Application of the dual-tail approach for the design and synthesis of novel Thiopyrimidine-Benzenesulfonamide hybrids as selective carbonic anhydrase inhibitors
| Autor: | Andrea Petreni, Claudiu T. Supuran, Rasha M. Allam, Ahmed M. El Kerdawy, Mohamed A. Omar, Hoda I. El Diwani, Heba T. Abdel‐Mohsen |
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| Rok vydání: | 2021 |
| Předmět: |
Stereochemistry
Cell Survival Antineoplastic Agents Apoptosis Structure-Activity Relationship Carbonic anhydrase Cell Line Tumor Drug Discovery Potency Moiety Humans Carbonic Anhydrase Inhibitors Carbonic Anhydrases Cell Proliferation Pharmacology chemistry.chemical_classification Sulfonamides biology Dose-Response Relationship Drug Molecular Structure Chemistry Organic Chemistry Active site General Medicine Amino acid Isoenzymes Molecular Docking Simulation Pyrimidines Cell culture Drug Design biology.protein Drug Screening Assays Antitumor Selectivity |
| Zdroj: | European journal of medicinal chemistry. 228 |
| ISSN: | 1768-3254 |
| Popis: | A dual-tail approach was applied to the design of a novel series of 2-thiopyrimidine–benzenesulfonamides as carbonic anhydrase (CA) inhibitors. The design strategy is based on the hybridization between a benzenesulfonamide moiety as Zn2+ binding group and 2,4-disubstituted thiopyridimidine as a tail. Among the synthesized compounds, 14h displayed the highest potency (Ki = 1.72 nM) and selectivity for CA II over the isoforms CA IX and CA XII with selectivity indexes of 50 and 5.26, respectively. Meanwhile, compounds 14a and 14l displayed a potent inhibitory activity against CA IX (Ki = 7.4 and 7.0 nM, respectively) compared with the reference drug acetazolamide (AAZ) (Ki = 25 nM), and compound 14l showed higher potency (Ki = 4.67 nM) than AAZ (Ki = 5.7 nM) against the tumor-associated isoform CA XII. Evaluation of the antiproliferative activity in NCI single-dose testing of selected hybrids revealed a pronounced potency of the selective CA II inhibitor 14h against most of the tested NCI cancer cell lines. Moreover, compound 14h demonstrated an IC50 values ranging from 2.40-4.50 μM against MCF-7, T-47D, MDA-MB-231, HCT-116, HT29 and SW-620. These results demonstrate that CA II inhibition can be an alternative therapeutic target for cancer treatment. A cell cycle analysis of MCF-7 and MDA-MB-231 showed that treatment with 14h arrested both cell lines at the G2/M phase with significant accumulation of cells in the pre-G1 phase. Moreover, compound 14h showed a noticeable induction of late apoptosis and necrotic cell death of both cell lines compared with untreated cells as a control. A molecular docking study suggested that the sulfonamide moiety accommodates deeply in the CA active site and interacts with the Zn2+ ion while the dual-tail extension interacts with the surrounding amino acids via several hydrophilic and hydrophobic interactions, which affects the potency and selectivity of the hybrids. |
| Databáze: | OpenAIRE |
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