Modulation of Antineoplastic Drug Cytotoxicity by Substrate-Based Design of Potent Human Glutathione S-Transferase (hGST) Inhibitors
| Autor: | Huang-Chi Du, 杜凰祺 |
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| Rok vydání: | 2007 |
| Druh dokumentu: | 學位論文 ; thesis |
| Popis: | 95 We choose the substrate, glutathione (γ-Glu-Cys-Gly, GSH), of human glutathione S-transferase (GST) as a building block to synthesize a series of GST substrate-based analogs where the Cys residue is substituted by serine. The overall synthesis was performed by utilizing both Cu(I)-catalyzed Huisgen 1,3-cycloaddition and peptide synthesis technique. Therefore, the final substrate-based analogs 13-17 were comprised of γ-Glu-Ser-Gly backbone, 1,2,3-trizole subunit, and hydrophobic moiety and subject to HPLC purification (total yields 12.8 ~ 16.5%) before biological testing. In protein level, promising results were displayed in the inhibition of human GST isozyme assay using substrate-based analogs 13-17. In the study of hGSTA2, the IC50 values of 13-17 are found between 14.3 μM and 164.0 μM. In the case of hGSTM1, the IC50 range is observed between 1.5 μM and 34.0 μM indicating the 3- to 20-fold enhancement of inhibitory property of 13-17 toward specific isozyme. Analogue 14, compound with a meta-chlorobenzene moiety as a hydrophobic unit, was the most active one with IC50 values of 15.1 and 1.5 μM toward hGSTA2 and hGSTM1, respectively. From the Lineweaver-Burk plots showed that compound 14 exhibited a competitive inhibition (Ki = 6.4 μM) toward hGSTA2 and also displayed a pattern of mixed-type inhibition (Ki = 0.6 μM) toward hGSTM1 under the same condition. In cellular study, the cytotoxic effect of antineoplastic agents, cisplatin and thiotepa, in the presence and absence of compound 14 was tested on human breast cancer cell, MDA-MB-231. Evidence of cytotoxicity enhancement (2- to 3-fold) of antineoplastic agents was observed in the presence of 14 suggesting that the hGSTs inhibitor plays an important role in regulating the efficacy of clinical anticancer drugs and reducing the side effect during the cancer therapy. |
| Databáze: | Networked Digital Library of Theses & Dissertations |
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