A Caged Hydrophobic Inhibitor of Carbonic Anhydrase II

Abstract

[formula: see text] 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.

Carbonic anhydrase inhibitors

“…Three of these compounds, 140-142 showed nanomolar affinity to hCA II, and the X-ray structure has also been resolved for two such adducts. 124 Jain's group 125 on the other hand reported a caged hydrophobic CAI of type 143, possessing a photolabile group derived from onitrophenylglycine. It is stated that such compounds might be useful for the site-specific delivery of prodrugs, for instance to the eye, but the high energy UV radiation needed to liberate the active inhibitor ( p-H 2 NO 2 S-C 6 H 4 CONHCH 2 C 6 F 5 ) would probably do more harm than good to the eye tissues.…”

“…It is stated that such compounds might be useful for the site-specific delivery of prodrugs, for instance to the eye, but the high energy UV radiation needed to liberate the active inhibitor ( p-H 2 NO 2 S-C 6 H 4 CONHCH 2 C 6 F 5 ) would probably do more harm than good to the eye tissues. 125 Sulfonamides incorporating 2-carboxy-benzenecarboxamido (phthaloyl) moieties in their molecules, of types 144, were prepared by reaction of phthalic anhydride with aromatic/heterocyclic sulfonamides A-T under mild conditions, whereas a closely related series of derivatives was prepared by reaction of the same reagents under more energetic conditions, when the corresponding phthalimides 145 were obtained. Some of these compounds showed very good in vitro CA isozymes I, II, and IV inhibitory properties, with affinities for the enzymes in the low nanomolar range for the best inhibitors.…”

A Model for Light‐Triggered Porphyrin Anticancer Prodrugs Based on an o‐Nitrobenzyl Photolabile Group

“…[12][13][14][15][16][17][18][19][20][21][22] rivatives for biomedical release applications, [15] Reinhard developed a series of o-nitrobenzyl-based photosensitive phosphoramide mustards, [16] Gong exploited a model of a photoactivated prodrug, [17] and Kehayova synthesized a caged hydrophobic inhibitor of carbonic anhydrase II. [18] Very recently, the group of McCoy provided an interesting example of drug dosing with precise control by photolysis of light-triggered compounds with the use of UV light. [19] The major concern of the application of a photochemical system in medicine is the tissue-damaging effect of UV light.…”

Phototriggered delivery of hydrophobic carbonic anhydrase inhibitors

“…1-3 Such properties have included acid-sensitivity 4 and susceptibility to enzymatic or antibody-directed processing, 2,3,5, 6 and solubility. 7 Biocompatibility 8 is also an important consideration in the design of a prodrug to resolve problems of solubility 7 and permeability. 1 Drugs that bind tightly to enzyme targets are often hydrophobic.…”

“…10 We increased the solubility of F 5 ؒCAI by modifying it with o-nitrodimethoxyphenylglycine (o-NDMPG) (Scheme 1). 7 This photolabile synthetic amino acid bears a carboxylate moiety, affording a polar cage at physiological pH.…”