- Synthesis, evaluation and in silico studies of novel BRD4 bromodomain inhibitors bearing a benzo[d]isoxazol scaffold
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Abstract: The BRD4 protein is associated with various diseases, which has been an attractive target for the treatment of cancer and inflammation. This paper is a follow-up to our previous studies, in which we report the structure-based design, synthesis, and evaluation of a new class of small-molecule BRD4 bromodomain inhibitors bearing a benzo[d]isoxazol scaffold. The SARs focused on exploration of the 2′ or 3′ position to afford novel inhibitors that may avoid potential metabolically unstable site. The most potent inhibitor 13f exhibited high binding affinity to BRD4(1) with a ΔTm value of 7.8 °C as evaluated in thermal shift assay (TSA). The potent activity was also demonstrated by a peptide competition assay with an IC50 value of 0.21?μM. The docking studies revealed the binding mode of the compounds with the active site of BRD4(1). In addition, in silico predictions indicated that these compounds possessed good drug-likeness and pharmacokinetic profile. Graphic abstract: This paper is a follow-up to our previous studies, in which we report the structure-based design,synthesis, and evaluation of a new class of small-molecule BRD4 bromodomain inhibitors bearing a benzo[d]isoxazolscaffold.[Figure not available: see fulltext.].
- Zhang, Maofeng,Liu, Zhuyun,Wang, Lizhong,Li, Yan,Ma, Yonggang
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- Method for synthesizing benzofuran heterocyclic sulfonyl chloride
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The invention provides a method for synthesizing benzofuran heterocyclic sulfonyl chloride. The benzofuran heterocyclic sulfonyl chloride has a structural formula of a formula I shown in the specification. The method comprises the following steps: 1) by taking a compound 1, that is, 2,3-dihydrobenzofuran, as a raw material, and dichloromethane as a solvent, under catalysis of pyridine, performingelectrophilic addition on a benzene ring by using bromine so as to obtain a compound 2, that is, 5-2,3-dihydrobenzofuran; and 2) performing a chlorosulfonation reaction on a benzene ring by using a compound 2 through chlorosulfonic acid so as to obtain a compound of the formula I shown in the specification, that is, 5-2,3-dihydrobenzofuran-7-sulfonyl chloride, wherein the mole ratio of the compound 2 to the chlorosulfonic acid is 1:(2-20), the reaction temperature is 0-60 DEG C, and the reaction time is 0.5-12 hours. The preparation process of the derivative is not reported in either domesticor overseas documents at present. The invention designs a novel synthesis route, condition optimization is implemented for key reaction steps in the route, and optimal process conditions are confirmed. The novel process has the characteristics of being cheap in initial raw material, easy in initial raw material obtaining, short I step, easy in aftertreatment, high in yield, and the like, and is applicable to industrial production.
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Paragraph 0019; 00021; 0026-0030; 0031; 0033-0041
(2019/11/28)
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- COMPOUNDS
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A compound of formula (I), or a pharmaceutical salt thereof.
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Page/Page column 108
(2020/01/11)
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