Thailandepsin A

Wang, C.; Cheng, Y.-Q.

doi:10.1107/S1600536811041390

organic compounds

CRYSTALLOGRAPHIC
COMMUNICATIONS

ISSN: 2056-9890

Volume 67| Part 11| November 2011| Pages o2948-o2949

doi:10.1107/S1600536811041390

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Thailandepsin A

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

^aDepartment of Biological Sciences, Department of Chemistry and Biochemistry, Univeristy of Wisconsin–Milwaukee, PO Box 413, Milwaukee, WI 53201, USA
^*Correspondence e-mail: wang35@uwm.edu, ycheng@uwm.edu

(Received 2 October 2011; accepted 7 October 2011; online 12 October 2011)

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, P 2₁ 2₁ 2₁
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[F² > 2σ(F²)] = 0.027
wR(F²) = 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)

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)
Symmetry codes: (i) $[-x+2, y-{\script{1\over 2}}, -z+{\script{3\over 2}}]$ ; (ii) $[-x+{\script{3\over 2}}, -y, z-{\script{1\over 2}}]$ .

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.

Supporting information

Crystal structure: contains datablocks I, global. DOI: 10.1107/S1600536811041390/zl2411sup1.cif

Supporting information file. DOI: 10.1107/S1600536811041390/zl2411Isup2.cdx

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

Supporting information file. DOI: 10.1107/S1600536811041390/zl2411Isup4.cml

checkCIF report

Comment top

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).

Related literature top

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 top

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.

Computing details top

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

Figures top

	Fig. 1. The molecular structure of thailandepsin A with displacement ellipsoids shown at the 50% probability level. For clarity, all H atoms attached to carbon atoms are omitted. Intramolecular hydrogen bonds are shown as dashed lines.
	Fig. 2. A packing diagram of thailandepsin A, viewed along the c axis. For clarity, all H atoms attached to carbon atoms are omitted. The dashed lines represent hydrogen bonds.

(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 top

Crystal data top

C₂₃H₃₇N₃O₆S₃	F(000) = 1168
M_r = 547.74	D_x = 1.389 Mg m⁻³
Orthorhombic, P2₁2₁2₁	Cu Kα radiation, λ = 1.54178 Å
Hall symbol: P 2ac 2ab	Cell parameters from 9793 reflections
a = 12.7747 (3) Å	θ = 3.5–71.2°
b = 13.2926 (3) Å	µ = 2.96 mm⁻¹
c = 15.4218 (4) Å	T = 100 K
V = 2618.76 (11) Å³	Block, colourless
Z = 4	0.45 × 0.42 × 0.38 mm

Data collection top

Bruker SMART APEXII area-detector diffractometer	4990 independent reflections
Radiation source: fine-focus sealed tube	4981 reflections with I > 2σ(I)
Graphite monochromator	R_int = 0.025
0.50° ω and 0.5 ° ϕ scans	θ_max = 71.7°, θ_min = 4.4°
Absorption correction: multi-scan (SADABS; Bruker, 2007)	h = −15→14
T_min = 0.352, T_max = 0.403	k = −15→16
34598 measured reflections	l = −18→17

Refinement top

Refinement on F²	Secondary atom site location: difference Fourier map
Least-squares matrix: full	Hydrogen site location: inferred from neighbouring sites
R[F² > 2σ(F²)] = 0.027	H atoms treated by a mixture of independent and constrained refinement
wR(F²) = 0.071	w = 1/[σ²(F_o²) + (0.051P)² + 0.7593P] where P = (F_o² + 2F_c²)/3
S = 1.05	(Δ/σ)_max = 0.001
4990 reflections	Δρ_max = 0.35 e Å⁻³
326 parameters	Δρ_min = −0.36 e Å⁻³
4 restraints	Absolute structure: Flack (1983), ???? Friedel pairs
Primary atom site location: structure-invariant direct methods	Absolute structure parameter: 0.000 (9)

