- Discovery of 1-(5-(1H-benzo[d]imidazole-2-yl)-2,4-dimethyl-1H-pyrrol-3-yl)ethan-1-one derivatives as novel and potent bromodomain and extra-terminal (BET) inhibitors with anticancer efficacy
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As epigenetic readers, bromodomain and extra-terminal domain (BET) family proteins bind to acetylated-lysine residues in histones and recruit protein complexes to promote transcription initiation and elongation. Inhibition of BET bromodomains by small molecule inhibitors has emerged as a promising therapeutic strategy for cancer. Herein, we describe our efforts toward the discovery of a novel series of 1-(5-(1H-benzo[d]imidazole-2-yl)-2,4-dimethyl-1H-pyrrol-3-yl)ethan-1-one derivatives as BET inhibitors. Intensive structural modifications led to the identification of compound 35f as the most active inhibitor of BET BRD4 with selectivity against BET family proteins. Further biological studies revealed that compound 35f can arrest the cell cycle in G0/G1 phase and induce apoptosis via decreasing the expression of c-Myc and other proteins related to cell cycle and apoptosis. More importantly, compound 35f showed favorable pharmacokinetic properties and antitumor efficacy in MV4-11 mouse xenograft model with acceptable tolerability. These results indicated that BET inhibitors could be potentially used to treat hematologic malignancies and some solid tumors.
- Bian, Yuanyuan,Chen, Yadong,Hong, Qianqian,Jiang, Fei,Kong, Bo,Li, Hongmei,Lu, Tao,Ma, Yu,Ran, Ting,Tang, Weifang,Wang, Cong,Yang, Na,Zhang, Zhimin,Zheng, Wan,Zhu, Jiapeng,Zhu, Zhaohong
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- 2,3-Diazaporphyrins Bearing Two Nitrogen Atoms at the Periphery
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The first synthesis of 2,3-diazaporphyrins 3 bearing two nitrogen atoms at peripheral positions from tripyrranes 1, prepared in situ by mild acidolysis and decarboxylation of the di-t-butyldicarboxylates, and 4H-1,2,4-triazol-3,5-dicarbaldehyde (2) is described, using the [3+1] principle of porphyrine cyclization. Similar to the parent porphyrins, the new diazaporphyrins 3 exhibit significantly shielded inner protons, reflecting the ring current of an 18 ? aromatic system and Soret bands in the UV-vis. spectra with extinctions comparable to those of octaethylporphyrin.
- Boehme, Roswitha,Breitmaier, Eberhard
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p. 2096 - 2102
(2007/10/03)
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