ORGANIC
LETTERS
1999
Vol. 1, No. 2
187-188
A Caged Hydrophobic Inhibitor of
Carbonic Anhydrase II
Polina D. Kehayova, Gregory E. Bokinsky, John D. Huber, and Ahamindra Jain*
Department of Chemistry, Swarthmore College, Swarthmore, PennsylVania 19081-1397
Received March 16, 1999
ABSTRACT
A tight-binding, hydrophobic inhibitor of carbonic anhydrase II has been masked with a water-solubilizing, photolabile group derived from
o-nitrophenylglycine. This caged inhibitor represents our first effort at the site-specific delivery of prodrugs that can be activated by light. Via
this approach, we have begun to address the problems of water insolubility and systemic side effects on administration of tight-binding
inhibitors of carbonic anhydrase.
The design of effective, useful pharmaceuticals requires
consideration of both the means by which a drug will be
delivered to its physiological target and the interactions that
will enable it to bind tightly to that receptor. The aqueous
medium in which many drug targets are found poses a
particularly challenging problem. To be delivered directly
to a receptor in water, a drug should be water-soluble.
Molecular recognition in water, however, is enhanced by
hydrophobic contacts between greasy, non-water-soluble
inhibitors and nonpolar surfaces of proteins.1,2 We have
modified a hydrophobic inhibitor of carbonic anhydrase II
(CA) with a polar caging group, which will (1) increase the
water solubility of this drug and (2) be removed by exposure
to light of an appropriate wavelength to reveal the active,
tight-binding hydrophobic inhibitor in situ. By this approach,
we intend to achieve site-specific delivery and activation of
a carbonic anhydrase inhibitor (CAI), without having to
sacrifice the tight binding that is afforded by hydrophobic
drugs.
candidates are water-insoluble.4 These drugs all contain a
primary sulfonamide group, which is essential for binding
to CA.5 By protecting this functional group with a water-
soluble, photolabile moiety, one solves the problem of
aqueous delivery of a tight-binding, hydrophobic drug and
addresses the issue of site-specific activation. The caging
group that we have prepared should be applicable in any
system where a significant component of molecular recogni-
tion involves hydrophobic contacts.1 o-Nitrophenylglycine
(NPG) derivatives are an ideal choice for this photolabile
group, since their photochemistry has been systematically
characterized6 and because these linkers have found applica-
tions in several biochemical systems.6-10 We also find NPG
attractive because this group bears a carboxylate moiety,
(3) Baldwin, J. J.; Ponticello, G. S.; Anderson, P. S.; Christy, M. E.;
Murcko, M. A.; Randall, W. C.; Schwam, H.; Sugrue, M. F.; Springer, J.
P.; Gautheron, P.; Grove, J.; Mallorga, P.; Viader, M.-P.; McKeever, B.
M.; Navia, M. A. J. Med. Chem. 1989, 32, 2510-2513.
(4) Ponticello, G. S.; Freedman, M. B.; Habecker, C. N.; Lyle, P. A.;
Schwam, H.; Varga, S. L.; Christy, M. E.; Randall, W. C.; Baldwin, J. J.
J. Med. Chem. 1987, 30, 491-497.
CA is the target of several successful drugs developed by
Merck for the treatment of high intraocular pressure associ-
ated with glaucoma.3,4 The preferred mode of delivery of
glaucoma medications is as aqueous drops, but the best drug
(5) King, R. W.; Burgen, A. S. V. Proc. R. Soc. London, Ser. B 1976,
193, 107-125.
(6) Holmes, C. P. J. Org. Chem. 1997, 62, 2370-2380.
(7) Niu, L.; Wieboldt, R.; Ramesh, D.; Carpenter, B. K.; Hess, G. P.
Biochemistry 1996, 35, 8136-8142.
(8) Chang, C.-Y.; Niblack, B.; Walker, B.; Bayley, H. Chem. Biol. 1995,
2, 391-400.
(1) Jain, A.; Alexander, R. W.; Christianson, D. C.; Whitesides, G. M.
J. Med. Chem. 1994, 37, 2100-2105.
(2) Gao, J.; Qiao, S.; Whitesides, G. M. J. Med. Chem. 1995, 38, 2292-
2301.
(9) Brubaker, M. J.; Dyer, D. H.; Stoddard, B.; Koshland, D. E., Jr.
Biochemistry 1996, 35, 2854-2864.
(10) England, P. M.; Lester, H. A.; Davidson, N.; Dougherty, D. A. Proc.
Natl. Acad. Sci. U.S.A. 1997, 94, 11025-11030.
10.1021/ol990526s CCC: $18.00 © 1999 American Chemical Society
Published on Web 06/04/1999