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Design and Synthesis of Cyclolipopeptide Mimics of Dysoxylactam A and Evaluation of the Reversing Potencies against P-Glycoprotein-Mediated Multidrug Resistance

文献类型：期刊论文

作者Yang, Guan-Zhou2,3; Wang, Lei3; Gao, Kun2; Zhu, Xi3; Lou, Li-Guang3; Yue, Jian-Min1,2,3
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2024-03-19
卷号67期号:6页码:4560-4582
ISSN号0022-2623
DOI10.1021/acs.jmedchem.3c01920
通讯作者Lou, Li-Guang(lglou@simm.ac.cn) ; Yue, Jian-Min(jmyue@simm.ac.cn)
英文摘要Inspired by the structure of dysoxylactam A (DLA) that has been demonstrated to reverse P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) effectively, 61 structurally simplified cyclolipopeptides were thus designed and synthesized via an effective method, and their reversing P-gp-mediated MDR potentials were evaluated, which provided a series of more potent analogues and allowed us to explore their structure-activity relationship (SAR). Among them, a well-simplified compound, 56, with only two chiral centers that all derived from amino acids dramatically reversed drug resistance in KBV200 cells at 10 mu M in combination with vinorelbine (VNR), paclitaxel (PTX), and adriamycin (ADR), respectively, which is more promising than DLA. The mechanism study showed that 56 reversed the MDR of tumor cells by inhibiting the transport function of P-gp rather than reducing its expression. Notably, compound 56 effectively restored the sensitivity of MDR tumors to VNR in vivo at a dosage without obvious toxicity.
WOS关键词GP INHIBITORS ; CANCER ; MODULATORS ; PHYTOCHEMICALS ; TETRANDRINE ; PROTEIN-1 ; DISCOVERY ; TRANSPORT
资助项目National Natural Science Foundation of China[22237007] ; National Natural Science Foundation of China[82293685] ; National Natural Science Foundation[2019-I2M-5-080] ; CAMS Innovation Fund for Medical Sciences[KFJ-BRP-008-001] ; Biological Resources Program of Chinese Academy of Sciences[18DZ2293200] ; Science and Technology Commission of Shanghai Municipality[202102AA310026] ; Yunnan Province Sciences and Technology plan ; P. R. China
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001187674800001
出版者AMER CHEMICAL SOC
源URL[http://119.78.100.183/handle/2S10ELR8/310115]  
专题新药研究国家重点实验室
通讯作者Lou, Li-Guang; Yue, Jian-Min
作者单位1.Chinese Acad Med Sci, Res Units Discovery New Drug Lead Mol, Shanghai 201203, Peoples R China
2.Lanzhou Univ, Coll Chem & Chem Engn, State Key Lab Appl Organ Chem, Lanzhou 730000, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Yang, Guan-Zhou,Wang, Lei,Gao, Kun,et al. Design and Synthesis of Cyclolipopeptide Mimics of Dysoxylactam A and Evaluation of the Reversing Potencies against P-Glycoprotein-Mediated Multidrug Resistance[J]. JOURNAL OF MEDICINAL CHEMISTRY,2024,67(6):4560-4582.
APA Yang, Guan-Zhou,Wang, Lei,Gao, Kun,Zhu, Xi,Lou, Li-Guang,&Yue, Jian-Min.(2024).Design and Synthesis of Cyclolipopeptide Mimics of Dysoxylactam A and Evaluation of the Reversing Potencies against P-Glycoprotein-Mediated Multidrug Resistance.JOURNAL OF MEDICINAL CHEMISTRY,67(6),4560-4582.
MLA Yang, Guan-Zhou,et al."Design and Synthesis of Cyclolipopeptide Mimics of Dysoxylactam A and Evaluation of the Reversing Potencies against P-Glycoprotein-Mediated Multidrug Resistance".JOURNAL OF MEDICINAL CHEMISTRY 67.6(2024):4560-4582.

入库方式： OAI收割

来源：上海药物研究所

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