The synthesis of 1,3,5‐triazine derivatives and JNJ7777120 analogues with histamine H4 receptor affinity and their interaction with PTEN promoter

The involvement of histamine and H-4 receptor (H4R) in cancer has been investigated recently using the H4R agonists and antagonists. The scope of the research project was synthesis and exploration of the consequences of a group of compounds with histamine H-4 receptor (H4R) affinity on the promoter of PTEN gene encoding the antitumor PTEN protein. The series of novel compounds based either on H4R antagonists JNJ7777120 structure or 1,3,5-triazine scaffold were synthesized, evaluated for histamine H4R 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 H4R with K-i 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 IC50 = 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 H4R with K-i value of 520 nM and may be considered as a new lead structure.