The dicyclo­hexyl­amine salt of RG108 (N-phthalyl-l-tryptophan), a potential epigenetic modulator

Julie Braun; Irving Boittiaux; Anaelle Tilborg; Didier Lambert; Johan Wouters

doi:10.1107/S160053681004626X

. 2010 Nov 13;66(Pt 12):o3175–o3176. doi: 10.1107/S160053681004626X

The dicyclohexylamine salt of RG108 (N-phthalyl-l-tryptophan), a potential epigenetic modulator

Julie Braun ^a, Irving Boittiaux ^a, Anaelle Tilborg ^a, Didier Lambert ^b, Johan Wouters ^a,^*

PMCID: PMC3011641 PMID: 21589471

Abstract

The dicyclohexylamine salt of RG108 (N-phthalyl-l-tryptophan) co-crystallizes with a water molecule and a disordered molecule of dimethylformamide (DMF), viz. dicyclohexylaminium (S)-2-(1,3-dioxoisoindolin-2-yl)-3-(1H-indol-3-yl)propanoate dimethylformamide solvate monohydrate, C₁₂H₂₄N⁺·C₁₉H₁₃N₂O₄ ⁻·C₃H₇NO·H₂O. The conformation of the deprotonated compound is constrained by charge-assisted strong hydrogen bonds with the dicyclohexylaminium ion and a dense hydrogen-bond network involving co-crystallized solvent molecules. The dihedral angle between the fused ring systems in the anion is 58.35 (4)°.

Related literature

For the synthesis and biological evaluation, see: Brueckner et al. (2005 ▶).

Experimental

Crystal data

C₁₂H₂₄N⁺·C₁₉H₁₃N₂O₄ ⁻·C₃H₇NO·H₂O
M _r = 606.75
Orthorhombic,
a = 9.0884 (1) Å
b = 15.0206 (3) Å
c = 24.4749 (5) Å
V = 3341.15 (10) Å³
Z = 4
Cu Kα radiation
μ = 0.67 mm⁻¹
T = 293 K
0.55 × 0.04 × 0.03 mm

Data collection

Oxford Diffraction Xcalibur diffractometer with a Ruby (Gemini ultra Cu) detector
Absorption correction: multi-scan (CrysAlis PRO; Oxford Diffraction, 2009 ▶) T _min = 0.967, T _max = 0.981
13362 measured reflections
5552 independent reflections
4936 reflections with I > 2σ(I)
R _int = 0.026

Refinement

R[F ² > 2σ(F ²)] = 0.037
wR(F ²) = 0.094
S = 1.01
5552 reflections
409 parameters
8 restraints
H atoms treated by a mixture of independent and constrained refinement
Δρ_max = 0.30 e Å⁻³
Δρ_min = −0.27 e Å⁻³
Absolute structure: Flack (1983 ▶), 2160 Friedel pairs
Flack parameter: 0.02 (18)

Data collection: CrysAlis PRO (Oxford Diffraction, 2009 ▶); cell refinement: CrysAlis PRO; data reduction: CrysAlis PRO; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 ▶); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 ▶); molecular graphics: ORTEPIII (Burnett & Johnson, 1996 ▶) and PLATON (Spek, 2009 ▶); software used to prepare material for publication: SHELXL97.

Supplementary Material

Crystal structure: contains datablocks I, global. DOI: 10.1107/S160053681004626X/vm2050sup1.cif

e-66-o3175-sup1.cif^{(28.2KB, cif)}

Structure factors: contains datablocks I. DOI: 10.1107/S160053681004626X/vm2050Isup2.hkl

e-66-o3175-Isup2.hkl^{(266.4KB, hkl)}

Additional supplementary materials: crystallographic information; 3D view; checkCIF report

Table 1. Hydrogen-bond geometry (Å, °).

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
N3—HN3B⋯O4ⁱ	0.86 (3)	1.88 (3)	2.7309 (19)	169 (2)
N2—H2⋯O5ⁱⁱ	0.86	1.97	2.813 (3)	165
N3—HN3A⋯O3ⁱⁱⁱ	0.99 (3)	1.79 (3)	2.7740 (19)	173 (2)
O5—H5B⋯O99	0.83 (4)	1.84 (4)	2.645 (4)	164 (4)
O5—H5C⋯O1^iv	0.89 (4)	1.99 (4)	2.857 (2)	164 (3)

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Symmetry codes: (i) Inline graphic ; (ii) ; (iii) ; (iv) .

Acknowledgments

This work was supported in part by the Fonds National de la Recherche Scientifique (FNRS, Belgium). Crystals were obtained during work for the Masters thesis of Miss Isabelle Bouhy. The authors thank Bernadette Norberg for her valuable help during the data collection.

supplementary crystallographic information

Comment

RG108 (N-phthalyl-L-tryptophan) is a DNA methyltransferase (DMNT) inhibitor that was discovered by virtual screening (Brueckner et al., 2005). It reactivates tumor suppressor gene expression in tumor cells by DNA demethylation. RG108 also inhibits human tumor cell line proliferation.

Isomer S (C9) of RG108 is obtained starting from L-tryptophan and phthalic anhydride in DMF.

The unprotonated carboxylate group (both C—O bond lenghts are similar with C19—O3 = 1.246 (2) Å and C19—O4 = 1.247 (2) Å) of RG108 is close to the protonated sp³ nitrogen atom (N3) of the amine (intermolecular O···N distances: O3···N3ⁱ = 2.774 (2) Å and O4···N3ⁱⁱ = 2.731 (2) Å; i = -1/2 + x,1/2 - y,-z, ii = -1 + x,y,z, see also Table 1).

A water molecule (O5) has co-crystallized and is involved in the stability of the packing as it forms a network of H-bonds connecting the N—H (N2) of the indole ring of RG108 with a carbonyl function (O1) of the phtalimide ring of a symmetry-related molecule and the oxygen atom (O99) of a molecule of DMF solvent (Table 1).

In addition to H-bonding to the water, the extra (disordered) co-crystallized solvent molecule of DMF is thightly packed in a cavity formed by the aromatic heterocycles of RG108 (the phtalimide and the indole rings).

As a consequence of the dense packing (salt bridge, H-bonds and van der Waals interactions), the two aromatic, planar, heterocycles of RG108 are perpendicular (acute angle between the planes defined by the phtalimide and the indole rings = 58.35 (4)°).

Experimental

Synthesis of the compound was made by micro-ave heating of L-tryptophane and phthalic anhydride in DMF by adapting the procedure described by Brueckner et al. (2005).

Crystals were obtained by evaporation at room temperature of a solution in mixture of methylene chloride and methanol (9/1).