title: Discovery of New Aminosubstituted Pyrrolopyrimidines with Antiproliferative Activity Against Breast Cancer Cells and Investigation of their Effect Towards the PI3Kα Enzyme.
abstract: OBJECTIVE
  A series of novel 2,4-diaminosubstituted pyrrolo[3,2-d]pyrimidines was synthesized together with their corresponding 7-phenyl or 7-isopropyl counterparts.
  
  
  RESULTS
  Among the target derivatives, the 7-substituted analogues exhibited interesting cytotoxic activity against a panel of PI3Kα related human breast cancer cell lines, namely MCF7, T47D, MDA-MB-231 and HCC1954. Selected compounds were tested for potential PI3Kα inhibitory activity as well as for their cytotoxic effect in prostate cancer cell lines (DU145 and PC3).
  
  
  CONCLUSIONS
  Derivatives bearing a specific substitution pattern consisting of 7-phenyl as well as a 2-(4- aminocyclohexylamino) moiety (16c, 16f) display kinase inhibitory activity, elucidated on the basis of molecular simulation studies, which revealed their interaction with the DFG motif of the kinase.
authors.affiliation: Division of Pharmaceutical Chemistry, Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimiopolis, 15771 Zografou. Greece.
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Daniilides
authors.affiliation: Division of Pharmaceutical Chemistry, Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimiopolis, 15771 Zografou. Greece.
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Lougiakis
authors.affiliation: Division of Pharmaceutical Chemistry, Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimiopolis, 15771 Zografou. Greece.
authors.forename: Thomas
authors.initials: T
authors.lastname: Evangelidis
authors.affiliation: Division of Pharmaceutical Chemistry, Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimiopolis, 15771 Zografou. Greece.
authors.forename: Ioannis K
authors.initials: IK
authors.lastname: Kostakis
authors.affiliation: Division of Pharmaceutical Chemistry, Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimiopolis, 15771 Zografou. Greece.
authors.forename: Nicole
authors.initials: N
authors.lastname: Pouli
authors.affiliation: Division of Pharmaceutical Chemistry, Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimiopolis, 15771 Zografou. Greece.
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Marakos
authors.affiliation: Division of Pharmaceutical Chemistry, Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimiopolis, 15771 Zografou. Greece.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Mikros
authors.affiliation: Division of Pharmacognosy and Natural Products Chemistry, Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, Panepistimiopolis, 15771 Zografou. Greece.
authors.forename: Alexios-Leandros
authors.initials: AL
authors.lastname: Skaltsounis
authors.affiliation: Sorbonne Universities, UPMC Univ Paris 06, CNRS USR 3151, Protein Phosphorylation & Human Diseases, Station Biologique de Roscoff, CS 90074, Roscoff Cedex F-29688. Greece.
authors.forename: Stephane
authors.initials: S
authors.lastname: Bach
authors.affiliation: Sorbonne Universities, UPMC Univ Paris 06, CNRS USR 3151, Protein Phosphorylation & Human Diseases, Station Biologique de Roscoff, CS 90074, Roscoff Cedex F-29688. Greece.
authors.forename: Blandine
authors.initials: B
authors.lastname: Baratte
authors.affiliation: Sorbonne Universities, UPMC Univ Paris 06, CNRS USR 3151, Protein Phosphorylation & Human Diseases, Station Biologique de Roscoff, CS 90074, Roscoff Cedex F-29688. Greece.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Ruchaud
authors.affiliation: Laboratory of Biological Chemistry, Department of Medicine, School of Health Sciences, University of Ioannina, 45110 Ioannina. Greece.
authors.forename: Valia
authors.initials: V
authors.lastname: Karamani
authors.affiliation: Laboratory of Biological Chemistry, Department of Medicine, School of Health Sciences, University of Ioannina, 45110 Ioannina. Greece.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Papafotika
authors.affiliation: Institute of Molecular Biology and Biotechnology, Division of Biomedical Research, Foundation for Research and Technology Hellas (IMBB-BR/FORTH), 45110 Ioannina. Greece.
authors.forename: Savvas
authors.initials: S
authors.lastname: Christoforidis
authors.affiliation: Division of Pharmacology-Pharmacotechnology, Biomedical Research Foundation Academy of Athens (BRFAA), Athens, 11527. Greece.
authors.forename: Orestis
authors.initials: O
authors.lastname: Argyros
authors.affiliation: Division of Pharmacology-Pharmacotechnology, Biomedical Research Foundation Academy of Athens (BRFAA), Athens, 11527. Greece.
authors.forename: Eva
authors.initials: E
authors.lastname: Kouvari
authors.affiliation: Division of Pharmacology-Pharmacotechnology, Biomedical Research Foundation Academy of Athens (BRFAA), Athens, 11527. Greece.
authors.forename: Constantin
authors.initials: C
authors.lastname: Tamvakopoulos
mesh_terms: D000586:Amination; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D001940:Breast / Q000187:drug effects / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D058534:Class I Phosphatidylinositol 3-Kinases; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D008297:Male; D062105:Molecular Docking Simulation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011467:Prostate / Q000187:drug effects / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology*; D011758:Pyrroles / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D058534:Class I Phosphatidylinositol 3-Kinases; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; C527741:pyrrolopyrimidine; C484760:PIK3CA protein, human
keywords: 2-d]pyrimidine; 9-deazapurine; PI3K inhibition; breast cancer; cytotoxicity; docking scoring; molecular dynamics; pyrrolo[3