The Synthesis of 1,3,5-triazine Derivatives and JNJ7777120 Analogues with Histamine H sub(4) Receptor Affinity and Their Interaction with PTEN Promoter

• Published in: Chemical biology & drug design Vol. 88; no. 2; pp. 254 - 263
• Main Authors: Latacz, Gniewomir, Kechagioglou, Petros, Papi, Rigini, aewska, Dorota, Wicek, Magorzata, Kamiska, Katarzyna, Wencel, Przemysaw, Karcz, Tadeusz, Schwed, Johannes S, Stark, Holger, Kyriakidis, Dimitrios A, Kiec-Kononowicz, Katarzyna
• Format: Journal Article
• Language: English
• Published: 01.08.2016
• ISSN: 1747-0277; 1747-0285
• DOI: 10.1111/cbdd.12752

The involvement of histamine and H sub(4) receptor (H sub(4)R) in cancer has been investigated recently using the H sub(4)R agonists and antagonists. The scope of the research project was synthesis and exploration of the consequences of a group of compounds with histamine H sub(4) receptor (H sub(4)R) affinity on the promoter of PTEN gene encoding the antitumor PTEN protein. The series of novel compounds based either on H sub(4)R antagonists JNJ7777120 structure or 1,3,5-triazine scaffold were synthesized, evaluated for histamine H sub(4)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 H sub(4)R with Ki value >100 mu m. 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 IC sub(50) = 23.27 mu m. 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 H sub(4)R with K sub(i) value of 520 nm and may be considered as a new lead structure. PTEN has been described as the most frequently mutated tumor suppressor gene in human cancer. We described here the synthesis of new H sub(4) receptor ligands and their interaction with the promoter of PTEN gene demonstrated by using electrophoretic mobility shift assay. Several compounds based on the well-known H sub(4)R antagonist JNJ7777120 structure showed high effect on PTEN promoter mobility. However, no correlation between PTEN interaction and anti-neuroblastoma activity was found. Moreover, one triazine derivative with the highest H sub(4)R affinity was shown as a promising and non-cytotoxic lead structure.