Background: The aim of the study is to identify a novel furan-based chalcone derivative as potent inhibitor against the H37Rv strain. Materials & methods: The in silico pharmacokinetic characteristics, toxicity tests, molecular modeling, chemical synthesis and minimum inhibitory concentration (MIC; IC₅₀) were carried out to evaluate the antitubercular potential of the synthesized furan-based chalcone analogues against H37Rv. Results & conclusion: Among the ten target compounds synthesized, DF02, DF05 and DF07 had MIC values of 1.6 μg/ml equivalent to isoniazid and DF10 showed MIC values of 3.25 μg/ml which is equipotent to pyrazinamide. All the other compounds had optimal concentrations 6.25-100 μg/ml against the H37Rv strain. Compounds DF02 and DF10 were further evaluated for cytotoxicity assay performed using HeLa cell lines.

2023-06-05·Molecular pharmaceutics

Coumarin-Based Fluorescent Inhibitors for Photocontrollable Bioactivation.

Article

作者: Ren, Fei ; Yang, Shuke ; Wen, Jian ; Zou, Liang-Hua ; Hou, Yingchao ; Zhang, Chun ; Gao, Min ; Wu, Zhihong ; Li, Runqi ; Wang, Wen-Long ; Zhu, Wendi ; Shao, Andong

Activation of the IRE-1/XBP-1 pathway is related to many human diseases. Coumarin-based derivatives acting as both IRE-1 inhibitors and bright fluorophores are highly desirable to establish an integrated fluorescent inhibitor system. Here, we take insights into the aqueous stability of a photocaged IRE-1 inhibitor PC-D-F07 through a structure activity relationship. The substituent effects indicate that the electron-withdrawing -NO₂ moiety in the photocage combined with the tricyclic coumarin fluorophore contribute to the structural stability of PC-D-F07. To optimize the photocage of PC-D-F07, we incorporate a 1-ethyl-2-nitrobenzyl or 2-nitrobenzyl photolabile moiety on the hydroxyl group of the IRE-1 inhibitor to generate RF-7 and RF-8. Upon photoactivation, both RF-7 and RF-8 present an increased fluorescence response, sequentially enabling the unlocking of the ortho-1,3-dioxane acetal for the release of active IRE-1 inhibitors. Moreover, RF-7 exhibits a high repolarization ratio of converting M2-type tumor-associated macrophages (M2-TAMs) to M1-type immune-responsive macrophages. This provides a novel prodrug strategy of modulating druggable fluorophore backbones to achieve spatiotemporally controllable drug release for precise cancer treatment.

2022-04-04·Molecular Pharmaceutics2区 · 医学

IRE-1-Targeting Caged Prodrug with Endoplasmic Reticulum Stress-Inducing and XBP-1S-Inhibiting Activities for Cancer Therapy

2区 · 医学

Article

作者: Del Valle, Juan R. ; Hu, Chih-Chi Andrew ; Tang, Chih-Hang Anthony ; Shao, Andong ; Xu, Qin ; Lee, Avery C. ; Cain, Christopher F. ; Kang, Chang Won

Activation of the IRE-1/XBP-1s pathway supports tumor progression. Here, we report a novel prodrug, TC-D-F07, in which a thiol-reactive dinitrobenzenesulfonyl (Dns) cage was installed onto the C8 hydroxyl of the covalent IRE-1 inhibitor D-F07. The electron-withdrawing Dns group in TC-D-F07 stabilizes the neighboring 1,3-dioxane acetal, allowing for stimulus-mediated control of its inhibitory activity. TC-D-F07 exhibits high sensitivity to intracellular thiols. Because tumor cells exhibit higher concentrations of glutathione and cysteine, treatment with TC-D-F07 results in more sustained levels of D-F07 in transformed versus normal cells. In addition, we show that a dinitrophenyl cysteine adduct resulting from cleavage of the Dns group induces endoplasmic reticulum (ER) stress, causing tumor cells to increase the expression of XBP-1s. The accumulated levels of D-F07 and its gradual decomposition into the active IRE-1 inhibitor eventually deprive tumor cells of XBP-1s, leading to more severe apoptosis than those treated with its uncaged analogue.

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适应症	最高研发状态	国家/地区	公司	日期
伯基特淋巴瘤	临床前	美国	University of South Florida	-
慢性淋巴细胞白血病	临床前	美国	The Wistar Institute of Anatomy & Biology	-
慢性淋巴细胞白血病	临床前	美国	University of South Florida	-