33852-43-6Relevant articles and documents
Design, synthesis, and biological evaluation of 4-Methyl quinazoline derivatives as anticancer agents simultaneously targeting phosphoinositide 3-kinases and histone deacetylases
Zhang, Kehui,Lai, Fangfang,Lin, Songwen,Ji, Ming,Zhang, Jingbo,Zhang, Yan,Jin, Jing,Fu, Rong,Wu, Deyu,Tian, Hua,Xue, Nina,Sheng, Li,Zou, Xiaowen,Li, Yan,Chen, Xiaoguang,Xu, Heng
, p. 6992 - 7014 (2019)
Polypharmacology is a promising paradigm in modern drug discovery. Herein, we have discovered a series of novel PI3K and HDAC dual inhibitors in which the hydroxamic acid moiety as the zinc binding functional group was introduced to a quinazoline-based PI3K pharmacophore through an appropriate linker. Systematic structure-activity relationship studies resulted in lead compounds 23 and 36 that simultaneously inhibited PI3K and HDAC with nanomolar potencies and demonstrated favorable antiproliferative activities. Compounds 23 and 36 efficiently modulated the expression of p-AKT and Ac-H3, arrested the cell cycle, and induced apoptosis in HCT116 cancer cells. Following pharmacokinetic studies, 23 was further evaluated in HCT116 and HGC-27 xenograft models to show significant in vivo anticancer efficacies with tumor growth inhibitions of 45.8% (po, 150 mg/kg) and 62.6% (ip, 30 mg/kg), respectively. Overall, this work shows promise in discovering new anticancer therapeutics by the approach of simultaneously targeting PI3K and HDAC pathways with a single molecule.
SUBSTITUTED 1-ALKYLCINNOLIN-4(1H)-ONE DERIVATIVES, PREPARATION THEREOF AND THERAPEUTIC APPLICATION OF SAME
-
, (2012/06/01)
The subject of the present invention is compounds corresponding to the formula (I) in which: X represents a divalent (C2-C5)alkylene radical which is unsubstituted or substituted one or more times by an Alk group; R1 represents a phenyl, a naphthyl, a pyridyl, a 1-benzothienyl or a 1,3-benzodioxolyl; R2 represents a hydrogen atom, a halogen atom, an Alk group, an OAlk group or else a group chosen from —S-Alk, —SO-Alk, —SO2-Alk, —CO—N(R4)-Alk, —N(R4)SO2-Alk, —N(R4)CO-Alk, —N(R4)SO2—N(Alk)2; R3 represents a hydrogen atom, a halogen atom, an Alk group or an OAlk group; R4 represents a hydrogen atom or a (C1-C4)alkyl; Alk represents an unsubstituted or substituted (C1-C4)alkyl. Preparation process and therapeutic application.
SUBSTITUTED 1-BENZYL-CINNOLIN-4(1H)-ONE DERIVATIVES, PREPARATION THEREOF, AND THERAPEUTIC USE THEREOF
-
, (2011/06/26)
The present invention is related to novel substituted 1-benzylcinnolin-4(1H)-one derivatives having affinity for cannabinoid CB2 receptors, their preparation and their therapeutic application.