Original article
Synthesis of aryl phosphates based on pyrimidine and triazine scaffolds

https://doi.org/10.1016/j.ejmech.2009.10.003Get rights and content

Abstract

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 IC50 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–π interactions with Grb2-SH2.

Introduction

The 2-arylaminopyrimidine and 1,3,5-triazine motifs are important as scaffolds in drug discovery chemistry. 2-Arylaminopyrimidine derivatives have exhibited biological activities such as antitumor activities involving different targets (e.g. CDKs, VEGF–TKRs, Bcr–Abl kinase) [1], [2], [3], [4], [5], [6], and antiinflammatory activity by inhibition of Lck [7]. 1,3,5-Triazine derivatives [8] have displayed a broad range of biological activities including cytotoxic activities [9], [10], [11], antiangiogenic activity by targeting either VEGF-R2 (KDR) [12] or direct modulation of Tie-2 tyrosine kinase phosphorylation [13], antiparasitic activities [14], [15], and glucocerebrosidase inhibition with potential as chemical chaperones for Gaucher disease [16]. To our knowledge, the syntheses of aryl phosphates based on pyrimidine and triazine scaffolds have not been reported to date. Importantly, the aryl phosphate group or its mimics are key pharmacophores in the design of cell signalling inhibitors as potential anticancer agents [17], [18], [19], [20], [21], [22].

As part of our efforts in the synthesis of non-peptidic inhibitors of the SH2 domain (Src homology) of Grb2 [23] (growth factor receptor-bound protein-2) which mediates protein–protein interactions in tyrosine kinase signal transduction pathways [17], [18], [19], [20], [21], [22], we have focused on the design and synthesis of aryl phosphates based on heterocycles allowing diverse functionalization [24]. Structure-based de novo design was carried out using 1 as a reference ligand [25], [26], [27], encompassing three pharmacophores [i.e., pTyr, (αMe)pTyr, CONH2] for binding to Grb2 (IC50 = 11 nM, ELISA assay). The complexes of two pseudopeptides with the Grb2-SH2 domain were recently reported by Martin and co-workers [28], [29], [30].

The structure of the best MD [25] pose of 1 with Grb2-SH2 is presented in the Supporting Information. Using this structure, 2 and 3 were designed by computer graphics upon replacing the peptide scaffold by a 1,3,5-trisubstituted triazine one while retaining a satisfactory overlap of the phosphate groups at the two extremities with those of 1. Within this context, we describe here the syntheses of the triazinyl-containing bis-aryl phosphates 2 and 3, and the synthesis of the 2-arylaminopyrimidyl-containing aryl phosphate 4 to mimic [31], [32] the phosphate moiety of 2. These novel compounds have in common a diaryl ether-phosphate structural motif (Fig. 1).

Importantly, the common substructure of 2 and 3 [33], [34], namely 4-(4-amino-1,3,5-triazin-2-ylamino)phenyl phosphate, was only published in recent patents (57) [35] reporting inhibition of smooth cell proliferation, treatment of inflammation, hyperproliferation, and modulation of glycosidase (Fig. 2). As for the substructure of 4, namely N-(4-(2H-tetrazol-5-yl)phenyl)pyrimidin-2-amine, it also appeared in the three patented compounds 810 [36], [37], [38], in the context of the syntheses of protein kinase inhibitors useful in treatment of diseases like cancer.

Section snippets

Results and discussion

The syntheses of the triazine scaffold-based bis-aryl phosphates 2 and 3 were carried out starting from 2,4,6-trichloro-1,3,5-triazine (cyanuric chloride) [8]. The latter and its derivatives (i.e., mono- or dichloride) are known to react very easily with various nucleophiles such as amines [9], [10], [11], [15], [39], [40], [41], [42], [43], [44], [45], [46], alcohols [47], [48], thiols [49], [50], and cyanide [51], [52]. It can also undergo organometallics couplings such as the Stille [53],

Conclusion

In summary, we have illustrated the syntheses of novel compounds, i.e., the triazinyl-based bis-aryl phosphates 2 and 3, and the 2-arylaminopyrimidyl-based aryl phosphate 4. Trifunctionalization of cyanuric chloride allowed us to prepare 2 and 3. The key step was the Suzuki cross-coupling between the required diaryl ether boronic acid (15, 18) and the 2,4-diamino-6-chloro-1,3,5-triazine derivative 12. Bis-phosphorylation completed the syntheses. The aminopyrimidine scaffold in 4 was prepared by

General information

All commercial reagents were used without purification and all solvents were reaction grade. When necessary, solvents were previously dried over molecular sieves. Tetrahydrofuran was also dried over molecular sieves 4 Å unless otherwise stated (distilled from sodium/benzophenone under argon). All reactions were performed under an inert atmosphere of argon unless otherwise stated. All reaction mixtures were stirred magnetically and monitored by thin-layer chromatography using Merck silica gel 60 F

Acknowledgements

We thank CNRS, Institut Curie and Ministère de la Recherche (ACI “Molécules et Cibles Thérapeutiques” 2002 N° 02L0521) for financial support. Fondation pour la Recherche Médicale (FRM) is gratefully acknowledged for a fellowship granted to Caroline Courme.

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