59115-08-1Relevant articles and documents
Synthesis, biological evaluation and structure-activity relationship of novel dichloroacetophenones targeting pyruvate dehydrogenase kinases with potent anticancer activity
Xu, Biao,Wang, Zhi-Peng,Liu, Qingwang,Yang, Xiaohong,Li, Xuemin,Huang, Ding,Qiu, Yanfei,Tam, Kin Yip,Zhang, Shao-Lin,He, Yun
, (2021/02/09)
Pyruvate dehydrogenase kinases (PDKs) are promising therapeutic targets that have received increasing attentions in cancer metabolism. In this paper, we report the synthesis and biological evaluation of a series of novel dichloroacetophenones as potent PDKs inhibitors. Structure-activity relationship analysis enabled us to identify a potent compound 6u, which inhibited PDKs with an EC50 value of 0.09 μM, and reduced various cancer cells proliferation with IC50 values ranging from 1.1 to 3.8 μM, while show weak effect against non-cancerous L02 cell (IC50 > 10 μM). In the A375 xenograft model, 6u displayed an obvious antitumor activity at a dose of 5 mg/kg, but with no negative effect to the mice weight. Molecular docking suggested that 6u formed direct hydrogen bond interactions with Ser75 and Gln61 in PDK1, and meanwhile the aniline skeleton in 6u was sandwiched by the conserved hydrophobic residues Phe78 and Phe65, which contribute to the biochemical activity improvement. Moreover, 6u induced A375 cell apoptosis and cell arrest in G1 phase, and inhibited cancer cell migration. In addition, 6u altered glucose metabolic pathway in A375 cell by decreasing lactate formation and increasing ROS production and OCR consumption, which could serve as a potential modulator to reprogram the glycolysis pathway in cancer cell.
Synthesis of 3-[4-(dimethylamino)phenyl]alkyl-2-oxindole derivatives and their effects on neuronal cell death
Furuta, Kyoji,Kawai, Yu,Mizuno, Yosuke,Hattori, Yurika,Koyama, Hiroko,Hirata, Yoko
supporting information, p. 4457 - 4461 (2017/09/12)
Novel 3-[4-(dimethylamino)phenyl]alkyl-2-oxindole analogs were synthesized by either of the following two pathways: (1) a sequence of Knoevenagel condensation of oxindole with (4-dimethylamino)cinnamaldehyde–hydrogenation, or (2) alkylation of oxindole dianion with [(4-dimethylamino)phenyl]alkyl halides. Subsequent alkylation at C-3 and/or N-1 of the oxindole skeleton by anion-based methods provided additional substituted derivatives for structure-activity relationship studies. Their effects on neuronal cell death induced by oxidative stress were evaluated by lactate dehydrogenase assay. Compounds with the alkyl chain length of 2–4 significantly suppressed the neuronal cell death. No significant change occurred in the activity by substitution with less-polar groups. The stereochemistry at C-3 of the oxindole core was also irrelevant for the neuroprotective effects of these compounds.
3. 4 - diphenyl - 4H - 1, 2, 4 - triazole derivative and its preparation method and application (by machine translation)
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Paragraph 0415; 0416; 0417; 0418, (2017/07/01)
The invention discloses 3, 4 - diphenyl - 4H - 1, 2, 4 - triazole derivative and its preparation method and application. In particular, the invention relates to the formula (I) structure of 3, 4 - diphenyl - 4H - 1, 2, 4 - triazole derivatives, its stereoisomers or its pharmaceutically acceptable salt, formula (I) in the definition of each substituent is as defined in the specification. These structure of novel compound with heat shock protein HSP90 inhibitory activity, can be used for treating cancer, neurodegenerative diseases, inflammatory diseases, autoimmune diseases, ischemic brain injury and the like, it has broad application prospects. (by machine translation)
