Di-, tri-, and tetranuclear zinc hydroxamate complexes as structural models for the inhibition of zinc hydrolases by hydroxamic acids

Attempts to produce Zn analogues of the structural model complexes [M-2(mu-O2CR)2(O2CR)(2)(mu-H2O)(tmen)(2)] (M = Ni, Co, Mn; R = CH3, C(CH3)(3), CF3) by the reaction of a series of zinc carboxylates with N,N,N',N'-tetramethylethylenediamine (tmen), resulted in the mononuclear complexes [Zn(OAc)(2)(tmen)] (1) and [Zn(crot)(2)-(tmen)]center dot 0.5H(2)O (2) for R = CH3 and (H)(2)CH3, respectively, and the dinuclear complexes [Zn-2(mu- piv)(2)(piv)(2)(mu-H2O)(tmen)(2)] (3) and [Zn-2(mu-OAcF)(2)(OAcF)(2)(mu-H2O)(tmen)(2)] (4) for R = C(CH3)(3) and CF3, respectively. In contrast to the analogous imidazole series, i.e., [M-2(mu-O2CR)(2)(O2CR)(2)(mu-H2O)(Im)(4)] (M = Ni, Co, Mn; R = CH3, C(CH3)(3), CF3), zinc carboxylates react with imidazole to give only the mononuclear complexes [ Zn(OAc) 2(Im) 2] (5), [ Zn(crot)(2)(Im)(2)]center dot H2O (6), [Zn(piv)(2)(Im)(2)]center dot 0.5H(2)O (7), and [Zn(OAcF)(2)(Im)(2)] (8). Reaction of 1, 2, and 3 with either acetohydroxamic acid (AHA) or benzohydroxamic acid (BHA) gives the dinuclear complexes [Zn-2(O2CR)(3)(R'A)-(tmen)], where R'A = acetohydroxamate (AA) (9, 10, 11) or benzohydroxamate (BA) (13, 14, 15). In these complexes, the zinc atoms are bridged by a single hydroxamate and two carboxylates, with a capping tmen ligand on one zinc and a monodentate carboxylate bonded to the second zinc atom. This composition models closely the observed structure of the active site of the p-iodo-D-phenylalanine hydroxamic acid inhibited Aeromonas proteolytica aminopeptidase enzyme. In contrast, 4 reacts with AHA to give [ Zn2(OAcF) 3(tmen) 2(AA)] (12) with an additional tmen ligand so that both Zn atoms are 6-coordinate, whereas reaction with BHA gives the trinuclear complex [Zn-3(OAcF)(4)(tmen)(2)(BA)(2)] (16). Reactions of 3 and 4 with glutarodihydroxamic acid (GluH(2)A(2)) produce the tetranuclear complexes [Zn4(piv)(6)(tmen)(4)(GluA(2))] (18) and [Zn-4(OAcF)(6)(tmen)(4)(GluA(2))] (19).