Discovery of 2,4-thiazolidinedione-tethered coumarins as novel selective inhibitors for carbonic anhydrase IX and XII isoforms

Abstract

Different 2,4-thiazolidinedione-tethered coumarins 5a–b , 10a–n and 11a–d were synthesised and evaluated for their inhibitory action against the cancer-associated h CAs IX and XII, as well as the physiologically dominant h CAs I and II to explore their selectivity. Un-substituted phenyl-bearing coumarins 10a , 10 h , and 2-thienyl/furyl-bearing coumarins 11a–c exhibited the best h CA IX (K I s between 0.48 and 0.93 µM) and h CA XII (K I s between 0.44 and 1.1 µM) inhibitory actions. Interestingly, none of the coumarins had any inhibitory effect on the off-target h CA I and II isoforms. The sub-micromolar compounds from the biochemical assay, coumarins 10a , 10 h and 11a–c , were assessed in an in vitro antiproliferative assay, and then the most potent antiproliferative agent 11a was tested to explore its impact on the cell cycle phases and apoptosis in MCF-7 breast cancer cells to provide more insights into the anticancer activity of these compounds.

Targeting carbonic anhydrase IX and XII isoforms with small molecule inhibitors and monoclonal antibodies

“…The inclusion of charged species, bulky entities such as FITC, albumin, or hydrophilic sugar moieties has been used to “dial in” the selectivity of small-molecule CAIX inhibitors. Other options include the use of sulfonamide or coumarin chemotypes that are naturally selective for extracellular CAs like CAIX 15 , 189 . It is however worth mentioning that CAIs have a spectrum of action from non-isoform-specific to isoform-specific, and hence whether to utilize pan-CAI treatment or isoform-specific CA inhibitor treatment depends on the type of therapy that is required 190 .…”

Derivatives of 4-methyl-1,2,3-benzoxathiazine 2,2-dioxide as selective inhibitors of human carbonic anhydrases IX and XII over the cytosolic isoforms I and II

“…Sixteen different α-CA isoforms have been identified in mammals so far 1 , 3 . hCA I and II are widely distributed isoforms which may serve as targets for some diseases and off-targets for others 7 . hCA IX and XII are two transmembrane, multi-domain, hypoxia-induced tumour-associated proteins discovered by Pastorek et al.…”

“…This can be used as a strategy for targeting of these enzymes as a new approach in cancer treatment. Selective inhibition of the tumour-associated hCA IX and XII over the other isoforms, especially the most prevalent cytosolic hCA I and II is important and will result in cancer treatment with fewer side effects 7 .…”

“…hCA IX is not significantly expressed in the majority of normal tissues and is present only in the stomach and gallbladder epithelia, but is overexpressed in variety of solid tumors 10 , 11 . On the other hand, hCA XII is abundant in many healthy tissues, like kidney, prostate, pancreas, intestine and lymphocytes, but overexpressed in a certain number of malignant tumours, and associated with less-aggressive, well-differentiated tumour phenotypes as compared to the hCA IX expressing tumours thus CA IX is the preferred isoform for pharmacological intervention 7 , 10–12 . hCA IX has been considered as a valuable marker for cancer, and the development of hCA IX inhibitors with selectivity over ubiquitous isoforms hCA I/II is a potential strategy for designing anticancer agents 3 , 12 .…”

Design and synthesis of benzothiazole-based SLC-0111 analogues as new inhibitors for the cancer-associated carbonic anhydrase isoforms IX and XII

“…Of special interest, the catalytic activity of CAs I-IV, VA, VB, VI, VII, IX, XII-XIV isoforms is due to the presence of three histidine residues in the active site in coordination with zinc 7 . Furthermore, h CAs are classified upon cellular distribution into cytosolic ( h CAs I, II, III, VII and XIII), trans membrane ( h CAs IV, IX, XII, and XIV), mitochondrial ( h CAs VA and VB), and h CA VI is secreted in milk and saliva 8 , 9 . The abnormal levels of these enzymes have been associated with many diseases; thus inhibitors of the CAs have potential applications in the treatment of glaucoma, edoema, obesity and mental problems 1 , 7 , 9 , 10 .…”