ORGANIC
LETTERS
2004
Vol. 6, No. 9
1353-1356
Remote Substituents Influence Both the
Thermodynamics and Kinetics of Zinc
Binding to Tris-pyridyl Methanol
Derivatives
Jiachang Gong and Bruce C. Gibb*
Department of Chemistry, UniVersity of New Orleans, New Orleans, Louisiana 70148
Received January 26, 2004
ABSTRACT
Three families of tris-pyridyl methanol ligands were synthesized. An analysis of the Zn2+ binding properties of the ligands revealed that both
steric and electronic properties of the pyridine substituents, as well as the nature of the group on the tertiary alcohol oxygen, control the
thermodynamics and kinetics of complex formation.
Our current knowledge of the carbonic anhydrase (CA)
family of enzymes derives from studies of the enzymes
themselves,1 complementary computational investigations,2-4
and the synthesis and analysis of ligands designed to mimic
the essential H2O-Zn(His)3 active site.5-7 On paper, tris-
ligands possessing sp2 nitrogen donors6,8-14 represent the
ideal type of mimic. However, as a result of a highly Lewis
acidic zinc ion in the corresponding [ZnL]2+ complex, they
frequently suffer from an inherent problem not observed in
sp3-hybridized aza-ligands.7 Thus, the initially formed [ZnL]2+
complex undergoes further reaction to form the thermo-
dynamically more stable [ZnL2]2+ complex or hydroxy-
bridged dimers.6,8-16 Without a zinc-bound hydroxide, these
complexes cannot act as CA mimics. To circumnavigate this
problem, steric barriers around the metal center have been
introduced to many ligands. However, in addition to inhibit-
ing these deleterious processes, such barriers can also inhibit
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10.1021/ol0498491 CCC: $27.50 © 2004 American Chemical Society
Published on Web 04/02/2004