1,3-Diaryl Triazenes Incorporating Disulfonamides Show Both Antiproliferative Activity and Effective Inhibition of Tumor-associated Carbonic Anhydrases IX and XII.

AIM: The aim of this study was to synthesize a library of novel di-sulfa drugs containing 1,3- diaryltriazene derivatives TS (1-13) by conjugation of diazonium salts of primary sulfonamides with sulfa drugs to investigate the cytotoxic effect of these new compounds in different cancer types and to determine their inhibitory activity against tumor-associated carbonic anhydrases IX and XII. MATERIALS AND METHODS: A carbonic anhydrase inhibitory activity of the obtained compounds was evaluated against four selected human carbonic anhydrase isoforms (hCA I, hCA II, hCA IX and hCA XII) by a stoppedflow CO2 hydrase assay. In addition, in vitro, cytotoxicity studies were applied by using A549 (lung cancer), BEAS-2B (normal lung), MCF-7 (breast cancer), MDA-MB-231 (breast cancer), CRL-4010 (normal breast epithelium), HT-29 (colon cancer), and HCT -116 (colon cancer) cell lines. RESULTS: As a result of the inhibition data, the 4-aminobenzenesulfonamide derivatives were more active than their 3-aminobenzenesulfonamide counterparts. More specifically, compounds TS-1 and TS-2, both of which have primary sulfonamides on both sides of the triazene linker, showed the best inhibitory activity against hCA IX with Ki values of 19.5 and 13.7 nM and also against hCA XII with Ki values of 6.6 and 8.3 nM, respectively. In addition, in vitro cytotoxic activity on the human breast cancer cell line MCF-7 showed that some derivatives of di-sulfa triazenes, such as TS-5 and TS-13, were more active than SLC-0111. CONCLUSION: With the aim of developing more potent and isoform-selective CA inhibitors, these novel hybrid molecules containing sulfa drugs, triazene linkers, and the classical primary sulfonamide chemotype may be considered an interesting example of effective enzyme inhibitors and important anticancer agents.

Discovery of New 1,1'-Biphenyl-4-sulfonamides as Selective Subnanomolar Human Carbonic Anhydrase II Inhibitors.

We report here the synthesis and human carbonic anhydrases (CA, EC 4.2.1.1) inhibitory properties of a series of 4'-substituted 1,1'-biphenyl-4-sulfonamides incorporating a 2″- or 3″-amino- or carboxyphenyl unit. Most compounds showed significant variations in their inhibition profiles against CA II and IX when compared to previously reported analogs 12-18 bearing a 4″-amino or a 4″-carboxy group. In particular, compounds 1-11 showed considerable improvement of the CA II inhibitory efficacy with K I values in the subnanomolar range (K Is spanning between 0.57 and 31.0 nM), a drop of activity against CA IX (K Is in the range 92.0 to 555.7 nM) and were as potent as 12-18 toward CA I (K Is in the range 5.9-217.7 nM). Docking and molecular dynamics were used to gain insights on the inhibition profiles. The reported inhibition data show that 1-11 have potential as novel agents to treat ocular pathologies, such as glaucoma, because of the potent and selective targeting of CA II, which is the isoform most implicated in this disease.