作者: Lin, Shuimu ; Li, Haizhou ; Liu, Shouping ; Cai, Qiongna ; Fang, Shanfang ; Zhong, Rongcui ; Liang, Wanxin ; Zeng, Minghui ; Yu, Qian ; Tao, Yiwen ; Kang, Wen-Tyng

The emergence of antibiotic resistance has brought a significant burden to public health. Here, we designed and synthesized a series of cannabidiol derivatives by biomimicking the structure and function of cationic antibacterial peptides. This is the first report on the design of cannabidiol derivatives as broad-spectrum antibacterial agents. Through the structure-activity relationship (SAR) study, we found a lead compound 23 that killed both Gram-negative and Gram-positive bacteria via a membrane-targeting mechanism of action with low resistance frequencies. Compound 23 also exhibited very weak hemolytic activity, low toxicity toward mammalian cells, and rapid bactericidal properties. To further validate the membrane action mechanism of compound 23, we performed transcriptomic analysis using RNA-seq, which revealed that treatment with compound 23 altered many cell wall/membrane/envelope biogenesis-related genes in Gram-positive and Gram-negative bacteria. More importantly, compound 23 showed potent in vivo antibacterial efficacy in murine corneal infection models caused by Staphylococcus aureus or Pseudomonas aeruginosa. These findings would provide a new design idea for the discovery of novel broad-spectrum antibacterial agents to overcome the antibiotic resistance crisis.

2011-11-01·Bioorganic & Medicinal Chemistry3区 · 医学

Melanin-concentrating hormone receptor 1 antagonists: Synthesis, structure–activity relationship, docking studies, and biological evaluation of 2,3,4,5-tetrahydro-1H-3-benzazepine derivatives

3区 · 医学

Article

作者: Michiko Tawada ; Kaoru Watanabe ; Yoshihide Nakano ; Shiro Takekawa ; Kazuyoshi Aso ; Koki Kato ; Shizuo Kasai ; Makoto Kamata ; Nobuhiro Suzuki ; Masahiro Kamaura ; Yasutaka Nagisa ; Yuji Ishihara ; Tomoko Kaisho ; Hitomi Ogino

Melanin-concentrating hormone receptor 1 (MCHR1) antagonists have been studied as potential agents for the treatment of obesity. Initial structure-activity relationship studies of in-house hit compound 1a and subsequent optimization studies resulted in the identification of tetrahydroisoquinoline derivative 23, 1-(2-acetyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-[4-(4-chlorophenyl)piperidin-1-yl]butan-1-one, as a potent hMCHR1 antagonist. A homology model of hMCHR1 suggests that these compounds interact with Asn 294 and Asp 123 in the binding site of hMCHR1 to enhance binding affinity. Oral administration of compound 23 dose-dependently reduced food intake in diet-induced obesity (DIO)-F344 rats.

Frontiers in Pharmacology2区 · 医学

A Dual PI3K/HDAC Inhibitor Downregulates Oncogenic Pathways in Hematologic Tumors In Vitro and In Vivo

2区 · 医学

ArticleOA

作者: Yan, Zheng ; Ji, Ming ; Chen, Xiaoguang ; Zhang, Kehui ; Xu, Heng

Purpose: To investigate the efficacy and mechanism of compound 23, a PI3K/HDAC dual-target inhibitor, on hematologic tumor cells in vitro and in vivo. Methods: The MTS Kit was used to study the antiproliferative effects in vitro. Western blot was used to analyze the involved signaling pathways. Flow cytometry was used to analyze apoptosis and the cell cycle. The antiproliferative effects were evaluated in vivo using EL4 and A20 xenograft models. The CCLE database was used to analyze gene expression. Results: Compound 23 significantly inhibited the proliferation of hematologic tumors; it simultaneously regulated PI3K/HDAC pathways and induced apoptosis and G1-phase arrest in EL4, NB4, and A20 cells in vitro. When tested in vivo, compound 23 significantly inhibited the proliferation of EL4 and A20. The expression levels of ErbB2 and ErbB3 decreased in hematologic tumors compared with it in solid tumors. Conclusion: Compound 23 modulates the PI3K/HDAC pathway, which results in significant inhibition of hematologic tumor proliferation in vivo and in vitro. The differential levels of ERBB2 and ERBB3 might be related to the difference in the effect of compound 23 on hematologic tumors and solid tumors.

100 项与 Compound 23(Polyketide Synthase 13-Thioesterase Inhibitors) 相关的药物交易

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