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 [M2(mu-O2CR)2(O2CR)2(mu-H2O)(tmen)2] (M = Ni, Co, Mn; R = CH(3), 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)].(0.5)H2O (2) for R = CH3 and (CH)2CH3, respectively, and the dinuclear complexes [Zn(2)(mu-piv)(2)(piv)(2)(mu-H2O)(tmen)2] (3) and [Zn2(mu-OAc(F))2(OAc(F))2(mu-H2O)(tmen)2] (4) for R = C(CH3)3 and CF3, respectively. In contrast to the analogous imidazole series, i.e., [M2(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].H2O (6), [Zn(piv)2(Im)2].(0.5)H2O (7), and [Zn(OAc(F))2(Im)2] (8). Reaction of 1, 2, and 3 with either acetohydroxamic acid (AHA) or benzohydroxamic acid (BHA) gives the dinuclear complexes [Zn2(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 proteolyticaaminopeptidase enzyme. In contrast, 4 reacts with AHA to give [Zn2(OAc(F))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 [Zn3(OAc(F))4(tmen)2(BA)2] (16). Reactions of 3 and 4 with glutarodihydroxamic acid (GluH2A2) produce the tetranuclear complexes [Zn4(piv)6(tmen)4(GluA2)] (18) and [Zn4(OAc(F))6(tmen)4(GluA2)] (19).
Brown
David A
DA
School of Chemistry and Chemical Biology, Centre for Synthesis and Chemical Biology, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland.
Fitzpatrick
Noel J
NJ
Müller-Bunz
Helge
H
Ryan
Aine T
AT
D000333:Aeromonas / Q000737:chemistry; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006859:Hydrogen / Q000737:chemistry; D006867:Hydrolases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007093:Imidazoles / Q000737:chemistry; D008958:Models, Molecular; D008961:Models, Structural; D009942:Organometallic Compounds / Q000138:chemical synthesis* / Q000494:pharmacology*; D011084:Polycyclic Aromatic Hydrocarbons / Q000737:chemistry; D013055:Spectrophotometry, Infrared; D015032:Zinc / Q000737:chemistry*
D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D007093:Imidazoles; D009942:Organometallic Compounds; D011084:Polycyclic Aromatic Hydrocarbons; D006859:Hydrogen; D006867:Hydrolases; D015032:Zinc