Crystal data top

C₂₃H₃₇N₃O₆S₃	V = 2618.76 (11) Å³
M_r = 547.74	Z = 4
Orthorhombic, P2₁2₁2₁	Cu Kα radiation
a = 12.7747 (3) Å	µ = 2.96 mm⁻¹
b = 13.2926 (3) Å	T = 100 K
c = 15.4218 (4) Å	0.45 × 0.42 × 0.38 mm

Data collection top

Bruker SMART APEXII area-detector diffractometer	4990 independent reflections
Absorption correction: multi-scan (SADABS; Bruker, 2007)	4981 reflections with I > 2σ(I)
T_min = 0.352, T_max = 0.403	R_int = 0.025
34598 measured reflections

Refinement top

R[F² > 2σ(F²)] = 0.027	H atoms treated by a mixture of independent and constrained refinement
wR(F²) = 0.071	Δρ_max = 0.35 e Å⁻³
S = 1.05	Δρ_min = −0.36 e Å⁻³
4990 reflections	Absolute structure: Flack (1983), ???? Friedel pairs
326 parameters	Absolute structure parameter: 0.000 (9)
4 restraints

Special details top

Geometry. All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.'s are taken into account individually in the estimation of e.s.d.'s in distances, angles and torsion angles; correlations between e.s.d.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.'s is used for estimating e.s.d.'s involving l.s. planes.

Refinement. Refinement of F² against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F², conventional R-factors R are based on F, with F set to zero for negative F². The threshold expression of F² > σ(F²) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F² are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å²) top

