Ординатура / Офтальмология / Английские материалы / Carbonic Anhydrase Its Inhibitors and Activators_Supuran, Scozzafava, Conway_2004

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ethoxzolamide and dichlorophenamide. The discovery of these drugs greatly benefited the chemistry of sulfonamides, as thousands of derivatives belonging to the heterocyclic, aromatic and bis-sulfonamide classes have been synthesized and investigated for their biological activity. In the late 1980s and early 1990s, the topically effective antiglaucoma CAIs were discovered, and two such drugs — dorzolamide and brinzolamide — are at present used clinically. Both have been designed by the ring approach, i.e., by investigating a very large number of ring systems incorporating sulfamoyl moieties. More recently, the tail approach has been reported for designing antiglaucoma CAIs with topical activity, but this approach can be extended for other applications of these pharmacological agents. It consists of attaching tails that induce the desired physicochemical properties to aromatic/heterocyclic sulfonamide scaffolds that possess derivatizable amino or hydroxy moieties. There has been progress in the discovery of inhibitors with higher affinity for a certain isozyme, although clear-cut isozyme-specific inhibitors are not available at present. Inhibitors selective for the membrane-associated (CAs IV, IX, XII and XIV) or the cytosolic isozymes are available, being either macromolecular compounds or the positively charged derivatives (of low molecular weight). CAIs possessing antitumor properties have also been discovered, with one such derivative — indisulam — in advanced clinical trials for treating solid tumors. CAIs with good anticonvulsant activity and several other biomedical applications have recently been reported. Some aliphatic sulfonamides show significant CA inhibitory properties, and compounds that possess zincbinding functions different from that of the classical one (of aromatic/heterocyclic sulfonamide type) have been reported, incorporating, among others, sulfamate, sulfamide and hydroxamate moieties. The field is in constant progress and can lead to the discovery of interesting pharmacological agents.

4.1 INTRODUCTION

The discovery of CA inhibition with sulfanilamide 4.1 by Mann and Keilin (1940) was the beginning of a great adventure that led to important drugs widely used to treat or prevent a multitude of diseases. Sulfonamides constitute an important class of drugs, with several types of pharmacological agents possessing, among others, antibacterial, antitumor, anticarbonic anhydrase (CA), diuretic, hypoglycemic, antithyroid or protease inhibitory activity (Northey 1948; Maren 1967; Scozzafava et al. 2003; Supuran et al. 2003; Owa and Nagasu 2000). The very simple sulfanilamide 4.1 lead molecule afforded the development of all these types of pharmacological agents that have a wide variety of biological actions, as exemplified later for the antibacterial agent sulfathiazole, the carbonic anhydrase inhibitor acetazolamide (clinically used for more than 45 years; Maren 1967), the widely used diuretic furosemide, the hypoglycemic agent glibenclamide, the anticancer sulfonamide indisulam (in advanced clinical trials), the aspartic HIV protease inhibitor amprenavir used to treat AIDS and HIV infection and the metalloprotease (MMP) inhibitors of the sulfonyl amino acid hydroxamate type (Scozzafava et al. 2003; Supuran et al. 2003; Supuran 2003; Supuran and Scozzafava 2000a, 2001, 2002a, 2002b; Figure 4.1).

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FIGURE 4.1 The main classes of pharmacolological agents developed from sulfanilamide

4.1as lead molecule: antibacterials (such as sulfathiazole); carbonic anhydrase inhibitors (such as acetazolamide); diuretics (such as furosemide); hypoglycaemic agents (such as glibenclamide); anticancer agents (such as indisulam); anti-AIDS agents (such as the HIV protease inhibitor amprenavir) as well as MMP inhibitors.

4.2CLASSICAL INHIBITORS

4.2.1 AROMATIC SULFONAMIDES

After the report of Mann and Keilin (1940) that sulfanilamide 4.1 acts as a potent and specific CA inhibitor (CAI), Krebs (1948) in a classical study showed that only unsubstituted sulfonamides of the type R-SO2NH2 act as strong inhibitors, the potency of the drug being drastically affected by N-substitution at the sulfonamide moiety. Among the active structures found by Krebs were also the azodyes 4.2 and 4.3.

