Study of pH-Dependent Zinc(II)−Carboxamide Interactions by Zinc(II)−Carboxamide-Appended Cyclen Complexes (Cyclen = 1,4,7,10-Tetraazacyclododecane)

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-1,4,7,10-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-1L1) with pKa = 8.59 at 25 °C and I = 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) Å) along with the four
nitrogen atoms of cyclen (average Zn−N distance 2.136 Å). Crystal data:  monoclinic, space group P21/n (No. 14)
with a = 10.838(1) Å, b = 17.210(2) Å, c = 12.113(2) Å, b = 107.38(1)°, V = 2156.2(5) Å3, 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.