57564-94-0Relevant articles and documents
Identification of new pyrrolo[2,3-d]pyrimidines as Src tyrosine kinase inhibitors in vitro active against Glioblastoma
Musumeci, Francesca,Brullo, Chiara,Grossi, Giancarlo,Schenone, Silvia,Fallacara, Anna Lucia,Calandro, Pierpaolo,Botta, Lorenzo,Chiariello, Mario,Kissova, Miroslava,Crespan, Emmanuele,Maga, Giovanni
, p. 369 - 378 (2017)
In the last few years, several pyrrolo-pyrimidine derivatives have been either approved by the US FDA and in other countries for the treatment of different diseases or are currently in phase I/II clinical trials. Herein we present the synthesis and the characterization of a novel series of pyrrolo[2,3-d]pyrimidines, compounds 8a-j, and their activity against Glioblastoma multiforme (GBM). Docking studies and MM-GBSA analysis revealed the ability of such compounds to efficiently interact with the ATP binding site of Src. Enzymatic assays against a mini-panel of kinases (Src, Fyn, EGFR, Kit, Flt3, Abl, AblT315I) have been performed, showing an unexpected selectivity of our pyrrolo[2,3-d]pyrimidines for Src. Finally, the derivatives were tested for their antiproliferative potency on U87 GBM cell line. Compound 8h showed a considerable cytotoxicity effect against U87 cell line with an IC50value of 7.1 μM.
PYRIMIDINE DERIVATIVES FOR PREVENTION AND TREATMENT OF BACTERIAL INFECTIONS
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, (2019/09/04)
New pyrimidine derivatives of formula (I), optionally with a detectable isotope, pharmaceutical composition and method of preparation thereof. New pyrimidine derivatives for use in treatment or prevention of bacterial infection in a host mammal in need of such treatment or prevention and use as inhibitors of biofilm formation on a surface of biomaterial or medical device, particularly of cardiovascular device such as prosthetic heart valve or pacemakers. New pyrimidine derivatives for use as radiotracer in diagnosing or prognosing bacterial infection in a host mammal.
Targeting conserved water molecules: Design of 4-aryl-5-cyanopyrrolo[2,3-d] pyrimidine Hsp90 inhibitors using fragment-based screening and structure-based optimization
Davies, Nicholas G.M.,Browne, Helen,Davis, Ben,Drysdale, Martin J.,Foloppe, Nicolas,Geoffrey, Stephanie,Gibbons, Ben,Hart, Terance,Hubbard, Roderick,Jensen, Michael Rugaard,Mansell, Howard,Massey, Andrew,Matassova, Natalia,Moore, Jonathan D.,Murray, James,Pratt, Robert,Ray, Stuart,Robertson, Alan,Roughley, Stephen D.,Schoepfer, Joseph,Scriven, Kirsten,Simmonite, Heather,Stokes, Stephen,Surgenor, Allan,Webb, Paul,Wood, Mike,Wright, Lisa,Brough, Paul
, p. 6770 - 6789 (2013/01/15)
Inhibitors of the Hsp90 molecular chaperone are showing promise as anti-cancer agents. Here we describe a series of 4-aryl-5-cyanopyrrolo[2,3-d] pyrimidine ATP competitive Hsp90 inhibitors that were identified following structure-driven optimization of purine hits revealed by NMR based screening of a proprietary fragment library. Ligand-Hsp90 X-ray structures combined with molecular modeling led to the rational displacement of a conserved water molecule leading to enhanced affinity for Hsp90 as measured by fluorescence polarization, isothermal titration calorimetry and surface plasmon resonance assays. This displacement was achieved with a nitrile group, presenting an example of efficient gain in binding affinity with minimal increase in molecular weight. Some compounds in this chemical series inhibit the proliferation of human cancer cell lines in vitro and cause depletion of oncogenic Hsp90 client proteins and concomitant elevation of the co-chaperone Hsp70. In addition, one compound was demonstrated to be orally bioavailable in the mouse. This work demonstrates the power of structure-based design for the rapid evolution of potent Hsp90 inhibitors and the importance of considering conserved water molecules in drug design.
