Carbonic anhydrase inhibitors: Copper(II) complexes of polyamino-polycarboxylamido aromatic/heterocyclic sulfonamides are very potent inhibitors of the tumor-associated isoforms IX and XII

2-Amino-3-cyanopyridine derivatives as carbonic anhydrase inhibitors

“…The effects of the six compounds that contain heterocyclic rings were the weakest. Our results are consistent with previous reports that phenols (amines) are weak inhibitors of hCA I and hCA II [15][16][17][18][19]40 . Spermine was found bound deep within the hCAII active site, in his inhibition mechanism, nevertheless not directly coordinated to the metal ion.…”

“…pK a values of the polyamines like spermidine and spermine and their derivatives are in the range of 7.9-10.9 [18][19][20][21] . Aminopyridines are weak bases with pK a values between 6 and 9.…”

“…Three mechanisms of inhibition have been proposed, one of which involves anchoring of the inhibitor to the Zn (II) bound solvent molecule (a water or hydroxide ion). Phenols and polyamines bind in this way [18][19][20][21] . A critical problem in the design of CA inhibitors with pharmacological applications for the treatment and prevention of various diseases is related to the high number of CA isoforms (16 in mammals), the diffuse localization of CAs in many tissues/organs, and the lack of isozyme selectivity of the presently available inhibitors 22,23 .…”

“…Coumarines 3 and thiocoumarines which have an inhibition mechanism independent of Zn (II) because they don't have protonshutting moieties in their molecules are the third class research artIcle 2-Amino-3-cyanopyridine derivatives as carbonic anhydrase inhibitors . In the recent studies polyamines such as spermine and spermidine 4 are reported a new class of CAI inhibitors 18,19 . The Zn (II) ion in CAs is critical for the inhibition of these enzymes.…”

Carbonic Anhydrase IX: From Biology to Therapy

“…Indeed, different classes of sulfonamides and related compounds can efficiently inhibit CA IX. In addition to classical sufonamides, such as acetazolamide (AZM), methazolamide, ethoxzolamide, and dichlorophenamide, good-to-excellent CA IX inhibitory properties were proven for aromatic and heterocyclic sulfonamides Jaiswal et al 2004;Ozensoy et al 2005), halogenosulfanilamide and halogenophenylaminobenzolamide derivatives (Ilies et al 2003), lipophilic sulfonamides , sulfamates (Winum et al 2003a), aliphatic sulfamates (Winum et al 2003b), fluorine-containing sulfonamides , sulfonamides incorporating 1,3,5-triazine and 1,2,4-triazine moieties (Garaj et al 2004(Garaj et al , 2005, sulfonamides derived from 4-isothiocyanato-benzolamide (Cecchi et al 2004), E7070 sulfonamide developed originally as an anticancer agent blocking the cell cycle (Abbate et al 2004), sulfonamides incorporating thioureido-sulfanilyl scaffolds , novel sulfanilamide/AZM derivatives obtained by the tail approach (Turkmen et al 2005), bis-sulfamates (Winum et al 2005a), sulfonamides incorporating hydrazine moieties (Winum et al 2005b), 1,3,4-thiadiazole-and 1,2,4-triazole-thiols (Almajan et al 2005), N-hydroxysulfamides (Winum et al 2005c), polyfluorinated aromatic/heterocyclic sulfonamides , benzo[b]thiophene 1,1 dioxide sulfonamides , substituted difluoromethanesulfonamides , indanesulfonamides (Thiry et al 2006), and copper(II) complexes of polyamino-polycarboxylamido aromatic/heterocyclic sulfonamides (Rami et al 2008). Interestingly, CA IX can be also efficiently inhibited by nanomolar concentrations of celecoxib and valdecoxib sulfonamide inhibitors of cyclooxygenase 2 (COX-2), which is a key enzyme of arachidonic acid metabolism involved in colorectal carcinoma (Weber et al 2004;Dogne et al 2007).…”