An NAD(P)H:Quinone Oxidoreductase 1 Responsive and Self-Immolative Prodrug of 5-Fluorouracil for Safe and Effective Cancer Therapy

Zhang, Xiaojin; Li, Xiang; Li, Zhihong; Wu, Xingsen; Wu, Yue; Qin, You

doi:10.1021/acs.orglett.8b01409

Cited by 30 publications

(15 citation statements)

References 27 publications

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“…Development of natural products to new analogues with improved properties is highly desired in the drug discovery process . Targeted prodrug design for anticancer drugs is one of the interesting strategies in drug discovery. − Many anticancer natural products are not target specific and might also be quite toxic to normal cells. To lower the toxicity while keeping the therapeutic property of active natural products, proper structure modification serves as an important and useful tool in drug discovery.…”

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confidence: 99%

“…Embedment of an additional molecular device, which is cleavable by a specific enzyme expressed predominantly in tumor cells, is a commonly applied method in contemporary drug design and development . A bioreductive prodrug can be designed to target a specific tumor followed by in situ release of the therapeutic drugs with the reductase (NAD(P)H:quinone oxidoreductase 1, NQO1) overexpressed in some tumor cells. − Fortunately, the reductases are often reported to be overexpressed in a variety of cancer cells, such as breast cancer, ovarian cancer, thyroid cancer, adrenal cancer, and colon cancer. ,− …”

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confidence: 99%

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A Bioreductive Prodrug of Cucurbitacin B Significantly Inhibits Tumor Growth in the 4T1 Xenograft Mice Model

Suebsakwong

Wang

Khetkam

et al. 2019

ACS Med. Chem. Lett.

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Cucurbitacin B (CuB), a highly cytotoxic constituent of the Cucurbitaceae plant, was identified to exhibit potent inhibitory activity against human cancer cells as well as normal cells. This disadvantage hampers the possibility of developing this compound into an anticancer drug candidate. In this work, several bioreductive prodrugs of CuB were designed to reduce toxicity to normal cells while maintaining the cytotoxic effect to cancer cells. Embedded with a bioreductive delivery and cleavable system in cancer tissues, cucurbitacin B-based prodrugs 1, 2, and 3 were synthesized and evaluated by in vitro and in vivo experiments. Compared with the parent CuB, prodrug 1 was found to significantly reduce the toxicity down to 310-fold lower against noncancerous cells. LC-MS analyses show that prodrug 1 efficiently releases the parent compound in the reductase-overexpressed MCF-7 cells. In addition, prodrug 1 shows satisfactory and comparable effectiveness in controlling tumor growth as that by tamoxifen in the 4T1 xenograft mice model.

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confidence: 99%

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confidence: 99%

A Bioreductive Prodrug of Cucurbitacin B Significantly Inhibits Tumor Growth in the 4T1 Xenograft Mice Model

Suebsakwong

Wang

Khetkam

et al. 2019

ACS Med. Chem. Lett.

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“…50 Xu et al tested various indolequinone-based prodrugs and found a compound that exhibited antiproliferative activity against both A549 and HT-29 cells. Lastly, well-known anticancer prodrugs, such as methotrexate, 49 5-fluorouracil, 51 camptothecin, 52,53 and SN-38, 54 with the self-immolative linker were synthesized. After the reduction of quinone moiety, the self-immolative linker of the prodrugs was degraded by itself and the free drugs were released.…”

Section: Enzymes For the Cleavage Linker Of Prodrugsmentioning

confidence: 99%

Recent Trends in In Situ Enzyme-Activatable Prodrugs for Targeted Cancer Therapy

et al. 2020

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Enzyme-activatable anticancer prodrugs are modified medications that are composed of an anticancer drug, cleavable linker, and functional moiety. The purpose of such a prodrug structure is to generate multipurpose functions that traditional drugs cannot perform and to reduce the toxicity of conventional anticancer drugs by the mask of the cleavable linker. Once the cleavable linker is degraded via a specific chemical reaction in the cancer microenvironment, the cytotoxicity of the degraded prodrugs is selectively recovered. Among many factors that cleave the linker, we focus on the overexpressed enzymes in cancer. Because of the selective enzymatic degradation of the cleavable linker and the high local concentration of specific enzymes in cancer, the enzyme-activatable prodrugs could show low toxicity in normal tissues, while showing comparable anticancer effect in tumors. In addition, some prodrugs provide additional features, such as cancer imaging, drug release monitoring, tumor targeting, and enhanced stability, which conventional anticancer drugs cannot possess. In this review, we summarize currently developed enzymeactivatable prodrugs according to their activating enzymes, and categorize them by their additional functions, e.g. targeting, imaging, and delivery. This summary of enzyme-activatable prodrugs may help in the design of anticancer prodrugs, and in the establishment of a personalized cancer treatment strategy.

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“…Compound 3 was prepared according to the methodology described by Zhang and coworkers. 14 To a solution of compound 2 (0.400 g, 1.60 mmol) and DCC (0.363 g, 1.76 mmol) in CH2Cl2 (10 mL) was added DMAP (0.022 g, 0.16 mmol), stirring at room temperature. After 30 min, propargyl alcohol (3 equivalents) was added and the mixture was stirred overnight.…”

Section: Synthetic Experimentsmentioning

confidence: 99%

Natural product-inspired profluorophores for imaging NQO1 activity in tumour tissues

Cheng

Valença

Dias

et al. 2019

Bioorganic & Medicinal Chemistry

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Herein we designed a collection of trimethyl-lock quinone profluorophores as activity-based probes for imaging NAD(P)H:quinone oxidoreductase (NQO1) in cancer cells and tumour tissues. Profluorophores were prepared via synthetic routes from naturally-occurring quinones and characterised in vitro using recombinant enzymes, to be further validated in cells and fresh frozen canine tumour tissues as potential new tools for cancer detection and imaging.

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An NAD(P)H:Quinone Oxidoreductase 1 Responsive and Self-Immolative Prodrug of 5-Fluorouracil for Safe and Effective Cancer Therapy

Cited by 30 publications

References 27 publications

A Bioreductive Prodrug of Cucurbitacin B Significantly Inhibits Tumor Growth in the 4T1 Xenograft Mice Model

A Bioreductive Prodrug of Cucurbitacin B Significantly Inhibits Tumor Growth in the 4T1 Xenograft Mice Model

Recent Trends in In Situ Enzyme-Activatable Prodrugs for Targeted Cancer Therapy

Natural product-inspired profluorophores for imaging NQO1 activity in tumour tissues

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