Novel dimeric aryldiketo containing inhibitors of HIV-1 integrase: Effects of the phenyl substituent and the linker orientation
文献类型：期刊论文
| 作者 | Zeng, Li-Fan2; Jiang, Xiao-Hua2; Sanchez, Tino1; Zhang, Hu-Shan2; Dayam, Raveendra1; Neamati, Nouri1; Long, Ya-Qiu2 |
| 刊名 | BIOORGANIC & MEDICINAL CHEMISTRY
 |
| 出版日期 | 2008-08-15 |
| 卷号 | 16期号:16页码:7777-7787 |
| 关键词 | HIV-1 integrase inhibitors aryl diketoacid strand transfer dimer conformationally constrained linker orientation substitution effect |
| ISSN号 | 0968-0896 |
| DOI | 10.1016/j.bmc.2008.07.008 |
| 文献子类 | Article |
| 英文摘要 | Aryl diketoacids (ADK) and their bioisosteres are among the most promising HIV-1 integrase (IN) inhibitors. Previously, we designed a series of ADK dimers as a new class of IN inhibitors that were hypothesized to target two divalent metal ions on the active site of IN. Herein we present a further structure-activity relationship (SAR) study with respect to the substituent effect of the ADK and the dimerization with conformationally constrained linkers such as piperazine, 4-amino-piperidine, piperidin-4-ol, and trans-cyclohexan-1,4-diamine. The substituents on the phenyl ring as well as the spatial orientation of the two diketo units were observed to play important roles in the IN inhibitory potency. The hydrophobic group was an optimal substitution at the 3-position of the aryl ring. The piperazine and 4-amino-piperidine linkers brought about the most potent analogs among the hydrophobic group or halogen substituted ADK dimers. The docking studies suggested that the bulky hydrophobic substitution at 3-phenyl ring and the linker of 4-amino-piperidine were beneficial for adopting an active conformation to achieve strong interactions with the active site Mg(2+) and the key residue E152 within the catalytic core domain. This study is a significant extension of our previous report on the dimeric ADK-containing IN inhibitors, providing a new promising template for further lead optimization. (c) 2008 Elsevier Ltd. All rights reserved. |
| WOS关键词 | BETA-DIKETO ACIDS ; ACTIVE-SITE ; CONFORMATIONAL COVERAGE ; STRAND TRANSFER ; BINDING ; REPLICATION ; DESIGN ; DOMAIN ; CELLS ; GOLD |
| 资助项目 | National Natural Science Foundation of China[30672528] ; Technology Commission of Shanghai Municipality[07QH14018] ; Campbell Foundation[00000000] |
| WOS研究方向 | Biochemistry & Molecular Biology ; Pharmacology & Pharmacy ; Chemistry |
| 语种 | 英语 |
| WOS记录号 | WOS:000258726300028 |
| 出版者 | PERGAMON-ELSEVIER SCIENCE LTD |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/272834]  |
| 专题 | 药物化学研究室 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 |
| 通讯作者 | Neamati, Nouri |
| 作者单位 | 1.Univ So Calif, Sch Pharm, Dept Pharmacol & Pharmaceut Sci, Los Angeles, CA 90089 USA; 2.Chinese Acad Sci, Shanghai Inst Biol Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Zeng, Li-Fan,Jiang, Xiao-Hua,Sanchez, Tino,et al. Novel dimeric aryldiketo containing inhibitors of HIV-1 integrase: Effects of the phenyl substituent and the linker orientation[J]. BIOORGANIC & MEDICINAL CHEMISTRY,2008,16(16):7777-7787. |
| APA | Zeng, Li-Fan.,Jiang, Xiao-Hua.,Sanchez, Tino.,Zhang, Hu-Shan.,Dayam, Raveendra.,...&Long, Ya-Qiu.(2008).Novel dimeric aryldiketo containing inhibitors of HIV-1 integrase: Effects of the phenyl substituent and the linker orientation.BIOORGANIC & MEDICINAL CHEMISTRY,16(16),7777-7787. |
| MLA | Zeng, Li-Fan,et al."Novel dimeric aryldiketo containing inhibitors of HIV-1 integrase: Effects of the phenyl substituent and the linker orientation".BIOORGANIC & MEDICINAL CHEMISTRY 16.16(2008):7777-7787. |
入库方式： OAI收割
来源：上海药物研究所
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