Many sulfonamides derived from monoor bicyclic aromatic hydrocarbons were then prepared and assayed for inhibitory action. The systematic study of Beasley

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et al. (1958) revealed some important features for inhibitors belonging to the class of aromatic sulfonamides: (1) 4-substituted derivatives of benzenesulfonamide, of the type 4.4, as well as of diphenyl-4-sulfonamide (4.4b; Table 4.1) are stronger inhibitors than are naphthalene-1- or 2-sulfonamides; (2) 4-substituents inducing good activities in compounds 4.4 include halogens, acetamido and alkoxycarbonyl, with esters of 4-sulfamoyl-benzoic acid (4.4f–m) needing special mention (see Table 4.1) because they are very potent CAIs (including the n-butyl, n-hexyl, n-nonyl and benzyl esters) in this class; (3) 2-substituted- and 2,4- and 3,4-disubstitued- benzenesulfonamides are generally weaker inhibitors than are 4-substituted derivatives; (4) promising activities as well as desired physicochemical properties (such as an increase in hydrosolubility) are seen for compounds possessing carboxy-, hydrazido-, ureido-, thioureidoand methylamino moieties in position 4, such as 4m–r (Beasley et al. 1958; Supuran 1994).

Some of these compounds were recently reinvestigated. To obtain compounds for the selective radiolabeling of erythrocytes (an important tool in diagnostic nuclear medicine) via the enzyme–inhibitor approach, Singh and Wyeth (1991) reported the use of CAIs of type 4.5. Such inhibitors possess lipophilic groups as well as reactive halogen atoms, which, by reaction with amino acid residues within the CA active site, can irreversibly inactivate the enzyme. Table 4.2 presents the comparative inhibition data for red cell isozymes (CA I and CA II) with compounds of type 4.5 incorporating reactive halogen atoms.

To obtain compounds that act as specific inhibitors for the brain enzyme, Cross et al. (1978) prepared substituted benzenedisulfonamides of type 4.8 starting from substituted sulfanilamides 4.6, as outlined in Scheme 4.1. Such compounds showed IC50 values of the order of magnitude 10–7 M, and one (4.8b) exhibited anticonvulsant activity in rats, with a minimal diuretic effect and a low level of metabolic acidosis as side effects.

A related approach for the preparation of diversely substituted sulfanilamide derivatives was reported by Shepard et al. (1991) for the preparation of CAIs with topical effects as antiglaucoma drugs. These researchers prepared hydroxyalkylsulfonylbenzenesulfonamide of types 4.12 and 4.13 (Scheme 4.2).

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TABLE 4.1

Inhibition with Substituted

Benzenesulfonamides

Source: From Beasley, Y.M. et al. (1958) 10, 696–705 and Supuran, C.T. (1994) In Carbonic Anhydrase and Modulation of Physiologic and Pathologic Processes in the Organism, Puscas, I., Ed., Helicon Press, Timisoara, Romania, pp. 29–111. With permission.

Because 4-chloro- and 4-bromobenzenesulfonamides hardly react with any nucleophile, the protection of the sulfonamido moiety of 4.9 was necessary, and this has been done by a sulfonilformamidino group (derivatives 4.10). This reaction was performed by using dimethylformamide-dimethylacetal. Compounds 4.10 prepared this way are treated thereafter with a hydroxythiol in anhydrous solvents, in the presence of NaH, which by SNAR reactions leads to the corresponding hydroxyalkylthio derivatives 4.11. These derivatives are deprotected in an alkaline medium to afford the corresponding sulfonamides 4.12. Oxidation of sulfides 4.12 to sulfones 4.13 was achieved with H2O2 in acetic acid, 3-chloroperoxibenzoic acid in ethyl acetate or oxone in water (Shepard et al. 1991). Among the benzenesulfonamides

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TABLE 4.2

CA Inhibition against Isozymes I and II with

Substituted Benzenesulfonamides 4.5 Prepared as

Selective Radiolabeling Agents for Erythrocytes

Source: From Singh, J., and Wyeth, P. (1991) Journal of Enzyme

Inhibition 5, 1–24. With permission.

SCHEME 4.1

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