Synthesis and biological characterization of ubenimex-fluorouracil conjugates for anti-cancer therapy

Synthesis and biological characterization of ubenimex-fluorouracil conjugates for anti-cancer... Previously a novel ubenimex-fluorouracil (5-FU) conjugate, BC-01 was identified and validated as a potent CD13 inhibitor with marked in vitro and in vivo antitumor potency. Herein, further structural modifications of the linker part of BC-01 was carried out to get more potent and stable ubenimex–fluorouracil conjugates. It was striking that most of these conjugates showed even more potent CD13 inhibitory activities than BC-01 and the approved CD13 inhibitor ubenimex. One representative compound 12a displayed significant in vitro anti-proliferation, pro-apoptosis, anti-metastasis, anti-angiogenesis and CD13+ cell elimination effects. In vitro stability and in vivo pharmacokinetic study revealed that compound 12a could release ubenimex and 5-FU slowly, which could act as a mutual prodrug of ubenimex and 5-FU. Compared with 5-FU or 5-FU plus ubenimex, 12a exhibited superior in vivo antitumor growth efficiency, even in our mice model of 5-FU-resistant liver cancer. Moreover, 12a exhibited more potent in vivo anti-metastasis and lifespan extension effects compared to the approved 5-FU prodrug capecitabine. Collectively, these results suggest that further optimization and evaluation of 12a as a promising anticancer candidate are warranted to develop effective therapeutic agents for human liver cancer. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png European Journal of Medicinal Chemistry Elsevier

Synthesis and biological characterization of ubenimex-fluorouracil conjugates for anti-cancer therapy

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Publisher
Elsevier
Copyright
Copyright © 2017 Elsevier Masson SAS
ISSN
0223-5234
eISSN
1768-3254
D.O.I.
10.1016/j.ejmech.2017.11.074
Publisher site
See Article on Publisher Site

Abstract

Previously a novel ubenimex-fluorouracil (5-FU) conjugate, BC-01 was identified and validated as a potent CD13 inhibitor with marked in vitro and in vivo antitumor potency. Herein, further structural modifications of the linker part of BC-01 was carried out to get more potent and stable ubenimex–fluorouracil conjugates. It was striking that most of these conjugates showed even more potent CD13 inhibitory activities than BC-01 and the approved CD13 inhibitor ubenimex. One representative compound 12a displayed significant in vitro anti-proliferation, pro-apoptosis, anti-metastasis, anti-angiogenesis and CD13+ cell elimination effects. In vitro stability and in vivo pharmacokinetic study revealed that compound 12a could release ubenimex and 5-FU slowly, which could act as a mutual prodrug of ubenimex and 5-FU. Compared with 5-FU or 5-FU plus ubenimex, 12a exhibited superior in vivo antitumor growth efficiency, even in our mice model of 5-FU-resistant liver cancer. Moreover, 12a exhibited more potent in vivo anti-metastasis and lifespan extension effects compared to the approved 5-FU prodrug capecitabine. Collectively, these results suggest that further optimization and evaluation of 12a as a promising anticancer candidate are warranted to develop effective therapeutic agents for human liver cancer.

Journal

European Journal of Medicinal ChemistryElsevier

Published: Jan 1, 2018

References

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