Heterocoumarins Are Selective Carbonic Anhydrase IX and XII Inhibitors with Cytotoxic Effects against Cancer Cells Lines

Abstract

We have synthesized a new series of coumarin-based compounds demonstrating high selectivity and potent effects with low nanomolar affinity against the tumor associated carbonic anhydrase (CA, EC 4.2.1.1) isoforms hCA IX and XII. A number of these compounds were evaluated against human prostate (PC3) and breast (MDA-MB-231) cancer cell lines. Compounds and revealed effective cytotoxic effects after 48 h of incubation in both normoxic and hypoxic conditions with PC3 cancer cell line. However, compound showed selective cytotoxic effects against MDA-MB-231 in hypoxic condition. These results may be of particular importance for the choice of future drug candidates targeting hypoxic tumors and metastases, considering the fact that a selective carbonic anhydrase CA IX inhibitor (SLC-0111) is presently in phase II clinical trials.

Syntesis of thio- and seleno-acetamides bearing benzenesulfonamide as potent inhibitors of human carbonic anhydrase II and XII

“…[1][2][3] Selenium and sulfur have been demonstrated to play an important role in biological systems as part of the active site in many proteins 4,5 and their organo-derivatives can be employed as antioxidant 6 , antimicrobial 7 , and antitumor agents. 8 These therapeutic agents also act as modulators on a variety of enzyme such as nitric oxide synthase (NOS), 9 inosine monophosphate dehydrogenase (IMDPH) 10 , lipoxygenases (LOX) 11 and more recently, as carbonic anhydrase (CA, E.C. 4.2.1.1) inhibitors.…”

Coumarin carbonic anhydrase inhibitors from natural sources

“…Apart from their highly interesting features as isoform-selective inhibitors, the discovery of coumarins as CAIs stimulated the research for the discovery of new chemotypes possessing such properties or similar inhibition mechanisms. Indeed, the monocyclic 5- and 6-ring lactones and thiolactones were reported to possess CA inhibitory effects 71 , as well as thio- and 2-thioxo-coumarins 72 , quinoline-2-ones 73 , sulfocoumarins 74 , homosulfocoumarins 75 , 76 and various hetero-coumarins incorporating selenium, tellurium and other elements 77 . More recently, this type of prodrug CAI inspired also other groups to investigate this type of suicide inhibitor, such as for example aspirin, reported by McKenna’s group 78 .…”

A Simple Yet Multifaceted Enzyme

“…A natural product coumarin was the starting point leading to the discovery of this CA inhibition mechanism [63] as well as a wealth of new types of CAIs belonging to various chemical classes [73][74][75][76][77][78][79][80][81]. When this coumarin was co-crystallized with hCA II, the original compound was not found in the electronic density; instead, its hydrolysis product, a cis-2-hydroxy-cinnamic acid derivative was found bound in a region of the CA active site where inhibitors were never observed to bind, the entrance of the cavity [63] - Figure 1C.…”

“…As a consequence, many drug design studies of coumarin [63][64][65][66][67][68][69][70][71] and coumarin-like compounds [72 -77] were reported, all of them leading to isoform-selective CAIs. These new classes of prodrug inhibitors include among others, 5-and 6-ring lactones/thiolactones [72], 3,4-dihydro-1H-quinoline-2-ones [73], heterocoumarins, such as selenocoumarins, thioselenocoumarins, tellurocoumarins and variously substituted quinoline-2(1H)-ones [77].…”

“…However, the determination of its X-ray crystal structure by De Simone's group in 2009 [117] was the breakthrough which helped the rational drug design of more effective CA IX inhibitors [1][2][3][4][5][6][7][8]. The emergence of coumarins already in 2009 as new CA inhibitory chemotype [73] with a significant selectivity for CA IX/XII over other isoforms [64][65][66][67][68][69][70][71][72][73][74][75][76][77], as well as the progress done in sulfonamide chemistry with the tail approach, led to a considerable number of highly CA IX/XII-selective inhibitors belonging to various classes [1][2][3][4][5][6][7][8][9][10]. Thus, the study of the multiple binding modes of various types of inhibitors to the three isoforms mentioned here, CA II, IX and XII, vas decisive for validating CA IX/XII as antitumor/antimetastatic drug targets.…”