1,3-Dipolar Cycloaddition, HPLC Enantioseparation, and Docking Studies of Saccharin/Isoxazole and Saccharin/Isoxazoline Derivatives as Selective Carbonic Anhydrase IX and XII Inhibitors.
J Med Chem
; 63(5): 2470-2488, 2020 03 12.
Article
de En
| MEDLINE
| ID: mdl-31972093
ABSTRACT
Two series of saccharin/isoxazole and saccharin/isoxazoline hybrids were synthesized by 1,3-dipolar cycloaddition. The new compounds showed to be endowed with potent and selective inhibitory activity against the cancer-related human carbonic anhydrase (hCA) IX and XII isoforms in the nanomolar range, while no affinity was encountered for off-targets, such as hCA I and II. Successive enantioseparation on a milligram scale of the most representative compounds led to the discovery that (S)-isomers were more potent than their corresponding (R)-enantiomers. Lastly, molecular modeling studies were conducted to define those structural requirements that were responsible for the discrimination among selected human isoforms of carbonic anhydrases. Two nanomolar hCA IX and XII inhibitors were also screened for their selective toxicity against non tumoral primary cells (fibroblasts) and against a breast adenocarcinoma cell line (MCF7) in hypoxic environment. The efficacious combination of these compounds with doxorubicin on MCF7 cells was demonstrated after 72 h of treatment.
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Saccharine
/
Inhibiteurs de l'anhydrase carbonique
/
Carbonic anhydrases
/
Carbonic anhydrase IX
/
Antigènes néoplasiques
Limites:
Humans
Langue:
En
Journal:
J Med Chem
Sujet du journal:
QUIMICA
Année:
2020
Type de document:
Article
Pays d'affiliation:
Italie