title: Challenges encountered during development of Mn porphyrin-based, potent redox-active drug and superoxide dismutase mimic, MnTnBuOE-2-PyP5+, and its alkoxyalkyl analogues.
abstract: We disclose here the studies that preceded and guided the preparation of the metal-based, redox-active therapeutic Mn(III) meso-tetrakis(N-n-butoxyethylpyridyl)porphyrin, MnTnBuOE-2-PyP5+(BMX-001), which is currently in Phase I/II Clinical Trials at Duke University (USA) as a radioprotector of normal tissues in cancer patients. N-substituted pyridylporphyrins are ligands for Mn(III) complexes that are among the most potent superoxide dismutase mimics thus far synthesized. To advance their design, thereby improving their physical and chemical properties and bioavailability/toxicity profiles, we undertook a systematic study on placing oxygen atoms into N-alkylpyridyl chains via alkoxyalkylation reaction. For the first time we show here the unforeseen structural rearrangement that happens during the alkoxyalkylation reaction by the corresponding tosylates. Comprehensive experimental and computational approaches were employed to solve the rearrangement mechanism involved in quaternization of pyridyl nitrogens, which, instead of a single product, led to a variety of mixed N-alkoxyalkylated and N-alkylated pyridylporphyrins. The rearrangement mechanism involves the formation of an intermediate alkyl oxonium cation in a chain-length-dependent manner, which subsequently drives differential kinetics and thermodynamics of competing N-alkoxyalkylation versus in situ N-alkylation. The use of alkoxyalkyl tosylates, of different length of alkyl fragments adjacent to oxygen atom, allowed us to identify the set of alkyl fragments that would result in the synthesis of a single compound of high purity and excellent therapeutic potential.
authors.affiliation: Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Zrinka
authors.initials: Z
authors.lastname: Rajic
authors.affiliation: Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Artak
authors.initials: A
authors.lastname: Tovmasyan
authors.affiliation: Departamento de Química, CCEN, Universidade Federal da Paraiba, João Pessoa, PB 58051-900, Brazil.
authors.forename: Otávio L
authors.initials: OL
authors.lastname: de Santana
authors.affiliation: Departamento de Química, CCEN, Universidade Federal da Paraiba, João Pessoa, PB 58051-900, Brazil.
authors.forename: Isabelle N
authors.initials: IN
authors.lastname: Peixoto
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA; Duke Cancer Institute, Pharmaceutical Research Shared Resource, PK/PD Core Laboratory, Durham, NC 27710, United States.
authors.forename: Ivan
authors.initials: I
authors.lastname: Spasojevic
authors.affiliation: Departamento de Química, CCEN, Universidade Federal da Paraiba, João Pessoa, PB 58051-900, Brazil.
authors.forename: Silmar A
authors.initials: SA
authors.lastname: do Monte
authors.affiliation: Departamento de Química, CCEN, Universidade Federal da Paraiba, João Pessoa, PB 58051-900, Brazil.
authors.forename: Elizete
authors.initials: E
authors.lastname: Ventura
authors.affiliation: Departamento de Química, CCEN, Universidade Federal da Paraiba, João Pessoa, PB 58051-900, Brazil. Electronic address: jsreboucas2@gmail.com.
authors.forename: Júlio S
authors.initials: JS
authors.lastname: Rebouças
authors.affiliation: Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710, USA. Electronic address: ibatinic@duke.edu.
authors.forename: Ines
authors.initials: I
authors.lastname: Batinic-Haberle
mesh_terms: D032701:Biomimetics; D008345:Manganese / Q000737:chemistry*; D008665:Metalloporphyrins / Q000737:chemistry*; D008958:Models, Molecular; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D011166:Porphyrins / Q000737:chemistry*; D013482:Superoxide Dismutase / Q000737:chemistry*
chemical_list: D008665:Metalloporphyrins; C575143:Mn(III) meso-tetrakis(N-n-butoxyethylpyridinium-2-yl)porphyrin; D011166:Porphyrins; D008345:Manganese; D013482:Superoxide Dismutase
keywords: Alkoxyalkyl tosylates; FP-15; Mechanism of pyridyl nitrogen quaternization; Mn N-alkoxyalkylpyridylporphyrins; MnTTEG-2-PyP(5+); MnTnBuOE-2-PyP(5+) (BMX-001); SOD mimics