91333-15-2Relevant academic research and scientific papers
Identification of a 2,4-diaminopyrimidine scaffold targeting Trypanosoma brucei pteridine reductase 1 from the LIBRA compound library screening campaign
Bandiera, Tiziano,Bartoccini, Francesca,Bertozzi, Fabio,Bertozzi, Sine Mandrup,Bolognesi, Maria Laura,Borsari, Chiara,Brambilla, Enzo,Cavalli, Andrea,Conti, Paola,Cordeiro da Silva, Anabela,Costi, Maria Paola,Cullia, Gregorio,Ellinger, Bernhard,Ferrari, Stefania,Goldoni, Luca,Gul, Sheraz,Kuzikov, Maria,Linciano, Pasquale,Piersanti, Giovanni,Pinto, Andrea,Piomelli, Daniele,Prati, Federica,Retini, Michele,Rizzo, Vincenzo,Roberti, Marinella,Santucci, Matteo,Witt, Gesa,Santarém, Nuno
, (2020)
The LIBRA compound library is a collection of 522 non-commercial molecules contributed by various Italian academic laboratories. These compounds have been designed and synthesized during different medicinal chemistry programs and are hosted by the Italian Institute of Technology. We report the screening of the LIBRA compound library against Trypanosoma brucei and Leishmania major pteridine reductase 1, TbPTR1 and LmPTR1. Nine compounds were active against parasitic PTR1 and were selected for cell-based parasite screening, as single agents and in combination with methotrexate (MTX). The most interesting TbPTR1 inhibitor identified was 4-(benzyloxy)pyrimidine-2,6-diamine (LIB_66). Subsequently, six new LIB_66 derivatives were synthesized to explore its Structure-Activity-Relationship (SAR) and absorption, distribution, metabolism, excretion and toxicity (ADMET) properties. The results indicate that PTR1 has a preference to bind inhibitors, which resemble its biopterin/folic acid substrates, such as the 2,4-diaminopyrimidine derivatives.
Discovery of novel substituted benzo-anellated 4-benzylamino pyrrolopyrimidines as dual EGFR and VEGFR2 inhibitors
Fischer, Tim,Krüger, Thomas,Najjar, Abdulkarim,Totzke, Frank,Sch?chtele, Christoph,Sippl, Wolfgang,Ritter, Christoph,Hilgeroth, Andreas
, p. 2708 - 2712 (2017)
The quinazoline scaffold is the main part of many marketed EGFR inhibitors. Resistance developments against those inhibitors enforced the search for novel structural lead compounds. We developed novel benzo-anellated 4-benzylamine pyrrolopyrimidines with varied substitution patterns at both the molecular scaffold and the attached residue in the 4-position. The structure-dependent affinities towards EGFR are discussed and first nanomolar derivatives have been identified. Docking studies were carried out for EGFR in order to explore the potential binding mode of the novel inhibitors. As the receptor tyrosine kinase VEGFR2 recently gained an increasing interest as an upregulated signaling kinase in many solid tumors and in tumor metastasis we determined the affinity of our compounds to inhibit VEGFR2. So we identified novel dually acting EGFR and VEGFR2 inhibitors for which first anticancer screening data are reported. Those data indicate a stronger antiproliferative effect of a VEGFR2 inhibition compared to the EGFR inhibition.
