Development of Macrocyclic Peptides Containing Epoxyketone with Oral Availability as Proteasome Inhibitors
文献类型：期刊论文
| 作者 | Li, Daqiang3; Zhang, Xiaotuan4,6; Ma, Xiaodong1; Xu, Lei5,6; Yu, Jianjun3; Gao, Lixin4; Hu, Xiaobei4; Zhang, Jiankang2; Dong, Xiaowu3; Li, Jia4
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| 刊名 | JOURNAL OF MEDICINAL CHEMISTRY
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| 出版日期 | 2018-10-25 |
| 卷号 | 61期号:20页码:9177-9204 |
| ISSN号 | 0022-2623 |
| DOI | 10.1021/acs.jmedchem.8b00819 |
| 文献子类 | Article |
| 英文摘要 | Macrocyclization has been frequently utilized for optimizing peptide or peptidomimetic-based compounds. In an attempt to obtain potent, metabolically stable, and orally available proteasome inhibitors, 30 oprozomib-derived macrocyclic peptides with structural diversity in their N-terminus and linker were successively designed and synthesized for structure- activity relationship (SAR) studies. As a consequence, the macrocyclic peptides with N-methyl-pyrazole (24p, 24x), imidazole (24t), and pyrazole (24v) as their respective N-termini exhibited favorable in vitro activity and metabolic stability, which translated into their potent in vivo proteasome inhibitory activity after oral administration. In particular, compound 24v, as the most distinguished one among this series, displayed excellent chymotrypsin-like (ChT-L, beta 5) inhibitory potency (IC50 = 16 nM), low nanomolar antiproliferative activity against all three of the tested cell lines, and superior metabolic stability in mouse liver microsome (MLM), as well as favorable inhibition against ChT-L compared to that of oprozomib in BABL/c mice following po administration at a comparatively low dose, thereby representing a promising candidate for further development. |
| WOS关键词 | REFRACTORY MULTIPLE-MYELOMA ; SINGLE-AGENT CARFILZOMIB ; BIOLOGICAL EVALUATION ; 20S PROTEASOME ; PERIPHERAL NEUROPATHY ; STRUCTURAL CLASS ; DESIGN ; BORTEZOMIB ; IMMUNOPROTEASOMES ; BELACTOSIN |
| 资助项目 | Zhejiang Provincial Natural Science Foundation of China[LZ15H300001] ; Science and Technology Commission of Shanghai Municipality[17431903000] ; "Personalized Medicines-Molecular Signature-Based Drug Discovery and Development" Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12020222] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000448754900013 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/279528]  |
| 专题 | 国家新药筛选中心 中科院受体结构与功能重点实验室 新药研究国家重点实验室 药物化学研究室 |
| 通讯作者 | Liu, Tao; Zhou, Yubo; Hu, Yongzhou |
| 作者单位 | 1.Anhui Univ Chinese Med, Sch Pharm, Dept Med Chem, Hefei 230031, Anhui, Peoples R China; 2.Zhejiang Univ, City Coll, Hangzhou 310015, Zhejiang, Peoples R China 3.Zhejiang Univ, Coll Pharmaceut Sci, ZJU ENS Joint Lab Med Chem, Zhejiang Prov Key Lab Anti Canc Drug Res, Hangzhou 310058, Zhejiang, Peoples R China; 4.Chinese Acad Sci, Natl Ctr Drug Screening, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China; 5.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201203, Peoples R China; 6.Univ Chinese Acad Sci, Grad Sch, 19A Yuquan Rd, Beijing 100049, Peoples R China; |
| 推荐引用方式 GB/T 7714 | Li, Daqiang,Zhang, Xiaotuan,Ma, Xiaodong,et al. Development of Macrocyclic Peptides Containing Epoxyketone with Oral Availability as Proteasome Inhibitors[J]. JOURNAL OF MEDICINAL CHEMISTRY,2018,61(20):9177-9204. |
| APA | Li, Daqiang.,Zhang, Xiaotuan.,Ma, Xiaodong.,Xu, Lei.,Yu, Jianjun.,...&Hu, Yongzhou.(2018).Development of Macrocyclic Peptides Containing Epoxyketone with Oral Availability as Proteasome Inhibitors.JOURNAL OF MEDICINAL CHEMISTRY,61(20),9177-9204. |
| MLA | Li, Daqiang,et al."Development of Macrocyclic Peptides Containing Epoxyketone with Oral Availability as Proteasome Inhibitors".JOURNAL OF MEDICINAL CHEMISTRY 61.20(2018):9177-9204. |
入库方式： OAI收割
来源：上海药物研究所
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