Abstract
Chalcone is a simple and potentially privileged structure in medicinal chemistry with a diverse repertoire of biological activities, among which cytotoxicity is of particular interest. The sharp structure–activity relationship (SAR) for chalcone's cytotoxicity suggests structure-specific target interactions. Despite the numerous putative targets proposed, evidence for direct target interactions in cells is unavailable. In this study, guided by the sharp cytotoxic SAR, we developed a cytotoxic chalcone-based photoaffinity labeling (PAL) probe, (E)-3-(3-azidophenyl)-1-[3,5-dimethoxy-4-(prop-2-yn-1-yloxy)phenyl]-2-methylprop-2-en-1-one (C95; IC50: 0.38±0.01 μm), along with two structurally similar non-cytotoxic probes. These probes were used to search for the direct cellular target responsible for chalcone's cytotoxicity through intact cell-based PAL experiments, in which β-tubulin was identified to specifically interact with the cytotoxic probe (i.e., C95) but not the non-cytotoxic probes. A set of phenotypical and biochemical assays further reinforced β-tubulin as the cytotoxic target of chalcones. Peptide mass quantitation by mass spectrometric analysis revealed one peptide potentially labeled by C95, providing information on chalcone's binding site on β-tubulin.
Original language | English (US) |
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Pages (from-to) | 1436-1445 |
Number of pages | 10 |
Journal | ChemMedChem |
Volume | 11 |
Issue number | 13 |
DOIs | |
State | Published - Jul 5 2016 |
Bibliographical note
Publisher Copyright:© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Keywords
- chalcones
- chemical probes
- cytotoxicity
- photoaffinity labeling
- tubulin