	x	y	z	U_iso*/U_eq
S1	1.10290 (3)	−0.14637 (3)	0.38774 (2)	0.02184 (10)
S2	0.97356 (3)	−0.08216 (3)	0.33328 (2)	0.01709 (9)
S3	0.91337 (3)	0.40012 (3)	0.40152 (3)	0.02362 (10)
O1	1.08885 (10)	−0.18335 (9)	0.67591 (8)	0.0223 (3)
O2	0.77376 (8)	−0.09984 (8)	0.61157 (7)	0.0141 (2)
O3	0.69383 (9)	−0.08629 (9)	0.74184 (7)	0.0190 (2)
O4	0.85790 (9)	−0.16775 (8)	0.88174 (7)	0.0140 (2)
H4	0.8699 (17)	−0.2254 (7)	0.9016 (13)	0.021*
O5	1.11125 (9)	0.14154 (8)	0.55597 (7)	0.0179 (2)
O6	0.86120 (9)	0.12479 (8)	0.64747 (7)	0.0158 (2)
N1	0.99720 (10)	−0.04020 (10)	0.70173 (8)	0.0128 (3)
H1	0.9652 (14)	0.0126 (9)	0.6798 (12)	0.015*
N2	1.00458 (10)	0.00984 (9)	0.52676 (8)	0.0121 (2)
H2	0.9444 (8)	−0.0082 (14)	0.5038 (12)	0.014*
N3	0.83857 (10)	0.13784 (10)	0.50282 (8)	0.0138 (3)
H3	0.7955 (12)	0.1335 (15)	0.4584 (8)	0.017*
C1	1.05386 (12)	−0.10227 (12)	0.65205 (10)	0.0143 (3)
C2	1.07489 (12)	−0.06840 (11)	0.55727 (9)	0.0131 (3)
H2A	1.1482	−0.0423	0.5537	0.016*
C3	1.06714 (13)	−0.16258 (12)	0.50086 (10)	0.0174 (3)
H3A	0.9943	−0.1877	0.5034	0.021*
H3B	1.1128	−0.2151	0.5262	0.021*
C4	0.88346 (14)	−0.18723 (13)	0.31638 (11)	0.0202 (3)
H4A	0.8850	−0.2082	0.2548	0.024*
H4B	0.9052	−0.2453	0.3524	0.024*
C5	0.77251 (12)	−0.15466 (13)	0.34132 (11)	0.0190 (3)
H5A	0.7542	−0.0927	0.3091	0.023*
H5B	0.7225	−0.2079	0.3240	0.023*
C6	0.76184 (12)	−0.13526 (13)	0.43705 (10)	0.0173 (3)
H6	0.7980	−0.1793	0.4752	0.021*
C7	0.70632 (12)	−0.06202 (12)	0.47258 (10)	0.0162 (3)
H7	0.6720	−0.0170	0.4341	0.019*
C8	0.69224 (12)	−0.04303 (12)	0.56827 (10)	0.0154 (3)
H8	0.6227	−0.0704	0.5865	0.018*
C9	0.76158 (12)	−0.12126 (11)	0.69723 (10)	0.0136 (3)
C10	0.84280 (12)	−0.19799 (11)	0.72498 (10)	0.0138 (3)
H10A	0.8877	−0.2133	0.6743	0.017*
H10B	0.8059	−0.2608	0.7409	0.017*
C11	0.91409 (12)	−0.16801 (11)	0.80094 (9)	0.0127 (3)
H11	0.9724	−0.2180	0.8051	0.015*
C12	0.96190 (12)	−0.06200 (11)	0.79096 (9)	0.0125 (3)
H12	0.9029	−0.0143	0.8019	0.015*
C13	1.04416 (12)	−0.03790 (11)	0.86101 (10)	0.0146 (3)
H13	1.0124	−0.0559	0.9182	0.017*
C14	1.06664 (13)	0.07539 (12)	0.86315 (10)	0.0184 (3)
H14A	1.1138	0.0927	0.8144	0.022*
H14B	1.0002	0.1125	0.8548	0.022*
C15	1.11702 (14)	0.10927 (13)	0.94810 (11)	0.0222 (3)
H15A	1.0677	0.0988	0.9960	0.033*
H15B	1.1350	0.1808	0.9443	0.033*
H15C	1.1807	0.0700	0.9585	0.033*
C16	1.14602 (12)	−0.09806 (13)	0.85283 (10)	0.0184 (3)
H16A	1.1848	−0.0752	0.8017	0.028*
H16B	1.1296	−0.1697	0.8467	0.028*
H16C	1.1888	−0.0878	0.9048	0.028*
C17	1.02739 (12)	0.10824 (11)	0.52881 (9)	0.0134 (3)
C18	0.94399 (12)	0.17890 (11)	0.49209 (10)	0.0138 (3)
H18	0.9480	0.2442	0.5241	0.017*
C19	0.80478 (12)	0.11430 (11)	0.58346 (10)	0.0141 (3)
C20	0.69604 (12)	0.06994 (12)	0.59060 (10)	0.0160 (3)
H20A	0.6486	0.1068	0.5510	0.019*
H20B	0.6701	0.0797	0.6505	0.019*
