Thailandepsin A

Cheng Wang; Yi-Qiang Cheng

doi:10.1107/S1600536811041390

. 2011 Oct 12;67(Pt 11):o2948–o2949. doi: 10.1107/S1600536811041390

Thailandepsin A

Cheng Wang ^a,^*, Yi-Qiang Cheng ^a,^*

PMCID: PMC3247358 PMID: 22219976

Abstract

Thailandepsin A [systematic name: (E)-(1S,5S,6R,9S,20R)-6-[(2S)-butan-2-yl]-5-hydroxy-20-[2-(methylsulfanyl)ethyl]-2-oxa-11,12-dithia-7,19,22-triazabicyclo[7.7.6]docosa-15-ene-3,8,18,21-tetraone], C₂₃H₃₇N₃O₆S₃, is a newly reported [Wang et al. (2011). J. Nat. Prod. doi:10.1021/np200324x] bicyclic depsipeptide that has potent histone deacetylase inhibitory activity and broad-spectrum antiproliferative activity. The absolute configuration of thailandepsin A has been determined from the anomalous dispersion and the stereochemistry of all chiral C atoms. Intramolecular N—H⋯O and N—H⋯S hydrogen bonds occur. Intermolecular N—H⋯O and O—H⋯O hydrogen bonds are observed in the crystal structure.

Related literature

For general background to histone deacetylase (HDAC) inhibitors as a new class of anticancer agents, see: FDA (2010 ▶); Furumai et al. (2002 ▶); Grant et al. (2010 ▶); Khan & La Thangue (2008 ▶); Mann et al. (2007 ▶); Ueda et al. (1994 ▶). For related structures, see: Shigematsu et al. (1994 ▶). For geometric data, see: Chou & Blinn (1997 ▶). For the biological activity of the title compound, see: Wang et al. (2011 ▶).

Experimental

Crystal data

C₂₃H₃₇N₃O₆S₃
M _r = 547.74
Orthorhombic,
a = 12.7747 (3) Å
b = 13.2926 (3) Å
c = 15.4218 (4) Å
V = 2618.76 (11) Å³
Z = 4
Cu Kα radiation
μ = 2.96 mm⁻¹
T = 100 K
0.45 × 0.42 × 0.38 mm

Data collection

Bruker SMART APEXII area-detector diffractometer
Absorption correction: multi-scan (SADABS; Bruker, 2007 ▶) T _min = 0.352, T _max = 0.403
34598 measured reflections
4990 independent reflections
4981 reflections with I > 2σ(I)
R _int = 0.025

Refinement

R[F ² > 2σ(F ²)] = 0.027
wR(F ²) = 0.071
S = 1.05
4990 reflections
326 parameters
4 restraints
H atoms treated by a mixture of independent and constrained refinement
Δρ_max = 0.35 e Å⁻³
Δρ_min = −0.36 e Å⁻³
Absolute structure: Flack (1983 ▶), 2102 Friedel pairs
Flack parameter: 0.000 (9)

Data collection: APEX2 (Bruker, 2007 ▶); cell refinement: SAINT (Bruker, 2007 ▶); data reduction: SAINT; program(s) used to solve structure: SHELXTL (Sheldrick, 2008 ▶); program(s) used to refine structure: SHELXTL; molecular graphics: SHELXTL and OLEX2 (Dolomanov et al., 2009 ▶); software used to prepare material for publication: SHELXTL.

Supplementary Material

Crystal structure: contains datablock(s) I, global. DOI: 10.1107/S1600536811041390/zl2411sup1.cif

e-67-o2948-sup1.cif^{(25.4KB, cif)}

Supplementary material file. DOI: 10.1107/S1600536811041390/zl2411Isup2.cdx

Structure factors: contains datablock(s) I. DOI: 10.1107/S1600536811041390/zl2411Isup3.hkl

e-67-o2948-Isup3.hkl^{(244.4KB, hkl)}

Supplementary material file. DOI: 10.1107/S1600536811041390/zl2411Isup4.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
O4—H4⋯O5ⁱ	0.84 (1)	1.90 (1)	2.7394 (15)	176 (2)
N1—H1⋯O6	0.88 (1)	2.06 (1)	2.9203 (17)	166 (2)
N2—H2⋯S2	0.88 (1)	2.83 (2)	3.2491 (13)	111 (2)
N3—H3⋯O4ⁱⁱ	0.88 (1)	2.33 (1)	3.1534 (16)	155 (2)

