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Bioorganic & medicinal chemistry letters (1)
PLoS ONE (1)
Barchi, Joseph J. (1)
Chen, Chin-Ho (1)
Chen, Huadong (1)
Dang, Zhao (1)
Ho, Phong (1)
Huang, Li (1)
Lee, Kuo-Hsiung (1)
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Soroka, Dominique N. (1)
Warin, Renaud F. (1)
Zhu, Yingdong (1)
Year of Publication
Metabolites of Ginger Component -Shogaol Remain Bioactive in Cancer Cells and Have Low Toxicity in Normal Cells: Chemical Synthesis and Biological Evaluation
Warin, Renaud F.
Barchi, Joseph J.
Our previous study found that -shogaol, a major bioactive component in ginger, is extensively metabolized in cancer cells and in mice. It is unclear whether these metabolites retain bioactivity. The aim of the current study is to synthesize the major metabolites of -shogaol and evaluate their inhibition of growth and induction of apoptosis in human cancer cells. Twelve metabolites of -shogaol (M1, M2, and M4–M13) were successfully synthesized using simple and easily accessible chemical methods. Growth inhibition assays showed that most metabolites of -shogaol had measurable activities against human cancer cells HCT-116 and H-1299. In particular, metabolite M2 greatly retained the biological activities of -shogaol, with an IC50 of 24.43 µM in HCT-116 human colon cancer cells and an IC50 of 25.82 µM in H-1299 human lung cancer cells. Also exhibiting a relatively high potency was thiol-conjugate M13, with IC50 values of 45.47 and 47.77 µM toward HCT-116 and H-1299 cells, respectively. The toxicity evaluation of the synthetic metabolites (M1, M2, and M4–M13) against human normal fibroblast colon cells CCD-18Co and human normal lung cells IMR-90 demonstrated a detoxifying metabolic biotransformation of -shogaol. The most active metabolite M2 had almost no toxicity to CCD-18Co and IMR-90 normal cells with IC50s of 99.18 and 98.30 µM, respectively. TUNEL (Terminal deoxynucleotidyl transferase dUTP nick end labeling) assay indicated that apoptosis was triggered by metabolites M2, M13, and its two diastereomers M13-1 and M13-2. There was no significant difference between the apoptotic effect of -shogaol and the effect of M2 and M13 after 6 hour treatment.
Synthesis and proteasome inhibition of lithocholic acid derivatives
Bioorganic & medicinal chemistry letters
A new class of proteasome inhibitors was synthesized using lithocholic acid as a scaffold. Modification at the C-3 position of lithocholic acid with a series of acid acyl groups yielded compounds with a range of potency on proteasome inhibition. Among them, the phenylene diacetic acid hemiester derivative (13) displayed the most potent proteasome inhibition with IC50 = 1.9 μM. Enzyme kinetic analysis indicates that these lithocholic acid derivatives are non-competitive inhibitors of the proteasome.
Lithocholic acid; proteasome; proteasome inhibitor
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