441283-98-3Relevant academic research and scientific papers
Study of pH-dependent zinc(II)-carboxamide interactions by zinc(II)-carboxamide-appended cyclen complexes (cyclen = 1,4,7,10-tetraazacyclododecane)
Kimura, Eiichi,Gotoh, Teruhiro,Aoki, Shin,Shiro, Motoo
, p. 3239 - 3248 (2002)
To elucidate intrinsic recognition of carboxamides by zinc(II) in carbonic anhydrase (CA) (as inhibitors) and carboxypeptidase A (CPA) (as substrates), a new series of Zn2+-carboxamide-appended cyclen complexes have been synthesized and characterized (cyclen = 1,4,7,10-tetraazacyclododecane). Two types of Zn2+-carboxamide interactions have been found. In the first case represented by a zinc(II) complex of carbamoylmethyl-l,4,7,10-tetraazacyclododecane (L1), the amide oxygen binds to zinc(II) at slightly acidic pH (to form ZnL1), and the deprotonated amide N- binds to zinc(II) at alkaline pH (to form ZnH-1,L1) with pKa = 8.59 at 25°C and l = 0.1 (NaNO3), as determined by potentiometric pH titrations, infrared spectral changes, and 13C and 1H NMR titrations. The X-ray crystal structure of ZnH-1L3 (where L3 = N-(4-nitrophenyl)carbamoylmethyl cyclen, pKa = 7.01 for ZnL3 ? ZnH-1L3) proved that the zinc(II) binds to the amidate N-(Zn-N- distance of 1.974(3) A) along with the four nitrogen atoms of cyclen (average Zn-N distance 2.136 A). Crystal data: monoclinic, space group P21/n (No. 14) with a = 10.838(1) A, b = 17.210(2) A, c = 12.113(2) A, b = 107.38(1)°, V = 2156.2(5) A3, Z = 4, R = 0.042, and Rw = 0.038. These model studies provide the first chemical support that carboxamides are CA- inhibitors by occupying the active Zn2+ site both in acidic and alkaline pH to prevent the occurrence of the catalytically active Zn2+-OH- species. In the second case represented by a zinc(II) complex of 1-(N-acetyl)aminoethylcyclen, ZnL6, the pendant amide oxygen had little interaction with zinc(II) at acidic pH. At alkaline pH, the monodeprotonation yielded a zinc(II)-bound hydroxide species ZnL6(OH-) (pKa = 7.64) with the amide pendant remaining intact. The ZnL6(OH-) species showed the same nucleophilic activity as Zn2+-cyclen-OH-. The second case may mimic the Zn2+-OH- mechanism of CPA, where the nucleophilic Zn2+-OH- species does not act as a base to deprotonate a proximate amide.
