Bioorganic & medicinal chemistry, 2015-12, Vol.23 (24), p.7585-7596
2015
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Details
- Autor(en) / Beteiligte
- Titel
- Discovery of novel quinoline-based mTOR inhibitors via introducing intra-molecular hydrogen bonding scaffold (iMHBS): The design, synthesis and biological evaluation
- Ist Teil von
- Bioorganic & medicinal chemistry, 2015-12, Vol.23 (24), p.7585-7596
- Ort / Verlag
- England: Elsevier Ltd
- Erscheinungsjahr
- 2015
- Quelle
- Elsevier ScienceDirect Journals
- Beschreibungen/Notizen
- [Display omitted] A series of quinoline derivatives featuring the novelty of introducing intra-molecular hydrogen bonding scaffold (iMHBS) were designed, synthesized and biologically evaluated for their mTOR inhibitory activity, as well as anti-proliferative efficacies against HCT-116, PC-3 and MCF-7 cell lines. As a result, six compounds exhibited significant inhibition against mTOR with IC50 values below 35nM. Compound 15a, the most potent mTOR inhibitor reported herein (IC50=14nM), also displayed the most favorable cellular activities, with the IC50 values of 0.46, 0.61 and 0.24μM against HCT-116, PC-3 and MCF-7, respectively. Besides, several compounds in this series were identified to be selective over class I PI3Ks. Further western blot analysis of 16b, a representative compound in this series, highlighted their advantage in surmounting the S6K/IRS1/PI3K negative feedback loop upon dual inhibition of mTORC1 and mTORC2. In addition to the remarkable activity, 15a demonstrated acceptable stability in simulated gastric fluid (SGF), simulated intestinal fluid (SIF) and liver microsome, thereby being valuable for extensive in vivo investigation.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0968-0896eISSN: 1464-3391DOI: 10.1016/j.bmc.2015.11.003Titel-ID: cdi_proquest_miscellaneous_1750439004
- Format
- –
- Schlagworte
- Anti-proliferative efficacy, Antineoplastic Agents - chemistry, Antineoplastic Agents - pharmacology, Cell Line, Tumor, Cell Proliferation - drug effects, Drug Design, HCT116 Cells, Humans, Hydrogen Bonding, MCF-7 Cells, Mechanistic Target of Rapamycin Complex 1, Mechanistic Target of Rapamycin Complex 2, Molecular Docking Simulation, mTOR inhibitor, Multiprotein Complexes - antagonists & inhibitors, Multiprotein Complexes - metabolism, Negative feedback loop, Neoplasms - drug therapy, Neoplasms - metabolism, Phosphatidylinositol 3-Kinases - metabolism, Protein Kinase Inhibitors - chemistry, Protein Kinase Inhibitors - pharmacology, Quinoline derivatives, Quinolines - chemistry, Quinolines - pharmacology, Selectivity, Signal Transduction - drug effects, Stability, TOR Serine-Threonine Kinases - antagonists & inhibitors, TOR Serine-Threonine Kinases - metabolism