83-01-2Relevant articles and documents
Synthetic method of aromatic amide alkene compound
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Paragraph 0037-0039, (2021/11/27)
The invention discloses a synthesis method of an aromatic amide alkene compound, which comprises the following steps: mixing a carbamyl chloride compound 1 and isopropyl magnesium bromide 2 in the presence of inert gas at low temperature, and then carrying out heating reaction to obtain the aromatic amide alkene compound 3. Compared with the prior art, the method has the advantages that the Grignard reagent isopropenyl magnesium bromide reacts with the carbamyl chloride compound, the aromatic amide alkene compound is synthesized in one step, the reaction speed is high, and the product yield is high.
N-heterocyclic (4-phenylpiperazin-1-yl)methanones derived from phenoxazine and phenothiazine as highly potent inhibitors of tubulin polymerization
Prinz, Helge,Ridder, Ann-Kathrin,Vogel, Kirsten,B?hm, Konrad J.,Ivanov, Igor,Ghasemi, Jahan B.,Aghaee, Elham,Müller, Klaus
, p. 749 - 766 (2017/02/05)
We report here a series of 27 10-(4-phenylpiperazin-1-yl)methanones derived from tricyclic heterocycles which were screened for effects on tumor cell growth, inhibition of tubulin polymerization, and induction of cell cycle arrest. Several analogues, among them the 10-(4-(3-methoxyphenyl)piperazine-1-carbonyl)-10H-phenoxazine-3-carbonitrile (16o), showed excellent antiproliferative properties, with low nanomolar GI50 values (16o, mean GI50 of 3.3 nM) against a large number (93) of cancer cell lines. Fifteen compounds potently inhibited tubulin polymerization. Analysis of cell cycle by flow cytometry revealed that inhibition of tumor cell growth was related to an induction of G2/M phase cell cycle blockade. Western blotting and molecular docking studies suggested that these compounds bind efficiently to β-tubulin at the colchicine binding site. Our studies demonstrate the suitability of the phenoxazine and phenothiazine core and also of the phenylpiperazine moiety for the development of novel and potent tubulin polymerization inhibitors.
Optimization of 1,2,5-thiadiazole carbamates as potent and selective ABHD6 inhibitors
Patel, Jayendra Z.,Nevalainen, Tapio J.,Savinainen, Juha R.,Adams, Yahaya,Laitinen, Tuomo,Runyon, Robert S.,Vaara, Miia,Ahenkorah, Stephen,Kaczor, Agnieszka A.,Navia-Paldanius, Dina,Gynther, Mikko,Aaltonen, Niina,Joharapurkar, Amit A.,Jain, Mukul R.,Haka, Abigail S.,Maxfield, Frederick R.,Laitinen, Jarmo T.,Parkkari, Teija
, p. 253 - 265 (2015/02/05)
At present, inhibitors of α/β-hydrolase domain 6 (ABHD6) are viewed as a promising approach to treat inflammation and metabolic disorders. This article describes the development of 1,2,5-thiadiazole carbamates as ABHD6 inhibitors. Altogether, 34 compounds were synthesized, and their inhibitory activity was tested using lysates of HEK293 cells transiently expressing human ABHD6 (hABHD6). Among the compound series, 4-morpholino-1,2,5-thiadiazol-3-yl cyclooctyl(methyl)carbamate (JZP-430) potently and irreversibly inhibited hABHD6 (IC50 = 44 nM) and showed ～ 230-fold selectivity over fatty acid amide hydrolase (FAAH) and lysosomal acid lipase (LAL), the main off-targets of related compounds. Additionally, activity-based protein profiling indicated that JZP-430 displays good selectivity among the serine hydrolases of the mouse brain membrane proteome. JZP-430 has been identified as a highly selective, irreversible inhibitor of hABHD6, which may provide a novel approach in the treatment of obesity and type II diabetes.
