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Synthesis and anticancer activity of Boc-Gly-Pro dipeptide-annonaceous acetogenin prodrugs targeting fibroblast activation protein or other hydrolytic enzymes

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Abstract

Annonaceous acetogenins are potent ubiquinone-linked NADH oxidase inhibitors and have potent anticancer activity. Their usage in the clinic is limited because of their significant toxicity to normal cells. To obtain novel low toxicity antitumoral prodrugs, squamocin and bullatacin were covalently linked to N-butoxycarbonyl protected glycine-proline dipeptide (Boc-Gly-Pro), which may be recognized and cleaved by fibroblast activation protein (FAP), a serine protease overexpressed on the surface of tumor-associated fibroblasts. Ten squamocin and bullatacin derivatives were synthesized by attaching Boc-Gly-Pro either directly or through 6-aminocaproic acid linker to a hydroxyl group of squamocin or bullatacin. All derivatives showed high potency to inhibit 4T1 breast cancer cell line growth in the sub-µM to µM range. Compound 8 was the most active (IC50 0.30 μM) and displayed higher activity than squamocin. Most derivatives, however, display reduced potency by up to 50 folds compared to the parent drug. In the presence of FAP enzyme, the anticancer potency of compound 3 against A549, HeLa, HepG2 and MCF-7 cells was increased by up to eight folds. The data suggest that Boc-Gly-Pro-acetogenin prodrugs may show improved therapeutic potential of these acetogenins by reducing the drug doses and the toxic side effects.

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Data availability

The data that support the findings of this study are available from the corresponding authors upon reasonable request.

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Acknowledgements

We thank Mr. Yunfei Yuan, South China Botanical Garden, Chinese Academy of Sciences, for NMR spectroscopic measurements, and Ms. Aijun Sun, South China Sea Institute of Oceanology, Chinese Academy of Sciences, for HRESIMS measurements.

Author contributions

J-FS performed experiments on chemical synthesis and wrote the first draft of the manuscript. PW performed experiments on biological studies. H-XL repeated part of the experiments on chemical synthesis. X-YW and Z-HJ supervised the whole study and revised the manuscript. X-YW funded the project. All authors have read and agreed to the published version of the manuscript.

Funding

This research was supported by the National Natural Science Foundation of China (NSFC) (Grant No. 31470423).

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Authors and Affiliations

  1. Guangdong Provincial Key Laboratory for Crop Germplasm Resources Preservation and Utilization, AgroBiological Gene Research Center, Guangdong Academy of Agricultural Sciences, Guangzhou, 510640, PR China

    Jing-Fang Shi

  2. Key Laboratory of Plant Resources Conservation and Sustainable Utilization, South China Botanical Garden, Chinese Academy of Sciences, Xingke Road 723, Tianhe District, Guangzhou, 510650, PR China

    Jing-Fang Shi, Ping Wu, Han-Xiang Li & Xiao-Yi Wei

  3. Department of Chemistry, Lakehead University, 955 Oliver Road, Thunder Bay, ON, P7B 5E1, Canada

    Zi-Hua Jiang

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  1. Jing-Fang Shi
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Shi, JF., Wu, P., Li, HX. et al. Synthesis and anticancer activity of Boc-Gly-Pro dipeptide-annonaceous acetogenin prodrugs targeting fibroblast activation protein or other hydrolytic enzymes. Med Chem Res 31, 605–616 (2022). https://doi.org/10.1007/s00044-022-02857-3

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  • DOI: https://doi.org/10.1007/s00044-022-02857-3

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