| RRC ID |
69711
|
| 著者 |
Yamali C, Sakagami H, Uesawa Y, Kurosaki K, Satoh K, Masuda Y, Yokose S, Ece A, Bua S, Angeli A, Supuran CT, Gul HI.
|
| タイトル |
Comprehensive study on potent and selective carbonic anhydrase inhibitors: Synthesis, bioactivities and molecular modelling studies of 4-(3-(2-arylidenehydrazine-1-carbonyl)-5-(thiophen-2-yl)-1H-pyrazole-1-yl) benzenesulfonamides.
|
| ジャーナル |
Eur J Med Chem
|
| Abstract |
In this research, rational design, synthesis, carbonic anhydrases (CAs) inhibitory effects, and cytotoxicities of the 4-(3-(2-arylidenehydrazine-1-carbonyl)-5-(thiophen-2-yl)-1H-pyrazole-1-yl)benzenesulfonamides 1-20 were reported. Compound 18 (Ki = 7.0 nM) was approximately 127 times more selective cancer-associated hCA IX inhibitor over hCA I, while compound 17 (Ki = 10.6 nM) was 47 times more selective inhibitor of hCA XI over hCA II compared to the acetazolamide. Compounds 11 (CC50 = 5.2 μM) and 20 (CC50 = 1.6 μM) showed comparative tumor-specificity (TS= > 38.5; >128.2) with doxorubicin (TS > 43.0) towards HSC-2 cancer cell line. Western blot analysis demonstrated that 11 induced slightly apoptosis whereas 20 did not induce detectable apoptosis. A preliminary analysis showed that some correlation of tumor-specificity of 1-20 with the chemical descriptors that reflect hydrophobic volume, dipole moment, lowest hydrophilic energy, and topological structure. Molecular docking simulations were applied to the synthesized ligands to elucidate the predicted binding mode and selectivity profiles towards hCA I, hCA II, and hCA IX.
|
| 巻・号 |
217
|
| ページ |
113351
|
| 公開日 |
2021-5-5
|
| DOI |
10.1016/j.ejmech.2021.113351
|
| PII |
S0223-5234(21)00200-2
|
| PMID |
33744685
|
| MeSH |
Carbonic Anhydrase Inhibitors / chemical synthesis
Carbonic Anhydrase Inhibitors / chemistry
Carbonic Anhydrase Inhibitors / pharmacology*
Carbonic Anhydrases / metabolism*
Cell Line
Dose-Response Relationship, Drug
Humans
Isoenzymes / antagonists & inhibitors
Isoenzymes / metabolism
Models, Molecular
Molecular Structure
Pyrazoles / chemical synthesis
Pyrazoles / chemistry
Pyrazoles / pharmacology*
Structure-Activity Relationship
Sulfonamides / chemical synthesis
Sulfonamides / chemistry
Sulfonamides / pharmacology*
|
| IF |
5.573
|
| リソース情報 |
| ヒト・動物細胞 |
HSC-2(RCB1945) |
