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

Carbonic Anhydrase

Its Inhibitors and Activators

Copyright © 2004 CRC Press, LLC

CRC Enzyme Inhibitors Series

Series Editors

H. John Smith and Claire Simons

Cardiff Univeristy

Cardiff, UK

Carbonic Anhydrase: Its Inhibitors and Activators

Edited by Claudiu T. Supuran, Andrea Scozzafava and Janet Conway

Copyright © 2004 CRC Press, LLC

CRC Enzyme Inhibitors Series

Carbonic Anhydrase

Its Inhibitors and Activators

Edited by

Claudiu T. Supuran

Andrea Scozzafava

Janet Conway

CRC PR E S S

Boca Raton London New York Washington, D.C.

Copyright © 2004 CRC Press, LLC

Library of Congress Cataloging-in-Publication Data

Carbonic anhydrase : its inhibitors and activators / edited by Claudiu T. Supuran, Andrea Scozzafava, and Janet Conway.

p. cm. -- (Enzyme inhibitors) Includes bibliographical references and index. ISBN 0-415-30673-6 (alk. paper)

1. Carbonic anhydrase. I. Supuran, Claudiu T., 1962II. Scozzafava, Andrea, 1947-

III.Conway, Janet. IV. Series.

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Preface

Carbonic anhydrases (CAs) are widespread metalloenzymes in higher vertebrates, wherein they play crucial physiological roles. Some of these isozymes are cytosolic (CA I, CA II, CA III and CA VII), others are membrane bound (CA IV, CA IX, CA XII and CA XIV), one is mitochondrial (CA V) and one is secreted in the saliva (CA VI). Three acatalytic forms, which are designated as CA-related proteins (CARPs), CARP VIII, CARP X and CARP XI, are also known. Representatives of the β- and γ-CA family are highly abundant in plants, bacteria and archaea. These enzymes are very efficient catalysts of the reversible hydration of carbon dioxide to bicarbonate, and at least the α-CAs possess a high versatility and are able to catalyze other hydrolytic processes. Recently, two new families have been discovered — the δ- and ε-CA classes of these enzymes.

Chapter 1 deals with the catalytic mechanism of CAs, which is understood in great detail at present. The active site consists of a Zn(II) ion coordinated by three histidine residues and a water molecule/hydroxide ion. Several important physiological and physiopathological functions are played by the CA isozymes present in organisms at all levels of the phylogenetic tree, such as respiration and transport of CO2/bicarbonate between metabolizing tissues and the lungs, pH and CO2 homeostasis, electrolyte secretion in a variety of tissues and organs, and biosynthetic reactions such as the gluconeogenesis and urea synthesis (in animals) and CO2 fixation (in plants and algae). The presence of these ubiquitous enzymes in so many tissues and in so many different isoforms makes them useful in designing inhibitors or activators that have biomedical applications.

Chapter 2 deals with the CARPs, the CA-related proteins that do not possess catalytic activity and have been discovered only recently. Many evidences connect these proteins with many types of tumors, and these new data are thoroughly presented by one of the major contributors in the field.

Chapter 3 presents a challenging finding regarding the multiple binding modes of different CA ligands to the enzyme, based on very recent x-ray crystallographic findings. This contribution is essential for those working in drug design and tries to develop isozyme-specific inhibitors, and the proposed solutions are quite surprising.

Chapter 4 deals with the unsubstituted aromatic/heterocyclic sulfonamides — the most investigated CA inhibitors (CAIs) — that were known to inhibit CAs since the beginning of research in this field. Starting with the 1950s, potent CAIs belonging to the heterocyclic sulfonamide class have been developed, which has led to benzothiadiazine and high-ceiling diuretics and to the systemic antiglaucoma drugs acetazolamide, methazolamide, ethoxzolamide and dichlorophenamide. The discovery of these drugs has highly 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

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and early 1990s, the topically effective antiglaucoma CAIs were discovered, with two such drugs — dorzolamide and brinzolamide — presently being used clinically. Both have been designed by the ring approach, i.e., by investigating many 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 will induce the desired physicochemical properties to aromatic/heterocyclic sulfonamide scaffolds possessing derivatizable amino or hydroxy moieties. Important progress has been achieved in finding inhibitors with a higher affinity for a certain isozyme, although clear-cut isozyme-specific inhibitors are not currently available. Inhibitors selective for membrane-associated (CAs IV, IX, XII and XIV) and cytosolic isozymes are available, belonging either to macromolecular compounds or to the positively charged derivatives (of low molecular weight). CAIs possessing relevant antitumor properties were also 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 possessing zinc-binding functions different from the classical one (of aromatic/heterocyclic sulfonamide type) have been reported, incorporating, among others, sulfamate, sulfamide and hydroxamate moieties. This field is in constant progress and might lead to the discovery of very interesting pharmacological agents.

Chapter 5 presents an updated review on QSAR of sulfonamide CAIs. Based on the most modern computer-assisted drug design techniques, different mathematical models that explain the biological activity of this class of pharmacological agents are presented, together with their impact on improving the actually available drugs.

Chapter 6 reviews metal complexes of sulfonamides with CA inhibitory activity. This type of inhibitors has been studied in detail only in the past 10 years and might provide a host of important biomedical applications. The detailed chemical and crystallographic studies leading to these CA inhibitors are presented.

Chapter 7 deals with the nonsulfonamide type of CAIs, i.e., the anions and the azoles. These compounds are primarily important for understanding the inhibition mechanism of these enzymes.

Chapter 8 to Chapter 11 deal with the many different clinical applications of CAIs: in ophthalmology, as antiglaucoma and antimacular degeneration agents (Chapter 8); in oncology — a new and hot topic (Chapter 9); in gastroenterology, neurology and nephrology (Chapter 10); and in dermatology (Chapter 11). Although used for many years to treat or prevent different diseases, CAIs might still play an important role in therapy, as exemplified by these reviews of well-known contributors in the field.

Activation of CAs (Chapter 12) has been a controversial phenomenon for a long time. Recently, kinetic, spectroscopic and x-ray crystallographic data have offered a clear-cut explanation of this phenomenon, based on the catalytic mechanism of these enzymes. It has been demonstrated that molecules acting as CA activators (CAAs) bind at the entrance of the enzyme active-site cavity and participate in facilitated proton transfer processes between the active site and the reaction medium,

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thereby facilitating the rate-determining step of the CA catalytic cycle. In addition to CA II–activator adducts, x-ray crystallographic studies have been reported for ternary complexes of this isozyme with activators and anion inhibitors. Drug design studies have been successfully performed for obtaining strong CAAs belonging to several chemical classes, such as amines and their derivatives, azoles, amino acids and oligopeptides. Structure–activity correlations for diverse classes of activators are discussed for the isozymes for which the phenomenon has been studied. The physiological relevance of CA activation and the possible application of CAAs in Alzheimer’s disease and for other memory therapies are also reviewed.

Claudiu T. Supuran

Andrea Scozzafava

Janet Conway

Copyright © 2004 CRC Press, LLC

Copyright © 2004 CRC Press, LLC

Copyright © 2004 CRC Press, LLC

Copyright © 2004 CRC Press, LLC