4-Nitro-N-phthalyl-l-tryptophan

Anaelle Tilborg; Irving Boittiaux; Bernadette Norberg; Didier Lambert; Johan Wouters

doi:10.1107/S1600536811029138

. 2011 Jul 23;67(Pt 8):o2116. doi: 10.1107/S1600536811029138

4-Nitro-N-phthalyl-l-tryptophan

Anaelle Tilborg ^a, Irving Boittiaux ^b, Bernadette Norberg ^a, Didier Lambert ^b, Johan Wouters ^a,^*

PMCID: PMC3213557 PMID: 22091134

Abstract

The crystal structure of the title compound [systematic name: (2R)-3-(1H-indol-3-yl)-2-(4-nitro-1,3-dioxoisoindolin-2-yl)propanoic acid], C₁₉H₁₃N₃O₆, an analogue of epigenetic modulator RG108, is constrained by strong hydrogen bonds between the indole N—H group and a carbonyl O atom of the phthalimide ring of a symmetry-related molecule, and between the protonated O atom of the carboxyl group and a carbonyl O atom of the phthalimide ring. π–π stacking interactions with centroid–centroid distances of 3.638 (1) and 3.610 (1) Å are also observed between indole and phthalimide rings.

Related literature

For crystallographic information and details of the RG108 analogue, see: Braun et al. (2010 ▶) and for details of the biological evaluation, see: Brueckner et al. (2005 ▶).

Experimental

Crystal data

C₁₉H₁₃N₃O₆
M _r = 379.33
Monoclinic,
a = 7.0569 (3) Å
b = 15.5302 (8) Å
c = 7.6947 (4) Å
β = 95.415 (4)°
V = 839.54 (7) Å³
Z = 2
Cu Kα radiation
μ = 0.97 mm⁻¹
T = 293 K
0.22 × 0.10 × 0.03 mm

Data collection

Oxford Diffraction Xcalibur Ruby Gemini ultra diffractometer
Absorption correction: multi-scan (CrysAlis PRO; Oxford Diffraction, 2009 ▶) T _min = 0.815, T _max = 0.972
9007 measured reflections
2966 independent reflections
2735 reflections with I > 2σ(I)
R _int = 0.029

Refinement

R[F ² > 2σ(F ²)] = 0.031
wR(F ²) = 0.091
S = 1.06
2966 reflections
262 parameters
1 restraint
H atoms treated by a mixture of independent and constrained refinement
Δρ_max = 0.15 e Å⁻³
Δρ_min = −0.13 e Å⁻³
Absolute structure: Flack (1983 ▶), 1371 Friedel pairs
Flack parameter: −0.1 (2)

Data collection: CrysAlis PRO (Oxford Diffraction, 2009 ▶); cell refinement: CrysAlis PRO; data reduction: CrysAlis PRO; program(s) used to solve structure: SIR92 (Altomare et al., 1994 ▶); 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 datablock(s) I, global. DOI: 10.1107/S1600536811029138/vm2109sup1.cif

e-67-o2116-sup1.cif^{(21KB, cif)}

Structure factors: contains datablock(s) I. DOI: 10.1107/S1600536811029138/vm2109Isup2.hkl

e-67-o2116-Isup2.hkl^{(142.6KB, hkl)}

Supplementary material file. DOI: 10.1107/S1600536811029138/vm2109Isup3.cml

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
N2—H2⋯O1ⁱ	0.86 (4)	2.28 (4)	3.002 (3)	142 (4)
O4—H1⋯O2ⁱⁱ	1.00 (4)	1.78 (4)	2.716 (2)	154 (3)

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

Acknowledgments

This work was supported in part by the Fonds National de la Recherche Scientifique (FRS – FNRS, Belgium) by a Télévie grant (IB). AT acknowledges the FRIA (Fonds pour la formation à la Recherche dans l’Industrie et dans l’Agriculture) for financial support.

supplementary crystallographic information

Comment

4-Nitro-N-phthalyl-L-tryptophan is an analog of RG108, a DNA methyltransferase (DNMT) inhibitor discovered by virtual screening (Brueckner et al. (2005)). Introduction of a nitro functional group on the phtalimide moiety is excepted to improve inhibition ability (unpublished results).

Isomer S (C9) of 4-nitro-N-phthalyl-tryptophan is obtained from L-tryptophan and nitrophthalic anhydride in DMF.

Two main types of H-bonding interactions are observed in the structure: one between N—H of the indole ring (N2) and O1 of the phtalimide ring, and the other between the protonated oxygen (O4) from the carboxylic moiety and O2 from the phtalimide ring (see Table 1).

In addition to H-bonds, crystal packing organization is further stabilized by π–π-stacking interactions involving symmetry-related molecules, in particularly between the 6-membered coupled rings of nitrophthalimide and indole moiety (see Table 2). No interactions of this type are present in the packing of the dicyclohexylamine salt of RG108 (Braun et al. (2010), because of the presence of the ammonium counter-cation and water molecules included in the crystalline network.

In contrast to the structure of the dicyclohexylamine salt of RG108 (Braun et al. (2010)), where the compound conformation is constrained by strong (charge-assisted) H-bonds with the dicyclohexylammonium ion and extra water molecules, the angle between the two fused rings is 14.23 (4)° in the present structure compared to 58.35 (4)° in the case of the RG108 salt. The torsion angle of the chain between the two aromatic moieties (N1—C9—C10—C11) is also distinct: -155.66 (17)° and -61.93 (17) ° for the title and RG108 salt structures, respectively.

Experimental

Synthesis of the compound was accomplished by micro-wave heating of L-tryptophan (1 mmol, 204 mg) and 4-nitro phthalic anhydride (1 mmol, 193 mg) in 5 ml of DMF. The mixture was then poured in cold aqueous buffer solution (pH = 2) and extracted with ethyl acetate. After drying with Na₂SO₄, the organic phase is evaporated and the residue is purified by flash chromatography (dichloromethane and methanol: 9/1; yield = 60%, 230 mg).