Synthesis of aryl phosphates based on pyrimidine and triazine scaffolds.
The syntheses of the triazinyl-based bis-aryl phosphates 2 and 3, and of the aminopyrimidyl-based aryl phosphate 4 are described. Each compound contains a diaryl ether-phosphate structural motif. The synthetic route to bis-aryl phosphates 2 and 3 consisted in two nucleophilic substitution reactions with amines from cyanuric chloride, followed by a Suzuki coupling with the resulting 2,4-diamino-6-chloro-1,3,5-triazine derivative 12 to introduce the diaryl ether functionality. Aryl phosphate 4 was obtained via condensation of aryl guanidine 34 with aryloxyphenyl butenone 31. These de novo-designed aryl phosphates were evaluated as potential inhibitors of the Grb2-SH2 domain using an ELISA assay. The water-soluble sodium salt 26 of 3 gave an IC(50) value in the high micromolar range. Molecular modeling studies were subsequently performed upon modifying the 1,3,5-trisubstituted triazine scaffold of 3. Non-phosphate derivatives encompassing cyclopropane, pyrrole, keto-acid, and IZD fragments were thus step-wise designed and their Grb2-SH2 complexes were modeled by molecular dynamics. Some derivatives gave rise to an enriched pattern of H-bonds and cation-pi interactions with Grb2-SH2.
Courme
Caroline
C
CNRS UMR 176, 26 rue d'Ulm, 75005 Paris, France.
Gresh
Nohad
N
Vidal
Michel
M
Lenoir
Christine
C
Garbay
Christiane
C
Florent
Jean-Claude
JC
Bertounesque
Emmanuel
E
D051380:GRB2 Adaptor Protein / Q000037:antagonists & inhibitors / Q000737:chemistry; D008958:Models, Molecular; D008968:Molecular Conformation; D010710:Phosphates / Q000737:chemistry*; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D014227:Triazines / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D018909:src Homology Domains
D051380:GRB2 Adaptor Protein; D010710:Phosphates; D011743:Pyrimidines; D014227:Triazines; C030986:pyrimidine