Atropo/Tropo Flexibility: A Tool for Design and Synthesis of Self-Adaptable Inhibitors of Carbonic Anhydrases and Their Antiproliferative Effect

Journal of Medicinal Chemistry 2023
Jekaterīna Ivanova, Alessio Nocentini, Kaspars Tārs, Janis Leitans, Elviss Dvinskis, Andris Kazaks, Ilova Domračeva, Claudiu T. Supuran, Raivis Žalubovskis

Here, we report for the first time a series of sulfonamide derivatives with scaffolds bearing flexible moieties, namely, rotamers or tropoisomers capable of adapting their geometry in the active center of enzymes thus being effective and selective carbonic anhydrase (CAs, EC 4.2.1.1) enzyme inhibitors. All compounds exhibited effective in vitro inhibition activity toward the main hCA isoforms related to cancer (i.e., hCA II, hCA IX, and hCA XII with KI values in the low nanomolar range). Three selected compounds showed a great cytotoxic effect on cancer cell lines ex vivo. X-ray crystallographic experiments assessed the binding modes of compound 35 with active centers of hCA IX and hCA XII.

DOI
10.1021/acs.jmedchem.3c00007
Hipersaite
https://pubs.acs.org/doi/10.1021/acs.jmedchem.3c00007

Ivanova, J., Nocentini, A., Tārs, K., Leitans, J., Dvinskis, E., Kazaks, A., Domračeva, I., Supuran, C., Žalubovskis, R. Atropo/Tropo Flexibility: A Tool for Design and Synthesis of Self-Adaptable Inhibitors of Carbonic Anhydrases and Their Antiproliferative Effect. Journal of Medicinal Chemistry, 2023, Vol. 66, No. 8, 5703.-5718.lpp. ISSN 0022-2623. e-ISSN 1520-4804. Pieejams: doi:10.1021/acs.jmedchem.3c00007

Publikācijas valoda
English (en)