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A Mitochondria-Targeted Phenylbutyric Acid Prodrug Confers Drastically Improved Anticancer Activities
D. Huang1; Q. Liu1; M. Zhang1; Y. Gao1; Z. Cui1; T. Li1; D. Luo1; B. Xu1; C. Huang1; J. Guo1; K.Y. Tam2; M. Zhang1; S.L. Zhang1; Y. He1
2022-07
Source PublicationJournal of Medicinal Chemistry
ISSN0022-2623
Volume65Pages:9955-9973
Abstract

Phenylbutyric acid (PBA) has been reported as a dual inhibitor of pyruvate dehydrogenase kinases (PDKs) and
histone deacetylases (HDACs), exhibiting anticancer effects. However, the low membrane permeability and poor cellular uptake limit its access to the target organelle, resulting in weak potencies against the intended targets. Herein, we report the design and identification of a novel 4-CF3-phenyl triphenylphosphonium-based PBA conjugate (53) with improved invitroand invivoanticancer activities. Compound 53 exhibited an IC50 value of 2.22 μM against A375 cells, outperforming the parent drug PBA by about 4000-fold. In the A375 cell-derived xenograft mouse model, 53 reduced the tumor growth by 76% at a dose of 40 mg/kg, while PBA only reduced the tumor growth by 10% at a dose of 80 mg/kg. On the basis of these results, 53 may be considered for further preclinical evaluations for cancer therapy.

DOI10.1021/acs.jmedchem.2c00640
URLView the original
Indexed BySCIE
Language英語English
WOS Research AreaPharmacology & Pharmacy
WOS SubjectChemistry, Medicinal
WOS IDWOS:000829250900001
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Document TypeJournal article
CollectionFaculty of Health Sciences
Corresponding AuthorS.L. Zhang; Y. He
Affiliation1.School of Pharmaceutical Sciences, Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, Chongqing University
2.Faculty of Health Sciences, University of Macau
Recommended Citation
GB/T 7714
D. Huang,Q. Liu,M. Zhang,et al. A Mitochondria-Targeted Phenylbutyric Acid Prodrug Confers Drastically Improved Anticancer Activities[J]. Journal of Medicinal Chemistry,2022,65:9955-9973.
APA D. Huang,Q. Liu,M. Zhang,Y. Gao,Z. Cui,T. Li,D. Luo,B. Xu,C. Huang,J. Guo,K.Y. Tam,M. Zhang,S.L. Zhang,&Y. He.(2022).A Mitochondria-Targeted Phenylbutyric Acid Prodrug Confers Drastically Improved Anticancer Activities.Journal of Medicinal Chemistry,65,9955-9973.
MLA D. Huang,et al."A Mitochondria-Targeted Phenylbutyric Acid Prodrug Confers Drastically Improved Anticancer Activities".Journal of Medicinal Chemistry 65(2022):9955-9973.
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