Indoline-5-Sulfonamides: A Role of the Core in Inhibition of Cancer-Related Carbonic Anhydrases, Antiproliferative Activity and Circumventing of Multidrug Resistance

Abstract

The overexpression and activity of carbonic anhydrase (CA, EC 4.2.1.1) isoforms CA IX and CA XII promote the accumulation of exceeding protons and acidosis in the extracellular tumor environment. Sulfonamides are effective inhibitors of most families of CAs. In this study, using scaffold-hopping, indoline-5-sulfonamide analogs 4a–u of the CA IX-selective inhibitor 3 were designed and synthesized to evaluate their biological properties. 1-Acylated indoline-5-sulfonamides demonstrated inhibitory activity against tumor-associated CA IX and XII with KI values up to 132.8 nM and 41.3 nM. Compound 4f, as one of the most potent inhibitors of CA IX and XII, exhibits hypoxic selectivity, suppressing the growth of MCF7 cells at 12.9 µM, and causes partial inhibition of hypoxia-induced CA IX expression in A431 skin cancer cells. 4e and 4f reverse chemoresistance to doxorubicin of K562/4 with overexpression of P-gp.

Cellular Pre-Adaptation to the High O2 Concentration Used in Standard Cell Culture Confers Resistance to Subsequent H2O2-Induced Cell Death

“…There was no significant difference in the nuclear protein levels of HIF-1α when comparing cells pre-adapted to 3.0% O 2 for 96 h to cells pre-adapted to 18.6% O 2 for 96 h ( Figure 2 c), which agrees with a previous report from our laboratory [ 15 ]. To activate HIF-1α in A431 cells, researchers have previously used an [O 2 ] of ≤1.0% O 2 [ 34 , 35 , 36 , 37 , 38 , 39 ]. Our results suggest that A431 cells, when pre-adapted to 3.0% O 2 for 96 h, were sensitised to H 2 O 2 -induced cell death in a manner which was independent of hypoxic conditions and HIF-1α activation.…”

Synthesis and evaluation of sulfonamide derivatives of quinoxaline 1,4-dioxides as carbonic anhydrase inhibitors

“…a hydrogen bond with the Gln67 residue. 41 Thus, the affinity of 6-and 7-sulfonamides of quinoxaline 1,4-dioxide highly depends on substituents at positions 2 and 3, forming interactions with amino acid residues of CA IX.…”

Synthesis and Biological Evaluation of Chalconesulfonamides: En Route to Proapoptotic Agents with Antiestrogenic Potency

“…For example, sulfonamides on an oxabicyclo [2.2.1] heptene scaffold ( 5 , Figure 2 ) are potent antiestrogens with nanomolar antiproliferative potency against breast cancer cells. In addition, other sulfonamides are known inhibitors of carbonic anhydrase IX, phosphatidylinositol-3-kinase (PI3K), and protein kinase BRAF with validated antitumor properties [ 22 , 23 , 24 , 25 ].…”