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<sub>2</sub>(μ-O<sub>2</sub>CR)<sub>2</sub>(O<sub>2</sub>CR)<sub>2</sub>(μ-H<sub>2</sub>O)(tmen)<sub>2</sub>] (M = Ni, Co, Mn; R = CH<sub>3</sub>, C(CH<sub>3</sub>)<sub>3</sub>, CF<sub>3</sub>) by the reaction of a series of zinc carboxylates with <i>N,N,N</i>‘,<i>N</i>‘-tetramethylethylenediamine (tmen), resulted in the mononuclear complexes [Zn(OAc)<sub>2</sub>(tmen)] (<b>1</b>) and [Zn(crot)<sub>2</sub>(tmen)]·0.5H<sub>2</sub>O (<b>2</b>) for R = CH<sub>3</sub> and (CH)<sub>2</sub>CH<sub>3</sub>, respectively, and the dinuclear complexes [Zn<sub>2</sub>(μ-piv)<sub>2</sub>(piv)<sub>2</sub>(μ-H<sub>2</sub>O)(tmen)<sub>2</sub>] (<b>3</b>) and [Zn<sub>2</sub>(μ-OAc<sub>F</sub>)<sub>2</sub>(OAc<sub>F</sub>)<sub>2</sub>(μ-H<sub>2</sub>O)(tmen)<sub>2</sub>] (<b>4</b>) for R = C(CH<sub>3</sub>)<sub>3</sub> and CF<sub>3</sub>, respectively. In contrast to the analogous imidazole series, i.e., [M<sub>2</sub>(μ-O<sub>2</sub>CR)<sub>2</sub>(O<sub>2</sub>CR)<sub>2</sub>(μ-H<sub>2</sub>O)(Im)<sub>4</sub>] (M = Ni, Co, Mn; R = CH<sub>3</sub>, C(CH<sub>3</sub>)<sub>3</sub>, CF<sub>3</sub>), zinc carboxylates react with imidazole to give only the mononuclear complexes [Zn(OAc)<sub>2</sub>(Im)<sub>2</sub>] (<b>5</b>), [Zn(crot)<sub>2</sub>(Im)<sub>2</sub>]·H<sub>2</sub>O (<b>6</b>), [Zn(piv)<sub>2</sub>(Im)<sub>2</sub>]·0.5H<sub>2</sub>O (<b>7</b>), and [Zn(OAc<sub>F</sub>)<sub>2</sub>(Im)<sub>2</sub>] (<b>8</b>). Reaction of <b>1</b>, <b>2</b>, and <b>3</b> with either acetohydroxamic acid (AHA) or benzohydroxamic acid (BHA) gives the dinuclear complexes [Zn<sub>2</sub>(O<sub>2</sub>CR)<sub>3</sub>(R‘A)(tmen)], where R‘A = acetohydroxamate (AA) (<b>9</b>, <b>10</b>, <b>11</b>) or benzohydroxamate (BA) (<b>13</b>, <b>14</b>, <b>15</b>). 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 <i>p</i>-iodo-d-phenylalanine hydroxamic acid inhibited <i>Aeromonas </i><i>proteolytica </i>aminopeptidase enzyme. In contrast, <b>4</b> reacts with AHA to give [Zn<sub>2</sub>(OAc<sub>F</sub>)<sub>3</sub>(tmen)<sub>2</sub>(AA)] (<b>12</b>) with an additional tmen ligand so that both Zn atoms are 6-coordinate, whereas reaction with BHA gives the trinuclear complex [Zn<sub>3</sub>(OAc<sub>F</sub>)<sub>4</sub>(tmen)<sub>2</sub>(BA)<sub>2</sub>] (<b>16</b>). Reactions of <b>3</b> and <b>4</b> with glutarodihydroxamic acid (GluH<sub>2</sub>A<sub>2</sub>) produce the tetranuclear complexes [Zn<sub>4</sub>(piv)<sub>6</sub>(tmen)<sub>4</sub>(GluA<sub>2</sub>)] (<b>18</b>) and [Zn<sub>4</sub>(OAc<sub>F</sub>)<sub>6</sub>(tmen)<sub>4</sub>(GluA<sub>2</sub>)] (<b>19</b>).