Computer-Aided Design (CAD) of Mn(II) Complexes:  Superoxide Dismutase Mimetics with Catalytic Activity Exceeding the Native Enzyme

Abstract

New Mn(II) macrocyclic pentaamine complexes derived from the biscyclohexyl-pyridine complex, M40403 ([manganese(II)dichloro[(4R,9R,14R,19R)-3,10,13,20,26-pentaazatetracyclo[20.3.1.0.(4,9)0(14,19)]hexacosa-1(26),-22(23),24-triene]]), are described here. The complex M40403 was previously shown to be a superoxide dismutase (SOD) catalyst with rates for the catalytic dismutation of superoxide to oxygen and hydrogen peroxide at pH = 7.4 of 1.2 x 10(+7) M(-1) s(-1).(1) The use of the computer-aided design paradigm reported previously for this class of Mn(II) complexes(2,3) led to the prediction that the 2S,21S-dimethyl derivative of M40403 should possess superior catalytic SOD activity. The synthesis of this new macrocyclic Mn(II) complex, [manganese(II)dichloro[2S, 21S-dimethyl-(4R,9R,14R,19R)-3,10,13,20,26-pentaazatetracyclo[20.3.1.0.(4,9)0(14,19)]hexacosa-1(26),22(23),24-triene]], 5, was accomplished via a high yield template condensation utilizing the linear tetraamine, N,N'-Bis[(1R,2R)-[2-(amino)]cyclohexyl]-1,2-diaminoethane, 1, 2,6-diacetylpyridine, and MnCl(2) to form the macrocyclic diimine complex, 2, which then is reduced. The two other possible dimethyl diastereomers of 5 (2R,21R-dimethyl,3, and 2R,21S-dimethyl, 6) were also prepared via reduction of the diimine complex 2. Two of these complexes, 3 and 5, were characterized by X-ray structure determination confirming their absolute stereochemistry as 2R,21R-dimethyl and 2S,21S-dimethyl, respectively. The results of the MM calculations which predict that the 2S,21S-dimethyl complex, 5, should be a high activity catalyst and that the 2R,21R-dimethyl complex, 3, should have little or no catalytic activity are presented. The catalytic SOD rates for these complexes are reported for each of these complexes and a correlation with the modeling predictions is established showing that 2R,21R-complex, 3, has no measurable catalytic rate, while the 2R,21S complex, 6, is identical to M40403, and the 2S,21S- complex, 5, possesses a very fast rate at pH = 7.4 of 1.6 x 10(+9) M(-1) s(-1) exceeding that of the native mitochondrial MnSOD enzymes.

SOD-like activity of Mn(II) β-octabromo-meso-tetrakis(N-methylpyridinium-3-yl)porphyrin equals that of the enzyme itself

“…Our data show that such high thermodynamic and kinetic facilitation, which leads to an exceptionally high k cat for the O 2 •− disproportionation, can be achieved not only with an N 5 -type coordination motif, as rationalized previously for aza crown ether (cyclic polyamines) complexes [47][48][49], but also with a N 4 -type motif as in the Mn porphyrin case. Interestingly, both aza crown ethers and β-octabrominated porphyrins [12] share a common alternating "up-down-up-down" steric arrangement of the nitrogens around the Mn center, which is presumably critical for the dismutation process [47][48][49]. Thus, future work on molecules that possess appropriate geometries for efficacious catalysis is highly justifiable.…”

Superoxide Dismutase Mimics: Chemistry, Pharmacology, and Therapeutic Potential

“…Riley et al (21,204,269,277) developed Mn complexes with cyclic polyamines=tetraaza crown ethers as catalysts for O 2 ·À dismutation (Fig. 9).…”

“…9). Structural modifications led to compounds of increased activity; complexes with k cat as high as 10 9 Ms have been reported (21). The detailed kinetic study published by Maroz et al (204) found that the reaction of a transient adduct (formed with the first O 2 ·À molecule) with the second molecule of O 2 ·À is particularly dependent on the structure of the polyamine.…”

“…With our ongoing goals to improve SOD-like activity in vitro and the efficacy in vivo, we recently synthesized and characterized the b-brominated meta isomer, MnBr 8 TM-3-PyP 4þ ; with an E 1=2 of þ 468 mV versus NHE and log k cat > 8. 85, this complex has, thus far, the highest dismuting ability among metalloporphyrins (85), which approximates that of the enzyme itself (21,26,100,136,218,269,325). As observed for the para analogue, MnBr 8 TM-4-PyP 4þ , the meta isomer has Mn in its þ 2 oxidation state and, thus, has insufficient metal=ligand stability for in vivo studies.…”

Only one of a wide assortment of manganese-containing SOD mimicking compounds rescues the slow aerobic growth phenotypes of both Escherichia coli and Saccharomyces cerevisiae strains lacking superoxide dismutase enzymes

“…Euk-8 and Euk-134 were generous gifts from Dr. Susan Doctrow, Eukarion Inc., Bedford, MA. The Metaphore compounds were generously supplied by Dr. Dennis Riley, Metaphore Pharmaceuticals, Fort Lee, NJ, or synthesized as described [39]. MnTBAP (manganese tetrakis (4-benzoic acid) porphyrin) was purchased from Oxis International Inc., Portland, OR or Calbiochem, San Diego, CA.…”