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Published on: March 20, 2018
Discovery, structural modification and structure-activity relationship study of Echinulin derivatives as tyrosyl-DNA
Chuan-Sheng Yao1, Jiaqi Zhu2, Xiang Gao1
1School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China.
Abstract:
Tyrosyl-DNA phosphodiesterase 1 (TDP1) is a DNA repair enzyme and a potential antitumor target. Inhibiting TDP1 can potentiate the efficacy of both chemotherapy and radiotherapy. Herein, we report the discovery of the natural product Echinulin as a novel TDP1 inhibitor (IC50 = 5.6 μM). The structural modification of Echinulin gave fifty-one derivatives. The evaluation of TDP1 inhibition indicated that eight derivatives 20, 25, 26, 27, 33, 64, 66, and 67 showed higher TDP1 inhibitory activity than Echinulin. 33 exhibited the highest TDP1 potency with an IC50 value of 0.90 μM, and a strong synergistic effect with camptothecin in human skin melanoma SK-Mel-2 cells, but not in three cancer cells A549, HCT-116, MCF-7, and non-cancerous Ges-1 cells. Structure-activity relationship (SAR) and the hypothetical binding mode of 33 with TDP1 protein were also analyzed. These results highlight that the Echinulin scaffold is a novel chemotype for the development of TDP1 inhibitors.
Insights
The natural product Echinulin inhibits the DNA repair enzyme Tyrosyl-DNA phosphodiesterase 1 (TDP1). Its derivative 33 shows enhanced TDP1 inhibition and synergistic effects with chemotherapy in melanoma cells.
Area of Science:
- Biochemistry
- Molecular Biology
- Medicinal Chemistry
Background:
- Tyrosyl-DNA phosphodiesterase 1 (TDP1) is a crucial DNA repair enzyme.
- TDP1 is a promising target for cancer therapy, as its inhibition can enhance chemotherapy and radiotherapy efficacy.
Purpose of the Study:
- To identify novel TDP1 inhibitors from natural products.
- To explore the potential of Echinulin and its derivatives as TDP1 inhibitors for cancer treatment.
Main Methods:
- Screening of natural products for TDP1 inhibitory activity.
- Synthesis and structural modification of Echinulin.
- Evaluation of TDP1 inhibition and synergistic effects with camptothecin in various cancer cell lines.
- Structure-activity relationship (SAR) analysis and hypothetical binding mode prediction.
Main Results:
- Echinulin was identified as a novel TDP1 inhibitor with an IC50 of 5.6 μM.
- Eight Echinulin derivatives demonstrated improved TDP1 inhibitory activity.
- Derivative 33 exhibited the highest potency (IC50 = 0.90 μM) and showed significant synergistic effects with camptothecin in SK-Mel-2 melanoma cells.
Conclusions:
- The Echinulin scaffold represents a novel chemotype for developing potent TDP1 inhibitors.
- Derivative 33 holds potential for further development as an anticancer agent, particularly for melanoma.
- TDP1 inhibition is a viable strategy to potentiate chemotherapy efficacy.
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