Continued exploration of 1,2,4-oxadiazole periphery for carbonic anhydrase-targeting primary arene sulfonamides: Discovery of subnanomolar inhibitors of membrane-bound hCA IX isoform that selectively kill cancer cells in hypoxic environment

Inhibitory activity against carbonic anhydrase IX and XII as a candidate selection criterion in the development of new anticancer agents

“…To our delight, however, there is a large number of mechanistically relevant experiments reported in the literature which address the ability of hCA IX/XII inhibitors to block the growth of hypoxic cancer cells overexpressing the target isozymes [49][50][51][52][53][54][55][56][57][58][59][60][61][62][63][64][65][66][67] . Moreover, a certain cohort of studies revealed compounds possessing both favourable hCA inhibitory profile and significant anticancer activity, as exemplified by structures 5-13 ( Figure 2) [49][50][51][52][53][54][55][56][58][59][60][61][64][65][66][67] . In fact, quite a number of single-digit nanomolar hCA IX/XII inhibitors significantly suppressed cancer cell growth.…”

Combining carbonic anhydrase and thioredoxin reductase inhibitory motifs within a single molecule dramatically increases its cytotoxicity

“…Compounds 1 and 2 were synthesised from common precursor À 5-sulphamoylthiophene-3-carboxylic acid (7) as described previously. 5 Carboxylic acid 7 was activated by treatment with CDI and the resulting imidazolide was reacted with amidoximes 8a-b. Addition of solid NaOH formed a superbase solution in DMSO which triggered cyclodehydration yielding compounds 1 and 2 in good yields (Scheme 1).…”

“…Isomeric 1,2,4-oxadiazole 3 was prepared also as described previously. 5 Amidoxime 9 was acylated with methyl cyclopropanecarboxylate in DMSO whereupon addition of solid NaOH, again, led to cyclodehydration to give compound 3 in 57% yield (Scheme 2).…”

“…3 Recently, we reported on the discovery of potent 1,2,4-oxadiazole-based inhibitors 1-3 of these two cancer-related isoforms of carbonic anhydrase. 4,5 These compounds possess subnanomolar to double-digit nanomolar potency against hCA IX and XII (Table 1), which makes them ideal tool compounds for further investigation of the role of these carbonic anhydrase isoforms in tumour growth.…”

Development of a cheminformatics platform for selectivity analyses of carbonic anhydrase inhibitors

“…Nevertheless, the interest on hCAs does not appear to be in decline. On the contrary, the recent studies confirming the potential of hCA IX and hCA XII as valuable targets for the treatment of hypoxic tumors spread a renewed interest in the identification of new and selective CAIs [9][10][11][12][13] . From one side, the availability of a large amount of literature data can surely facilitate the design of novel compounds with both high activity and selectivity for the desired hCA isoforms.…”