Carbonic anhydrase inhibitors: Selective inhibition of the extracellular, tumor-associated isoforms IX and XII over isozymes I and II with glycosyl-thioureido-sulfonamides

Carbonic Anhydrase IX: From Biology to Therapy

“…These extensive studies revealed several compounds with a reasonable selectivity ratio favoring inhibition activities against CA IX compared to other isoforms, in particular CA XII and CA II. For example, selectivity ratios for the inhibition of CA IX over the cytosolic isozymes CA I and II were in the range of 107-955 for glycosyl-thioureido-sulfonamides (Smaine et al 2007). Another sophisticated strategy was used to generate hypoxia-activatable inhibitors.…”

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

“…As mentioned above, the main problem with the drug design of CA IX inhibitors was to obtain compounds which should selectively inhibit CA IX without a significant inhibitory effect against the physiologically dominant, highly abundant isoforms CA I and II (and also other off‐target isoforms) . This goal seemed to be difficult to achieve initially, but several classes of sulfonamides and their isosteres (sulfamates, sulfamides), most of which were obtained using the tail approach, allowed to obtain compounds with these features . Only the most relevant studies will be mentioned here, as this class of CAIs is the most investigated one and a high number of drug design studies (>400) have been reported since 2003 .…”

“…All these studies allowed the detailed understanding of the factors governing activity and selectivity for inhibiting CA IX over other CA isoforms, and are summarized below: the zinc‐binding group of the sulfonamide, sulfamate, and sulfamide is not highly influential for obtaining potent and CA IX‐selective inhibitors. In fact, many classes of such derivatives show similar CA IX inhibitory/selectivity profiles, such as various sulfonamides, sulfamates, and sulfamides The scaffold of the potent and isoform‐selective CA IX inhibitors of this type incorporates aromatic,…”

“…In fact, many classes of such derivatives show similar CA IX inhibitory/selectivity profiles, such as various sulfonamides, sulfamates, and sulfamides The scaffold of the potent and isoform‐selective CA IX inhibitors of this type incorporates aromatic, heterocyclic, aliphatic, sugar, or combinations of such moieties, and is obviously highly important for the inhibitory activity, as it makes extensive interactions with the active site of the enzyme in the enzyme‐inhibitor complex (as shown by extensive X‐ray crystallographic studies) . Again, effective and isoform‐selective CA IX inhibitors were obtained from all these classes of derivatives mentioned here (examples will be disclosed shortly). Probably the most important structural element influencing potency and selectivity is the tail that the zinc‐binding inhibitors incorporate, which has also been the topic mostly used for modulating the activity and selectivity profile of all these classes of CAIs.…”

“…As shown in many studies, the tail is orientated in such a way to bind the border of the active site cavity, which is the most variable region among the hCA isoforms; as a consequence, the tail strongly influences the selectivity profile for the binding of all classes of inhibitors . Among the many diverse tails which have been introduced in the molecules of CA IX inhibitors, the ones which led to the best efficacy and selectivity profile are the substituted pyridinium ones (as in compounds 1–3 ), the substituted‐1,3,5‐triazinyl ones (as in compounds 4–6 ), the fluoresceine or other fluorescent moieties (as in compounds 7, 8 ), and the alkyl/aryl/hetaryl‐ureido/thioureido ones, as in compounds 9–13 (Figure ) …”