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.

Computer-Aided Studies for Novel Arylhydantoin 1,3,5-Triazine Derivatives as 5-HT6 Serotonin Receptor Ligands with Antidepressive-Like, Anxiolytic and Antiobesity Action In Vivo

“…The final compounds 5 – 26 were obtained using four different synthesis pathways ( Scheme 1 a–d). The synthesis of 5,5-dimethylhydantoin triazine derivative 4 was described earlier [ 14 ]. As for the syntheses of the 3-benzyl derivative ( 5 ) and the 1-arylmethyl ones ( 6 , 9 – 18 ), the commercial 5,5-dimethylhydantoin (DMH) was a starting material, which was substituted with an appropriate arylmethyl halide and methyl bromoacetate in a different order, respectively (a and b, Scheme 1 ).…”

“…The benzyl intermediate was used to perform a cyclic condensation with urea providing 5,5- bis (4-chlorophenyl)hydantoin ( 70 ), followed by an alkylation with methyl bromoacetate in position 3 of the hydantoin, in the aforementioned conditions of two-phase alkylation, to produce ester 71 ( Scheme 1 d). All ester hydantoin intermediates ( 28 , 30 – 40 , 59 – 67 , and 71 ) were converted into the 1,3,5-triazine final products ( 5 – 26 ) via cyclic condensation with 1-(imino(4-methylpiperazin-1-yl)methyl)guanidine, which proceeded in sodium methanolate under the conditions corresponding to those for a series of benzyl-1,3,5-triazines described previously [ 13 , 14 ].…”

Synthesis and PI 3-Kinase Inhibition Activity of Some Novel 2,4,6-Trisubstituted 1,3,5-Triazines

“…Triazines offer synthetic advantages over pyrimidines in that the addition of substituents onto its core does not produce regioisomers that have to be separated. The synthesis and characterization of trisubstituted triazines and pyrimidines remains an active area of PI3K inhibition research [ 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 ]. We focused most of our synthetic efforts on trisubstituted triazines ( Scheme 1 ; 1 ) which contain (1) a linker group terminating in a primary alcohol which can be used as a peptide linkage point, (2) a secondary amine (largely morpholine due to its known importance [ 47 ]), and (3) a hydrogen-bonding aromatic or heteroaromatic group.…”

Synthesis and PI3 Kinase Inhibition Activity of Some Novel Trisubstituted Morpholinopyrimidines

“…Synthesis and characterization of trisubstituted triazines and pyrimidines remains an active area of PI3K inhibition research [ 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 ]. Since both core structures provide inhibitors that are quite active, we decided to prepare both trisubstituted triazines and trisubstituted pyrimidines, and here we report our work on the pyrimidines ( Scheme 1 ).…”