title: The Synthesis of 1,3,5-triazine Derivatives and JNJ7777120 Analogues with Histamine H4 Receptor Affinity and Their Interaction with PTEN Promoter.
abstract: The involvement of histamine and H4 receptor (H4 R) in cancer has been investigated recently using the H4 R agonists and antagonists. The scope of the research project was synthesis and exploration of the consequences of a group of compounds with histamine H4 receptor (H4 R) affinity on the promoter of PTEN gene encoding the antitumor PTEN protein. The series of novel compounds based either on H4 R antagonists JNJ7777120 structure or 1,3,5-triazine scaffold were synthesized, evaluated for histamine H4 R affinity and used in this study. Compounds 5 and 7 belonging to the group of JNJ7777120 analogues showed the highest interaction with the promoter of PTEN gene and weak affinity against H4 R with Ki value >100 μm. These compounds showed no significant effect on neuroblastoma IMR-32 cells viability indicating no correlation between PTEN gene promoter affinity and antitumor activity. Compound 6, another JNJ7777120 analogue, showed the highest effect on IMR-32 viability with calculated IC50 = 23.27 μm. The 1,3,5-triazine derivatives exhibited generally low or medium interaction with PTEN gene promoter. However, the 1,3,5-triazine derivative 11 with the para-bromo substituent showed the highest affinity against H4 R with Ki value of 520 nm and may be considered as a new lead structure.
authors.affiliation: Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Medyczna 9, Kraków, 30-688, Poland.
authors.forename: Gniewomir
authors.initials: G
authors.lastname: Latacz
authors.affiliation: Laboratory of Biochemistry, Institute of Pharmaceutical Chemistry, Aristotle University of Thessaloniki, Thessaloniki, GR-54124, Greece.
authors.forename: Petros
authors.initials: P
authors.lastname: Kechagioglou
authors.affiliation: Laboratory of Biochemistry, Institute of Pharmaceutical Chemistry, Aristotle University of Thessaloniki, Thessaloniki, GR-54124, Greece.
authors.forename: Rigini
authors.initials: R
authors.lastname: Papi
authors.affiliation: Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Medyczna 9, Kraków, 30-688, Poland.
authors.forename: Dorota
authors.initials: D
authors.lastname: Łażewska
authors.affiliation: Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Medyczna 9, Kraków, 30-688, Poland.
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Więcek
authors.affiliation: Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Medyczna 9, Kraków, 30-688, Poland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Kamińska
authors.affiliation: Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Medyczna 9, Kraków, 30-688, Poland.
authors.forename: Przemysław
authors.initials: P
authors.lastname: Wencel
authors.affiliation: Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Medyczna 9, Kraków, 30-688, Poland.
authors.forename: Tadeusz
authors.initials: T
authors.lastname: Karcz
authors.affiliation: Biozentrum, Goethe University, Max-von-Laue-Str. 9, Frankfurt/Main, 60438, Germany.|Institute of Pharmaceutical and Medicinal Chemistry, Heinrich-Heine-University, Universitaetsstr. 1, Duesseldorf, 40225, Germany.
authors.forename: Johannes S
authors.initials: JS
authors.lastname: Schwed
authors.affiliation: Biozentrum, Goethe University, Max-von-Laue-Str. 9, Frankfurt/Main, 60438, Germany.|Institute of Pharmaceutical and Medicinal Chemistry, Heinrich-Heine-University, Universitaetsstr. 1, Duesseldorf, 40225, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Stark
authors.affiliation: Laboratory of Biochemistry, Institute of Pharmaceutical Chemistry, Aristotle University of Thessaloniki, Thessaloniki, GR-54124, Greece.
authors.forename: Dimitrios A
authors.initials: DA
authors.lastname: Kyriakidis
authors.affiliation: Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Medyczna 9, Kraków, 30-688, Poland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Kieć-Kononowicz
mesh_terms: D049109:Cell Proliferation / Q000187:drug effects; D024202:Electrophoretic Mobility Shift Assay; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D011968:Receptors, Histamine / Q000187:drug effects*; D014227:Triazines / Q000138:chemical synthesis* / Q000494:pharmacology*
chemical_list: D007211:Indoles; D010879:Piperazines; D011968:Receptors, Histamine; D014227:Triazines; C484309:1-((5-chloro-1H-indol-2-yl)carbonyl)-4-methylpiperazine; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
keywords: 1,3,5-triazines; JNJ7777120 analogues; PTEN promoter; histamine H4 receptor ligands