New derivatives of sulfonylhydrazone as potential antitumor agents: Design, synthesis and cheminformatics evaluation
| Autor: | Kamal Sweidan, Ghassan Abu Sheikha, Sawsan Shraim, Bara’a A. Al-Azaideh, Wamidh H. Talib, Rima Hajjo, Aya M. Al-Zuheiri, Dima A. Sabbah |
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| Rok vydání: | 2021 |
| Předmět: |
Pharmacology
0303 health sciences Chemistry pi3kα-inhibitors cheminformatics Pharmaceutical Science General Medicine Combinatorial chemistry 03 medical and health sciences 0302 clinical medicine Docking (dog) Design synthesis Cheminformatics 030220 oncology & carcinogenesis docking hct-116 HD9665-9675 sulfonylhydrazones Pharmaceutical industry antitumor 030304 developmental biology |
| Zdroj: | Acta Pharmaceutica, Vol 71, Iss 4, Pp 545-565 (2021) |
| ISSN: | 1846-9558 |
| DOI: | 10.2478/acph-2021-0043 |
| Popis: | Phosphoinositide 3-kinase α (PI3Kα) is a propitious target for designing anticancer drugs. A series of new N’-(diphenylmethylene)benzenesulfonohydrazide was synthesized and characterized using FT-IR, NMR (1H and 13C), HRMS, and elemental analysis. Target compounds exhibited an antiproliferative effect against the human colon carcinoma (HCT-116) cell line. Our cheminformatics analysis indicated that the para-tailored derivatives [p-NO2 (3) and p-CF3 (7)] have better ionization potentials based on calculated Moran autocorrelations and ionization potentials. Subsequent in vitro cell proliferation assays validated our cheminformatics results by providing experimental evidence that both derivatives 3 and 7 exhibited improved antiproliferative activities against HCT-116. Hence, our results emphasized the importance of electron-withdrawing groups and hydrogen bond-acceptors in the rational design of small-molecule chemical ligands targeting PI3Kα. These results agreed with the induced-fit docking against PI3Kα, highlighting the role of p-substituted aromatic rings in guiding the ligand-PI3Kα complex formation, by targeting a hydrophobic pocket in the ligand-binding site and forming π-stacking interactions with a nearby tryptophan residue. |
| Databáze: | OpenAIRE |
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