A bidentate terephthalamide ligand, TAMmeg, as an entry into terephthalamide-containing therapeutic iron chelating agents

A new bidentate 2,3-dihydroxyterephthalamide ligand, 2,3-dihydroxy-N,N'-bis(2-methoxyethyl)terephthalamide (TAMmeg), has been prepared. The ligand, its synthetic precursor 2,3-bis(benzyloxy)-N,N'-bis(2-methoxy-ethyl)terephthalamide (BnTAMmeg), and its iron complex have been structurally characterized by X-ray diffraction. BnTAMmeg crystallizes in the monoclinic space group P2(1)/n with cell parameters a = 14.4976(14) angstrom, b = 11.5569(11) angstrom, c = 16.3905(16) angstrom, beta = 113.621 (1)degrees, and Z = 4. TAMmeg crystallizes in the monoclinic space group P2(1)/c with cell parameters a = 13.8060(36) angstrom, b = 8.0049(21) angstrom, c = 19.4346(50) angstrom, beta = 106.855(4)degrees, and Z = 4. Fe[TAMmeg] crystallizes in the triclinic space group P (1) over bar with cell parameters a = 12.9565(14) angstrom, b = 13.4514(14) angstrom, c = 20.2092(21) angstrom, alpha = 102.093(2)degrees, beta = 95.433(2)degrees, gamma = 101.532(2)degrees, and Z = 2. The aqueous protonation and ferric ion coordination chemistry of TAMmeg were examined using potentiometric and spectrophotometric methods. Proton association constants and iron complex formation constants for the ligand are as follows: log beta(011) = 10.32, log beta(012) = 16.49, log beta(110) = 17.9, log beta(120) = 32.1, and 109 beta(130) = 43.0. The ferric complex of TAMmeg is surprisingly stable for a bidentate terephthalamide iron complex. The only more-stable bidentate terephthalamide iron complex that has been reported contains a ligand with positively charged pendant arms.