1379521-08-0Relevant articles and documents
Click-tailed coumarins with potent and selective inhibitory action against the tumor-associated carbonic anhydrases IX and XII
Nocentini, Alessio,Carta, Fabrizio,Ceruso, Mariangela,Bartolucci, Gianluca,Supuran, Claudiu T.
, p. 6955 - 6966 (2015)
Coumarins behave as inhibitors of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) with a mechanism of inhibition distinct from other classes of inhibitors. A series of 7-substituted coumarins incorporating aryl-triazole moieties were prepared by click chemistry procedures starting from 7-hydroxycoumarin or 4-methyl-7-aminocoumarin. The panel of new compounds was assayed for the inhibition of the cytosolic, widespread human (h) isoforms hCA I and II, and the transmembrane, tumor-associated ones hCA IX and XII. Most of the coumarins were weak inhibitors or did not inhibit significantly hCA I and II, but showed low nanomolar inhibitory action against the transmembrane isoforms (KI of 14.3-34.4 nM against hCA IX and of 4.7-37.8 nM against hCA XII). Since many hypoxic tumors overexpress hCA IX/XII, and as these targets were recently validated for obtaining antitumor/antimetastatic agents, with one inhibitor in Phase I clinical trials, the present findings constitute an interesting extension to the knowledge of non-sulfonamide, selective inhibitors of CA isoforms involved in serious pathologies.
Highly Efficient Ultrasonic-Assisted CuCl-Catalyzed 1,3-Dipolar Cycloaddition Reactions in Water: Synthesis of Coumarin Derivatives Linked with 1,2,3-Triazole Moiety
Li, Xu,Chen, Xiaolan,Jiang, Yuqin,Chen, Senshen,Qu, Lingbo,Qu, Zhibo,Yuan, Jinwei,Shi, Hanyu
, p. 1402 - 1411 (2016/09/23)
By introducing ultrasound irradiation into “on water” CuCl-catalyzed 1,3-dipolar Huisgen cycloaddition, the reaction efficiencies were notably promoted toward a wide variety of applicable azides and alkynes at room temperature, and a series of coumarin de
Thioxocoumarins Show an Alternative Carbonic Anhydrase Inhibition Mechanism Compared to Coumarins
Ferraroni, Marta,Carta, Fabrizio,Scozzafava, Andrea,Supuran, Claudiu T.
, p. 462 - 473 (2016/01/28)
A series of coumarins and the corresponding 2-thioxocoumarines were prepared and tested for their inhibition profiles against four physiologically relevant human carbonic anhydrases (hCAs, EC 4.2.1.1), isoforms hCA I, II, IX, and XII. The X-ray crystal structure of 6-hydroxy-2-thioxocoumarin bound to hCA II revealed an unprecedented and unexpected inhibition mechanism for this new class of inhibitors when compared to isostructural coumarins. Unlike coumarins which are hydrolyzed by the esterase CA activity to the corresponding 2-hydroxy-cinnamic acid derivatives, the 2-thioxocoumarin was observed intact when bound to hCA II, with its exo-sulfur atom anchored to the zinc-coordinated water molecule, whereas the scaffold establishing favorable contacts with amino acid residues from the active site. This inhibition mechanism is very different from the one observed for hydrolyzed coumarins, which occlude the entrance of the active site cavity. This versatility in the binding mode of coumarins/thioxocoumarins has important consequences for the design of isoform-selective CA inhibitors, some of which are in clinical use or clinical development for various pathologies, among which glaucoma, edema, epilepsy, neuropathic pain, and hypoxic tumors.
CARBONIC ANHYDRASE INHIBITORS WITH ANTIMETASTATIC ACTIVITY
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Page/Page column 30-34, (2012/06/15)
Compositions for the treatment of cancer comprising coumarin and thiocoumarin derivatives of Formulas I- XII are disclosed. Said derivatives preferentially inhibit carbonic anhydrase IX and XII (which are associated with hypoxic and metastatic tumours) over inhibiting carbonic anhydrase I and II activity. The compositions therefore are suited for treatment of hypoxic or metastatic cancers due to this selective mechanism of action.
