and high bioavailability. Two of those [Mn(III) meso-tetrakis(N-ethylpyridinium-2-yl)porphyrin, MnTE-2-PyP5+ (BMX-010, AEOL10113) and Mn(III) meso-tetrakis(Nn-butoxyethylpyridinium-2-yl)porphyrin, MnTnBuOE-2-PyP5+ (BMX-001)] are now in five Phase II clinical trials. Studies of ours, and those of others, contributed to the understanding of the diverse activities of these compounds. With biologically compatible potentials and four biologically accessible oxidation states, Mn porphyrins interact with numerous reactive species, both as oxidants and reductants. Among those reactions, their abilities to (catalytically) oxidize S-glutathionylate protein thiols may perhaps be their major in vivo mode of action. Via S-glutathionylation, MnPs modulate actions of signaling proteins and, in turn, cellular apoptotic and proliferative pathways. During the major part of our stay in the USA, our lives have been dedicated to Mn porphyrins. Our families and especially our son and his three babies have been our inspiration not to give up on a life often burdened with hardship. It is thus our immense pleasure to see our compounds in clinical trials. Above all, we hope that our story will inspire future researchers to persevere-women in particular.

Duke Scholars

Author Ivan Spasojevic Medicine, Medical Oncology

Author Ines Batinic-Haberle Radiation Oncology