7-Aryl-triazolyl-substituted sulfocoumarins are potent, selective inhibitors of the tumor-associated carbonic anhydrase IX and XII

Lansoprazole and carbonic anhydrase IX inhibitors sinergize against human melanoma cells

“…We also showed that PPIs have a clear cytotoxic anti-tumor effect when used at high dosages as single agent 29,30 . It is demonstrated that CA IX represents a valuable antitumor target [51][52][53][54][55][56][57][58][59] . In fact, CA IX has been shown to be upregulated in a number of human cancer tissues as a consequence of either hypoxia-induced or constitutive hypoxia-inducible factor-1 activation, whereas it is not expressed in their normal counterparts, except for gastric mucosa 60 .…”

Inhibition of carbonic anhydrase IX targets primary tumors, metastases, and cancer stem cells: Three for the price of one

“…Thus, starting from coumarins as leads, a large number of other classes of CAIs were detected (Figure ), such as the thiocoumarins, thioxocoumarins, dithiocoumarins, the coumarin oximes, the sulfocoumarins, the five‐ and six‐membered lactones, and thiolactones . Among all these new chemotypes, the most investigated ones are the sulfocoumarins …”

“…The simple sulfocoumarin 43 is a micromolar CA IX/XII inhibitor (but it does not inhibit significantly CA I and II, see Table ). However, in subsequent studies a large number of low nanomolar sulfocoumarin derivatives of types 46–48 were discovered (Figure ) . It may be observed (Table ) that the introduction of substituted‐triazolyl or tetrazolyl moieties in the 7 position of the sulfocoumarin ring leads to low nanomolar CA IX/XII inhibitors, whereas these compounds do not significantly inhibit CA I and II.…”

“…However, in subsequent studies a large number of low nanomolar sulfocoumarin derivatives of types 46-48 were discovered (Figure 15). [245][246][247][248][249][250][251][252][253] It may be observed (Table 2) that the introduction of substituted-triazolyl or tetrazolyl moieties in the 7 position of the sulfocoumarin ring leads to low nanomolar CA IX/XII inhibitors, whereas these compounds do not significantly inhibit CA I and II. Thus, from relatively weak, but CA IX-selective leads, such as the coumarins shown in Table 2 and the simple sulfocoumarin 43, highly effective, isoform-selective CA IX inhibitors were obtained.…”

Deciphering the Mechanism of Human Carbonic Anhydrases Inhibition with Sulfocoumarins: Computational and Experimental Studies

“…To date, a detailed reaction mechanism for the CA‐mediated intramolecular sulfonic esters hydrolysis has not yet been reported. In recent studies, we investigated a variety of sulfocoumarins bearing electro‐withdrawing (EWG) or electro‐donating (EDG) groups placed at the 6‐ and 7‐position . Herein, as an extension of our previous investigations, we report novel analogues decorated at the 6‐ and 7‐positions with chemical moieties endowed with different electronic properties (EWG and EDG, Scheme ) and their inhibition profiles against the most relevant human (h)CAs are reported.…”