151266-23-8Relevant articles and documents
A conformational mimetic approach for the synthesis of carbocyclic nucleosides as anti-HCV leads
Kasula, Mohan,Balaraju, Tuniki,Toyama, Massaki,Thiyagarajan, Anandarajan,Bal, Chandralata,Baba, Masanori,Sharon, Ashoke
, p. 1673 - 1680 (2013)
Computer-aided approaches coupled with medicinal chemistry were used to explore novel carbocyclic nucleosides as potential anti-hepatitisC virus (HCV) agents. Conformational analyses were carried out on 6-amino-1H-pyrazolo[3,4-d]pyrimidine (6-APP)-based carbocyclic nucleoside analogues, which were considered as nucleoside mimetics to act as HCV RNA-dependent RNA polymerase (RdRp) inhibitors. Structural insight gained from the modeling studies revealed the molecular basis behind these nucleoside mimetics. The rationally chosen 6-APP analogues were prepared and evaluated for anti-HCV activity. RdRp SiteMap analysis revealed the presence of a hydrophobic cavity near C7 of the nucleosides; introduction of bulkier substituents at this position enhanced their activity. Herein we report the identification of an iodinated compound with an EC50 value of 6.6μM as a preliminary anti-HCV lead.
Rapid Discovery and Structure-Activity Relationships of Pyrazolopyrimidines That Potently Suppress Breast Cancer Cell Growth via SRC Kinase Inhibition with Exceptional Selectivity over ABL Kinase
Fraser, Craig,Dawson, John C.,Dowling, Reece,Houston, Douglas R.,Weiss, Jason T.,Munro, Alison F.,Muir, Morwenna,Harrington, Lea,Webster, Scott P.,Frame, Margaret C.,Brunton, Valerie G.,Patton, E. Elizabeth,Carragher, Neil O.,Unciti-Broceta, Asier
, p. 4697 - 4710 (2016)
Novel pyrazolopyrimidines displaying high potency and selectivity toward SRC family kinases have been developed by combining ligand-based design and phenotypic screening in an iterative manner. Compounds were derived from the promiscuous kinase inhibitor PP1 to search for analogs that could potentially target a broad spectrum of kinases involved in cancer. Phenotypic screening against MCF7 mammary adenocarcinoma cells generated target-agnostic structure-activity relationships that biased subsequent designs toward breast cancer treatment rather than to a particular target. This strategy led to the discovery of two potent antiproliferative leads with phenotypically distinct anticancer mode of actions. Kinase profiling and further optimization resulted in eCF506, the first small molecule with subnanomolar IC50 for SRC that requires 3 orders of magnitude greater concentration to inhibit ABL. eCF506 exhibits excellent water solubility, an optimal DMPK profile and oral bioavailability, halts SRC-associated neuromast migration in zebrafish embryos without inducing life-threatening heart defects, and inhibits SRC phosphorylation in tumor xenografts in mice.
Design, synthesis and biological evaluation of novel 3-substituted pyrazolopyrimidine derivatives as potent Bruton's tyrosine kinase (BTK) inhibitors
Zheng, Nan,Pan, Jing,Hao, Qun,Li, Yingxia,Zhou, Weicheng
, p. 2165 - 2172 (2018)
A series of 3-substituted pyrazolopyrimidine derivatives as BTK inhibitors were designed by structure-based drug design and they were synthesized, evaluated by enzyme-based assay and anti-proliferation against Ramos and Raji cells. Most of them displayed good inhibitory activities against both BTK and B-cell lymphoblastic leukemia lines in vitro. Among them, compound 8a exhibited excellent potency (IC50 = 7.95 nM against BTK enzyme, 8.91 μM against Ramos cells and 1.80 μM against Raji cells), with a better hydrophilicity (ClogP = 3.33). These explorations provided new clues to discover 3-substituted pyrazolopyrimidine derivatives as novel anti-tumor agents.
Aminopyrimido pyrazole/pyrrole derivatives and preparation method and application thereof
-
Paragraph 0105-0107, (2021/06/21)
The invention relates to aminopyrimidinopyrazole/pyrrole derivatives as well as a preparation method and application thereof, belonging to the field of medicines. The invention provides compounds as shown in a formula I which is described in the specification and stereoisomers thereof, and further provides pharmaceutically acceptable salts of the compounds or the stereoisomers thereof. Biological experiments prove that the compounds can remarkably inhibit proliferation of various cancer cells such as breast cancer, lung cancer, gastric cancer, bile duct cancer and urinary tract epithelial cancer, have a broad-spectrum anti-cancer effect, also show an inhibiting effect on proliferation of fibroblasts and hepatic stellate cells, can inhibit the growth of tumors in vivo, and provide new options for the development of medicines used for resisting tumors and pulmonary and hepatic fibrosis.
Revisiting Pyrazolo[3,4- d]pyrimidine Nucleosides as Anti- Trypanosoma cruzi and Antileishmanial Agents
Bouton, Jakob,Ferreira De Almeida Fiuza, Ludmila,Cardoso Santos, Camila,Mazzarella, Maria Angela,De Nazaré Correia Soeiro, Maria,Maes, Louis,Karalic, Izet,Caljon, Guy,Van Calenbergh, Serge
, p. 4206 - 4238 (2021/05/04)
Chagas disease and visceral leishmaniasis are two neglected tropical diseases responsible for numerous deaths around the world. For both, current treatments are largely inadequate, resulting in a continued need for new drug discovery. As both kinetoplastid parasites are incapable of de novo purine synthesis, they depend on purine salvage pathways that allow them to acquire and process purines from the host to meet their demands. Purine nucleoside analogues therefore constitute a logical source of potential antiparasitic agents. Earlier optimization efforts of the natural product tubercidin (7-deazaadenosine) involving modifications to the nucleobase 7-position and the ribofuranose 3′-position led to analogues with potent anti-Trypanosoma brucei and anti-Trypanosoma cruzi activities. In this work, we report the design and synthesis of pyrazolo[3,4-d]pyrimidine nucleosides with 3′- and 7-modifications and assess their potential as anti-Trypanosoma cruzi and antileishmanial agents. One compound was selected for in vivo evaluation in an acute Chagas disease mouse model.
