title: [Pyrido[2,3-b]pyrazines inhibiting both erlotinib-sensitive and erlotinib-resistant cell lines, and their preparation via regioselective condensation reaction].
abstract: The EGFR inhibitor erlotinib possesses high anti-tumor effect but despite the good clinical responses in most of the cases recrudescence occures. This can be attributed to a secondary, acquired mutation causing resistance to tyrosine kinase inhibitors. In our work we were looking for small-molecule inhibitors, which simultaneously affect on the proliferation of erlotinib-sensitive PC9 cells and PC9-ER erlotinib-resistant cells. A set of molecules were selected from Vichem Chemie Research Ltd.'s kinase inhibitor compound library (Nested Chemical Library™). According to the results of medium throughput screening (MTS) of this set of compounds, novel structures with pyrido[2,3-b]pyrazine core were designed. These compounds were proved to be effective inhibitors of resistant cells in phenotypic screening. Based on these results structure-activity relationships were set up. The pyrido[2,3-b]pyrazine core was synthesized by a condensation reaction, which resulting two asymmetric products. In the reaction two regioisomer intermediates formed, and one of the products is the intermediate of the effective compounds. This condensation reaction was optimized, the regioisomers were identified by NMR analysis and X-ray crystallography. As a result of optimization we found that lower reaction temperature and replacement of dimethylformamide solvent with trifluoroacetic acid provided the undesired isomer in less than 2 % ratio.
authors.forename: László
authors.initials: L
authors.lastname: Kékesi
authors.forename: Anna
authors.initials: A
authors.lastname: Sipos
authors.forename: Gábor
authors.initials: G
authors.lastname: Németh
authors.forename: András
authors.initials: A
authors.lastname: Dancsó
authors.forename: Eszter
authors.initials: E
authors.lastname: Illyés
authors.forename: Sándor
authors.initials: S
authors.lastname: Boros
authors.forename: Nóra
authors.initials: N
authors.lastname: Breza
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Nemes
authors.forename: Bálint
authors.initials: B
authors.lastname: Hegymegi-Barakonyi
authors.forename: János
authors.initials: J
authors.lastname: Pató
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Greff
authors.forename: György
authors.initials: G
authors.lastname: Kéri
authors.forename: László
authors.initials: L
authors.lastname: Őrfi
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001671:Biochemistry / Q000379:methods*; D045744:Cell Line, Tumor / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D000069347:Erlotinib Hydrochloride; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011719:Pyrazines / Q000138:chemical synthesis* / Q000494:pharmacology*; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011719:Pyrazines; D011725:Pyridines; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors