45954-03-8Relevant academic research and scientific papers
Discovery of CDK5 Inhibitors through Structure-Guided Approach
Khair, Nishat Z.,Lenjisa, Jimma L.,Tadesse, Solomon,Kumarasiri, Malika,Basnet, Sunita K. C.,Mekonnen, Laychiluh B.,Li, Manjun,Diab, Sarah,Sykes, Matthew J.,Albrecht, Hugo,Milne, Robert,Wang, Shudong
supporting information, p. 786 - 791 (2019/05/17)
Specific abrogation of cyclin-dependent kinase 5 (CDK5) activity has been validated as a viable approach for the development of anticancer agents. However, no selective CDK5 inhibitor has been reported to date. Herein, a structure-based in silico screenin
Discovery of 5-(2-(phenylamino)pyrimidin-4-yl)thiazol-2(3H)-one derivatives as potent Mnk2 inhibitors: Synthesis, SAR analysis and biological evaluation
Diab, Sarah,Teo, Theodosia,Kumarasiri, Malika,Li, Peng,Yu, Mingfeng,Lam, Frankie,Basnet, Sunita K. C.,Sykes, Matthew J.,Albrecht, Hugo,Milne, Robert,Wang, Shudong
, p. 962 - 972 (2014/05/20)
Phosphorylation of eIF4E by human mitogen-activated protein kinase (MAPK)-interacting kinases (Mnks) is crucial for human tumourigenesis and development. Targeting Mnks may provide a novel anticancer therapeutic strategy. However, the lack of selective Mnk inhibitors has so far hampered pharmacological target validation and clinical drug development. Herein, we report, for the first time, the discovery of a series of 5-(2-(phenylamino) pyrimidin-4-yl)thiazole-2(3H)-one derivatives as Mnk inhibitors. Several derivatives demonstrate very potent Mnk2 inhibitory activity. The most active and selective compounds were tested against a panel of cancer cell lines, and the results confirm the cell-type-specific effect of these Mnk inhibitors. Detailed cellular mechanistic studies reveal that Mnk inhibitors are capable of reducing the expression level of anti-apoptotic protein Mcl-1, and of promoting apoptosis in MV4-11 acute myeloid leukaemia cells. Highly active Mnk2 inhibitors: Mnk-related cancer biology is an area of intensive research, but its inhibitor discovery has lagged behind due to a lack of understanding of the protein structure. Herein we report the discovery of Mnk2 inhibitors (e.g. 8 e). These potent and selective inhibitors are extremely valuable for target validation and drug discovery.
Reaction of quinones and guanidine derivatives: Simple access to bis-2-aminobenzimidazole moiety of benzosceptrin and other benzazole motifs
Tran, Minh Quan,Ermolenko, Ludmila,Retailleau, Pascal,Nguyen, Thanh Binh,Al-Mourabit, Ali
supporting information, p. 920 - 923 (2014/03/21)
A new strategy for the synthesis of 2-aminobenzimidazol-6-ols via a reaction of quinones with guanidine derivatives is reported. Sequential application of this methodology provided a simple access to the first benzosceptrin analogue bearing a bis-2-aminoimidazole moiety. A concomitant addition of two guanidines to the naphtho[1′,2′:4,5]imidazo[1,2-a] pyrimidine-5,6-dione, which includes the redox neutral debenzylation and guanidine-assisted cleavage of the 2-aminopyrimidine part resulted in the synthesis of the free challenging contiguous bis-2-aminoimidazole moiety of benzosceprins in one step.
Design and synthesis of a novel series of N,4-diphenylpyrimidin-2-amine derivatives as potent and selective PI3Kγ inhibitors
Yang, Hua-Lin,Fang, Fei,Zhao, Chang-Po,Li, Dong-Dong,Li, Jing-Ran,Sun, Jian,Du, Qian-Ru,Zhu, Hai-Liang
, p. 219 - 225 (2014/03/21)
Due to the increasing evidence linking the PI3Kγ pathway to various disease states, PI3Kγ is becoming an important target for cancer treatment. Herein we designed and synthesized a novel series of N,4-diphenylpyrimidin-2-amine derivatives with low CDOCKER-INTERACTION-ENERGY and then evaluated their PI3Kγ in vitro inhibitory activities and in vitro antiproliferation assays against four human cancer cells. Among the compounds we synthesized, compound C8 (IC50 = 65 nM) demonstrated the most potent inhibitory activity against PI3Kγ kinase as well as at the cellular level, compared to the control drug TG100713 (IC50 = 127 nM). Moreover, molecular docking analysis was also performed to determine possible binding modes between PI3Kγ and the target compounds.
Identification of pyrimidine derivatives as hSMG-1 inhibitors
Gopalsamy, Ariamala,Shi, Mengxiao,Bennett, Eric M.,Bard, Joel,Zhang, Wei-Guo,Yu, Ker
, p. 6636 - 6641,6 (2012/12/12)
hSMG-1 kinase plays a dual role in a highly conserved RNA surveillance pathway termed nonsense-mediated RNA decay (NMD) and in cellular genotoxic stress response. Since deregulation of cellular responses to stress contributes to tumor growth and resistance to chemotherapy, hSMG-1 is a potential target for cancer treatment. From our screening efforts, we have identified pyrimidine derivatives as hSMG-1 kinase inhibitors. We report structure-based optimization of this pan-kinase scaffold to improve its biochemical profile and overall kinome selectivity, including mTOR and CDK, to generate the first reported selective hSMG-1 tool compound.
Palladium-catalyzed C-H functionalization using guanidine as a directing group: Ortho arylation and olefination of arylguanidines
Shao, Jiaan,Chen, Wenteng,Giulianotti, Marc A.,Houghten, Richard A.,Yu, Yongping
supporting information, p. 5452 - 5455 (2013/01/15)
Palladium-catalyzed C-H functionalization using guanidine as the directing group was achieved under mild reaction conditions. Various guanidine derivatives were produced in moderate to good yields by using simple unactivated arenes or ethyl acrylate as the source of arylation or olefination, respectively.
