92952-84-6Relevant articles and documents
The first bridged, bifunctional cyclopentadienyl-imidazolylidene ligand and complexes with titanium and zirconium
Müller, J?rn,Piotrowski, Ingo,Von Chrzanowski, Lars
, p. 467 - 474 (2007)
Starting from imidazole, l-[2-(cyclopenta-2,4-dienyl)ethyl]-3- methylimidazolium iodide (3) was obtained as a mixture of isomers by a simple three-step synthesis. The reaction of 3 with Ti(NEt2)4 or Zr(NEt2)4 by double deprotonation of the imidazolium salt led to the isomerically pure cationic complexes [{η5-C 5H4-(CH2)2-NHC}M(NEt 2)2]+I- (NHC = N-heterocyclic carbene) 4a (M = Ti) and 4b (M = Zr), respectively, in which a cyclopentadienyl and a methylimidazol-2-ylidene unit are linked by an ethylidene-1,2 bridge to form a novel chelating ligand system. In the case of the reaction of 3 with Zr(NEt2)4 the neutral compound [{η5-C 5H4-(CH2)2-NHC}Zr(NEt 2)I2] (5) is formed as an additional product. According to the X-ray structure analyses, the titanium atom of 4a is terracoordinated while no coordinative interaction exists with the iodide anion; on the other hand, in 5 the zirconium centre is pentacoordinated.
RET INHIBITORS, PHARMACEUTICAL COMPOSITIONS AND USES THEREOF
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Paragraph 00230; 00400, (2020/07/05)
Provided herein are a RET inhibitor, a pharmaceutical composition thereof and uses thereof. In particular, provided is a compound having Formula (I) or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof. Provided is a pharmaceutical composition comprising the compound, and uses of the compound and pharmaceutical composition thereof for the preparation of a medicament, in particular for treatment and prevention of RET-related diseases and conditions, including cancer, irritable bowel syndrome, and/or pain associated with irritable bowel syndrome.
3,5,7-Substituted Pyrazolo[4,3- d]pyrimidine Inhibitors of Cyclin-Dependent Kinases and Their Evaluation in Lymphoma Models
Jorda, Radek,Havlí?ek, Libor,?turc, Antonín,Tu?ková, Diana,Daumová, Lenka,Alam, Mahmudul,?kerlová, Jana,Nekardová, Michaela,Pe?ina, Miroslav,Pospí?il, Tomá?,?iroká, Jitka,Urbánek, Lubor,Pachl, Petr,?ezá?ová, Pavlína,Strnad, Miroslav,Klener, Pavel,Kry?tof, Vladimír
, p. 4606 - 4623 (2019/05/06)
Cyclin-dependent kinases are therapeutic targets frequently deregulated in various cancers. By convenient alkylation of the 5-sulfanyl group, we synthesized 3-isopropyl-7-[4-(2-pyridyl)benzyl]amino-1(2)H-pyrazolo[4,3-d]pyrimidines with various substitutions at position 5 with potent antiproliferative activity in non-Hodgkin lymphoma cell lines. The most potent derivative 4.35 also displayed activities across more than 60 cancer cell lines. The kinase profiling confirmed high selectivity of 4.35 toward cyclin-dependent kinases (CDKs) 2, 5, and 9, and the cocrystal with CDK2/cyclin A2 revealed its binding in the active site. Cultured lymphoma cell lines treated with 4.35 showed dephosphorylation of CDK substrates, cleavage of PARP-1, downregulation of XIAP and MCL-1, and activation of caspases, which collectively confirmed ongoing apoptosis. Moreover, 4.35 demonstrated significant activity in various cell line xenograft and patient-derived xenograft mouse models in vivo both as a monotherapy and as a combination therapy with the BCL2-targeting venetoclax. These findings support further studies of combinatorial treatment based on CDK inhibitors.