Synthesis and Biological Evaluation of Paclitaxel and Camptothecin Prodrugs on the Basis of 2‑Nitroimidazole

Due to the low esterase activity in human plasma, many ester and carbonate prodrugs tested in humans may be less effective than that in preclinical animals. In this letter, PTX and SN-38 were attached to the N-1 position of 2-nitroimidazole via a carbonate linker. Presumably, 2-aminoimidazole may he...

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Published inACS medicinal chemistry letters Vol. 8; no. 7; pp. 762 - 765
Main Authors Jin, Chen, Wen, Shuai, Zhang, Qiumeng, Zhu, Qiwen, Yu, Jiahui, Lu, Wei
Format Journal Article
LanguageEnglish
Published WASHINGTON American Chemical Society 13.07.2017
Amer Chemical Soc
Subjects
Chemistry, Medicinal
Letter
Life Sciences & Biomedicine
Pharmacology & Pharmacy
Science & Technology
prodrug
paclitaxel
SN-38
2-Nitroimidazole
NATURAL-PRODUCTS
PLANT ANTITUMOR AGENTS
TOPOISOMERASE-I
HYPOXIA-ACTIVATED PRODRUGS
CANCER-THERAPY
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Summary:Due to the low esterase activity in human plasma, many ester and carbonate prodrugs tested in humans may be less effective than that in preclinical animals. In this letter, PTX and SN-38 were attached to the N-1 position of 2-nitroimidazole via a carbonate linker. Presumably, 2-aminoimidazole may help promote the intramolecular hydrolysis of the carbonate bond. The prodrugs exhibited a considerable stability in buffers at different pH values as well as in human plasma. Furthermore, a rapid reduction was exhibited in the presence of nitroreductase. An in vitro cytotoxicity assay demonstrated that hypoxic conditions could increase the toxicity of prodrugs. Potentially, the compound species may form a new class of promising antitumor agents.
Bibliography:ObjectType-Article-1
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ISSN:1948-5875
1948-5875
DOI:10.1021/acsmedchemlett.7b00189