Current Pharmaceutical Design - Volume 16, Issue 29, 2010

I use this title to introduce this issue of Curr Pharm Des. dedicated to the carbonic anhydrase (CA) conference held in September 2009 in Florence, Italy, as I found it in the not very happy comments of a reviewer of one of my manuscripts sent recently for publication, who was complaining that we publish too much in this field. Thus, I found this situation quite illustrative for this entire research field, in which important advancem Read More

Carbonic anhydrases (CAs, EC 4.2.1.1) are metalloenzymes which catalyze CO2 hydration to bicarbonate and protons. Five genetically distinct classes are known, which represent an excellent example of convergent evolution. Inhibition of α-CAs from vertebrates, including humans, with sulfonamides was exploited clinically for decades for various classes of diuretics and systemically acting antiglaucoma agents, whereas Read More

The carbonic anhydrase (CA) family has recently become an important target for the drug design of inhibitors with potential use as diagnostic and therapeutic tools. However, given the high degree of sequence and structure similarity among the different CA isoforms, no CA-directed drug developed so far has displayed selectivity for a specific isozyme. Since X-Ray crystallography is a very useful tool for the rational drug de Read More

Carbonic anhydrase IX (CA IX) is a suitable target for various anticancer strategies. It is a cell surface protein that is present in human tumors, but not in the corresponding normal tissues. Expression of CA IX is induced by hypoxia and correlates with cancer prognosis in many tumor types. Moreover, CA IX is functionally implicated in cancer progression as a pro-survival factor protecting cancer cells against hypoxia and acid Read More

Mammalian carbonic anhydrase (α-CA) gene family comprises sixteen isoforms, thirteen of which are active isozymes and three isoforms lack classical CA activity of reversible hydration of CO2 due to absence of one or more histidine residues required for CA catalytic activity. The inactive isoforms are known as carbonic anhydrase related proteins (CARPs) VIII, X and XI. Among these three, CARP VIII was reported first in 19 Read More

In recent years there has been renewed activity in the literature concerning the 1,3-dipolar cycloaddition reaction (1,3-DCR) of organic azides (R-N3) with alkynes (R´ C≡CH)to form 1,2,3-triazoles, i.e. the Huisgen synthesis. The use of catalytic Cu(I) leads to a dramatic rate enhancement (up to 107-fold) and exclusive synthesis of the 1,4-disubstituted 1,2,3-triazole product. The reaction, now referred to as the copper-catalyzed a Read More

Hypoxia is a crucial factor in tumour aggressiveness and its treatment resistance, particularly in human brain cancer. Tumour resistance against radiation- and chemo- therapy is facilitated by oxygenation reduction at tumour areas. HIF-1α regulated genes are mostly responsible for this type of resistance. Among these genes, carbonic anhydrase isoform 9 (CA9) is highly overexpressed in many types of cancer especially in hig Read More

Three β-carbonic anhydrases (CAs, EC 4.2.1.1), encoded by the gene Rv1284 (mtCA 1) Rv3588c (mtCA 2) and Rv3273 (mtCA 3) are present in the human pathogen Mycobacterium tuberculosis. These enzymes were cloned and they showed appreciable catalytic activity for CO2 hydration, with kcat of 3.9 x 105 s-1, and kcat/Km of 3.7 x 107 M-1.s-1 for mtCA 1, of 9.8 x 105 s-1, and kcat/Km of 9.3 x 107 M-1.s-1 for mtCA 2 and kc Read More

The facultative intracellular pathogen and zoonotic agent Brucella sp. possesses two carbonic anhydrases (CAs, EC 4.2.1.1), termed bsCA I and bsCA II (in Brucella suis), belonging to the β-class of these metalloproteins. These zinc enzymes, present in many other pathogenic bacteria, have been considered recently as potential antibacterial targets. The catalytic activity of bsCA II is higher than that of bsCA I (for the conversi Read More

A series of 2-(hydrazinocarbonyl)-3-substituted-phenyl-1H-indole-5-sulfonamides possessing various 2-, 3- or 4- substituted phenyl groups with methyl-, halogeno- and methoxy- functionalities, as well as the perfluorophenyl moiety have been synthesized and evaluated as inhibitors of both α- and β-class carbonic anhydrases (CAs, EC 4.2.1.1). All human isoforms with medicinal chemistry applications were included in such studi Read More

The β-carbonic anhydrase from Saccharomyces cerevisiae (CA, EC 4.2.1.1), scCA, which is encoded by the Nce103 gene, is an effective catalyst for CO2 hydration to bicarbonate and protons, with a kcat of 9.4 x 105 s-1, and kcat/KM of 9.8 x 107 M-1.s-1. Its inhibition with anions and sulfonamides has been investigated, as well as its activation with amines and amino acids. Bromide, iodide and sulfamide, were the best anion inhibito Read More