Computer-aided design (CAD) of Mn(II) complexes: Superoxide dismutase mimetics with catalytic activity exceeding the native enzyme

New Mn(II) macrocyclic pentaamine complexes derived from the biscyclohexyl- pyridine complex, M40403 ([manganese(II)dichloro{(4R,9R,14R,19R)-3,20,26-pe ntaazatetracyclo[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 super oxide 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 act ivity. The synthesis of this new macrocyclic Mn(II) complex, [manganese(II) dichloro{2S, 21S-dimethyl-(4R,9R,14R,19R)-3,10,13,20,26-pentaazatetracylo[2 0.3.1.0.(4.9)0(14,19)]hexacosa- 1(26),22(23),24-triene}], 5, was accomplish ed via a high yield template condensation utilizing the linear tetraamine, N,N'-Bis-{(1R12R)-[2-(amino)]cyclohexyl}-1,2-diaminoethane, 1, 2,6-diacetyl pyridine, and MnCl2 to form the macrocyclic diimine complex, 2, which then is reduced. The two other possible dimethyl diastereomers of 5 (2R,21R-dime thyl, 3. and 2R,21S-dimethyl, 6) were also prepared via reduction of the di imine complex 2. Two of these complexes, 3 and 5, were characterized by X-r ay structure determination confirming their absolute stereochemistry as 2R, 21S-dimethyl and 2S,21S-dimethyl, respectively. The results of the MM calcu lations 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 lit tle or no catalytic activity are presented. The catalytic SOD rates for the se complexes are reported for each of these complexes and a correlation wit h the modeling predictions is established showing that 2R,21R-complex, 3, h as 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 MnS OD enzymes.