Investigation of B,C-ring truncated deguelin derivatives as heat shock protein 90 (HSP90) inhibitors for use as anti-breast cancer agents
| Autor: | Kyung Chul Kim, Ji Hae Seo, Kyu-Won Kim, Mannkyu Hong, Hoon Choi, Jun Yong Kim, Jeewoo Lee, Jie Chen, Sang Kook Lee, Cong Truong Nguyen, Young-Ger Suh, Jihyae Ann, Seungbeom Lee, Woong Sub Byun, Jae Hong Seo, Ji Young Kim, Tae Min Cho, Ho Shin Kim, Hyun Ju Park, Van-Hai Hoang |
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| Rok vydání: | 2019 |
| Předmět: |
Models
Molecular Molecular model Cell Survival Stereochemistry Clinical Biochemistry Pharmaceutical Science Antineoplastic Agents Breast Neoplasms 01 natural sciences Biochemistry Structure-Activity Relationship chemistry.chemical_compound Cell Line Tumor Rotenone Heat shock protein Drug Discovery Humans Structure–activity relationship HSP90 Heat-Shock Proteins Cytotoxicity Molecular Biology Cell Proliferation Dose-Response Relationship Drug Molecular Structure biology 010405 organic chemistry Chemistry Organic Chemistry Hsp90 0104 chemical sciences 010404 medicinal & biomolecular chemistry biology.protein Molecular Medicine Phosphorylation Female Drug Screening Assays Antitumor Linker Deguelin |
| Zdroj: | Bioorganic & Medicinal Chemistry. 27:1370-1381 |
| ISSN: | 0968-0896 |
| Popis: | On the basis of deguelin, a series of the B,C-ring truncated surrogates with N-substituted amide linkers were investigated as HSP90 inhibitors. The structure activity relationship of the template was studied by incorporating various substitutions on the nitrogen of the amide linker and examining their HIF-1α inhibition. Among them, compound 57 showed potent HIF-1α inhibition and cytotoxicity in triple-negative breast cancer lines in a dose-dependent manner. Compound 57 downregulated expression and phosphorylation of major client proteins of HSP90 including AKT, ERK and STAT3, indicating that its antitumor activity was derived from the inhibition of HSP90 function. The molecular modeling of 57 demonstrated that 57 bound well to the C-terminal ATP-binding pocket in the open conformation of the hHSP90 homodimer with hydrogen bonding and pi-cation interactions. Overall, compound 57 is a potential antitumor agent for triple-negative breast cancer as a HSP90 C-terminal inhibitor. |
| Databáze: | OpenAIRE |
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