A Mitochondria-Targeted Phenylbutyric Acid Prodrug Confers Drastically Improved Anticancer Activities

作者全名："Huang, Ding; Liu, Qingwang; Zhang, Maojie; Guo, Yizhen; Cui, Zhiying; Li, Tao; Luo, Dong; Xu, Biao; Huang, Chao; Guo, Jian; Tam, Kin Yip; Zhang, Min; Zhang, Shao-Lin; He, Yun"

作者地址："[Huang, Ding; Zhang, Maojie; Cui, Zhiying; Li, Tao; Luo, Dong; Huang, Chao; Guo, Jian; Zhang, Min; Zhang, Shao-Lin; He, Yun] Chongqing Univ, Sch Pharmaceut Sci, Chongqing Key Lab Nat Prod Synth & Drug Res, Chongqing 401331, Peoples R China; [Liu, Qingwang] Chinese Acad Sci, Inst Hlth & Med Technol, Hefei Inst Phys Sci, Hefei 230031, Anhui, Peoples R China; [Guo, Yizhen] Univ Macau, Fac Hlth Sci, Macau 999078, Peoples R China; [Xu, Biao] Chongqing Med Univ, Sch Pharm, Dept Med Chem, Key Lab Biochem & Mol Pharmacol Chongqing, Chongqing 400016, Peoples R China"

通信作者："Zhang, SL; He, Y (通讯作者)，Chongqing Univ, Sch Pharmaceut Sci, Chongqing Key Lab Nat Prod Synth & Drug Res, Chongqing 401331, Peoples R China."

来源：JOURNAL OF MEDICINAL CHEMISTRY

ESI学科分类：CHEMISTRY

WOS号：WOS:000829250900001

JCR分区：Q1

影响因子：7.3

年份：2022

卷号：65

期号：14

开始页：9955

结束页：9973

文献类型：Article

关键词：　

摘要："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 in vitro and in vivo anticancer activities. Compound 53 exhibited an IC50 value of 2.22 mu M 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."

基金机构：National Natural Science Foundation of China [21807008]; Natural Science Foundation of Chongqing of China [cstc2020jcyj-msxmX0650]; Fundamental Research Funds for the Central Universities [2020CDJ-LHZZ-008]

基金资助正文："? ACKNOWLEDGMENTS This work was supported by the National Natural Science Foundation of China (21807008) , the Natural Science Foundation of Chongqing of China (cstc2020jcyj-msxmX0650) , and the Fundamental Research Funds for the Central Universities (2020CDJ-LHZZ-008) ."