Discovery of novel isatin-based sulfonamides with potent and selective inhibition of the tumor-associated carbonic anhydrase isoforms IX and XII

Abstract

A series of 2/3/4-[(2-oxo-1,2-dihydro-3H-indol-3-ylidene)amino]benzenesulfonamides, obtained from substituted isatins and 2-, 3- or 4-aminobenzenesulfonamide, showed low nanomolar inhibitory activity against the tumor associated carbonic anhydrase (CA, EC 4.2.1.1) isoforms IX and XII - recently validated antitumor drug targets, being much less effective as inhibitors of the off-target cytosolic isoforms CA I and II.

Isatin-pyrazole benzenesulfonamide hybrids potently inhibit tumor-associated carbonic anhydrase isoforms IX and XII

“…The Schiff base VI showed a potent inhibitory activity against hCA IX (Ki ¼ 1.1 nM) and had a high selectivity for isoform hCA IX compared to the cytosolic isozymes hCA I and hCA II [23] (Fig. 1).…”

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 .…”

“…Thus, these three subclasses of CAIs will be dealt with together here in this section. 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 …”

“…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.…”

Design, synthesis and biological evaluation of some novel N-arylpyrazole derivatives bearing the sulfonamide moiety as cytotoxic agents

“…Indeed, they have also been reported to possess various types of biological properties such as anticancer [17], antibacterial [18], antimicrobial [19,20], antimalarial [21], antihypertensive [22], antitumor [23], and antiinflammatory activities [24][25][26][27][28][29][30][31], among others. Among these, the anticancer activity was found to take place through a variety of mechanisms such as disruption of the microtubule assembly, cell cycle arrest in the G1 phase, functional suppression of the transcriptional activator NF-Y, angiogenesis and carbonic anhydrase inhibition [15,16].…”