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

Acknowledgments

Support for this work was obtained from a Research Growth Initiative Award from the University of Wisconsin–Milwaukee and NIH/NCI grant R01 CA 152212 (both to Y-QC). The authors thank Lara C. Spencer and Ilia A. Guzei (University of Wisconsin-Madison Department of Chemistry Crystallography Facility) for collecting the crystallographic data.

supplementary crystallographic information

Comment

With the FDA approval of both SAHA (Vorinostat) and FK228 (Romidepsin) for the treatment of cutaneous T-cell lymphoma (FDA, 2010; Mann et al., 2007), histone deacetylase (HDAC) inhibitors have been in the spotlight in recent years as a new class of anticancer agents (Grant et al., 2010; Khan & La Thangue, 2008). FK228, a natural product produced by Chromobacterium violaceum No. 968 (Ueda et al., 1994), represents a family of natural products that contain a signature disulfide bond that is known or presumed to mediate a novel mode of anticancer action in which a reduced thiol group "warhead" chelates a Zn²⁺ in the catalytic center of Class I and Class II HDACs thereby inhibiting the enzyme activities (Furumai et al., 2002; Wang et al., 2011). The crystal structure of FK228 was reported in 1994 (Shigematsu et al., 1994).

Thailandepsin A is a natural analogue of FK228 newly discovered from Burkholderia thailandensis E264 by a genomics-guided approach; it has potent histone deacetylase inhibitory activities and broad-spectrum antiproliferative activities (Wang et al., 2011). The chemical structure of thailandepsin A was established by a combination of spectroscopic analyses, chemical derivatization and degradation. Here we report the crystal structure of thailandepsin A.

Thailandepsin A is a bicyclic depsipeptide and consists of four building blocks, D-cysteine (D-Cys), D-methionine (D-Met), 4-amino-3-hydroxy-5-methylheptanoic acid (Ahhp, derived from an isoleucine and an acetate unit) and 3-hydroxy-7-mercapto-4-heptenoic acid (Acyl, derived from a cysteine and two acetate units). The primary structure of thailandepsin A is D-Met-D-Cys-Ahhp-Acyl. X-ray crystallographic analysis indicates that the skeleton of thailandepsin A consists of a [7,7,6] 22-membered ring adopting an uncommon cage-shape that includes a 15-membered macrocyclic lactone and a 15-membered ring and a signature disulfide bond. The bridge ring is almost perpendicular to the main ring and the dihedral angle of these two least-squares planes is 77.7 (1)°. The side chains of methionine and isoleucine have less strain and can freely rotate on the single bonds. In order to obtain minimum energy positions, the alkyl groups arrange so on the molecular skeleton that they point away from each other.

The absolute configurations at C2, C8, C11 and C13 are S and the absolute configurations at C12 and 18 are R as established based on the results of anomalous dispersion. The geometric isomerism of the double bond in the Acyl component is determined as E. The backbone moiety from the carboxyl group of Acyl through methionine and cysteine to the amine group of Ahhp, (Acyl)-CO¹—Met²—Cys³—NH⁴-(Ahhp), forms a peculiar secondary structure, a type I' β-turn, and the value of Ψ and Φ are 57.26 (17)°, 29.76 (18)°, 95.49 (16)° and -18.11 (19)° (Chou & Blinn, 1997). There are two intramolecular and two intermolecular hydrogen bonds present (Table 1, Fig. 1 and 2).

Experimental

Thailandepsin A was purified from the fermentation broth of B. thailandensis E264 as described earlier (Wang et al., 2011). Pure thailandepsin A was dissolved in methanol and block-like crystals were obtained after evaporation of the solvent at room temperature.