C21	0.96752 (13)	0.19916 (11)	0.39575 (10)	0.0158 (3)
H21A	1.0409	0.2224	0.3904	0.019*
H21B	0.9613	0.1351	0.3634	0.019*
C22	0.89580 (13)	0.27705 (12)	0.35353 (10)	0.0168 (3)
H22A	0.8220	0.2558	0.3605	0.020*
H22B	0.9112	0.2807	0.2907	0.020*
C23	0.82077 (15)	0.46899 (14)	0.33643 (12)	0.0250 (4)
H23A	0.8190	0.5393	0.3554	0.037*
H23B	0.7510	0.4392	0.3431	0.037*
H23C	0.8419	0.4659	0.2754	0.037*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
S1	0.01829 (19)	0.0340 (2)	0.01321 (18)	0.00771 (17)	−0.00022 (14)	−0.00696 (15)
S2	0.01714 (18)	0.02111 (19)	0.01302 (16)	0.00009 (15)	−0.00063 (14)	−0.00078 (14)
S3	0.0279 (2)	0.0207 (2)	0.0222 (2)	0.00109 (16)	−0.00648 (16)	0.00032 (16)
O1	0.0286 (6)	0.0210 (6)	0.0172 (6)	0.0118 (5)	0.0048 (5)	0.0045 (5)
O2	0.0140 (5)	0.0171 (5)	0.0112 (5)	0.0017 (4)	0.0001 (4)	0.0034 (4)
O3	0.0199 (5)	0.0216 (6)	0.0156 (5)	0.0040 (5)	0.0037 (4)	0.0017 (5)
O4	0.0190 (5)	0.0131 (5)	0.0098 (5)	0.0019 (4)	0.0019 (4)	0.0018 (4)
O5	0.0167 (5)	0.0166 (5)	0.0205 (5)	−0.0020 (4)	−0.0032 (5)	−0.0018 (5)
O6	0.0197 (5)	0.0159 (5)	0.0119 (5)	0.0022 (4)	0.0004 (4)	−0.0001 (4)
N1	0.0161 (6)	0.0129 (6)	0.0093 (6)	0.0026 (5)	−0.0002 (5)	0.0029 (5)
N2	0.0122 (6)	0.0137 (6)	0.0103 (6)	−0.0004 (5)	−0.0003 (4)	−0.0003 (5)
N3	0.0139 (6)	0.0155 (6)	0.0121 (6)	0.0005 (5)	−0.0008 (5)	0.0010 (5)
C1	0.0145 (7)	0.0156 (7)	0.0129 (7)	0.0005 (6)	0.0002 (5)	0.0013 (6)
C2	0.0146 (7)	0.0142 (7)	0.0104 (6)	0.0017 (6)	0.0001 (5)	−0.0004 (6)
C3	0.0227 (7)	0.0153 (7)	0.0142 (7)	0.0037 (6)	−0.0015 (6)	−0.0014 (6)
C4	0.0243 (8)	0.0191 (7)	0.0170 (8)	−0.0014 (7)	−0.0020 (7)	−0.0043 (6)
C5	0.0184 (8)	0.0213 (8)	0.0172 (8)	−0.0030 (6)	−0.0031 (6)	−0.0015 (6)
C6	0.0167 (7)	0.0196 (7)	0.0156 (7)	−0.0045 (6)	−0.0035 (6)	0.0037 (6)
C7	0.0150 (7)	0.0194 (7)	0.0143 (7)	−0.0019 (6)	−0.0042 (6)	0.0040 (6)
C8	0.0126 (7)	0.0182 (7)	0.0154 (7)	0.0001 (6)	−0.0011 (6)	0.0038 (6)
C9	0.0165 (7)	0.0135 (7)	0.0107 (6)	−0.0032 (6)	−0.0007 (6)	0.0002 (5)
C10	0.0183 (7)	0.0118 (7)	0.0111 (7)	0.0006 (6)	−0.0002 (6)	−0.0001 (5)
C11	0.0157 (7)	0.0136 (7)	0.0087 (6)	0.0015 (6)	0.0001 (6)	0.0010 (5)
C12	0.0152 (7)	0.0133 (6)	0.0089 (6)	0.0014 (6)	0.0010 (6)	0.0009 (5)
C13	0.0176 (7)	0.0156 (7)	0.0106 (7)	0.0009 (6)	−0.0008 (6)	0.0000 (5)
C14	0.0249 (8)	0.0155 (7)	0.0148 (7)	−0.0014 (6)	−0.0034 (6)	0.0017 (6)
C15	0.0287 (9)	0.0189 (8)	0.0190 (8)	−0.0025 (7)	−0.0021 (7)	−0.0013 (6)
C16	0.0161 (7)	0.0208 (8)	0.0182 (8)	0.0011 (6)	−0.0020 (6)	0.0011 (6)
C17	0.0164 (7)	0.0158 (7)	0.0079 (6)	−0.0003 (6)	0.0022 (6)	−0.0004 (5)
C18	0.0153 (7)	0.0133 (7)	0.0127 (7)	−0.0014 (6)	0.0000 (6)	0.0000 (6)
C19	0.0160 (7)	0.0119 (7)	0.0144 (7)	0.0037 (6)	0.0017 (6)	0.0005 (6)
C20	0.0154 (7)	0.0184 (7)	0.0142 (7)	0.0036 (6)	0.0020 (6)	0.0026 (6)
C21	0.0192 (7)	0.0154 (7)	0.0128 (7)	−0.0013 (6)	0.0012 (6)	0.0013 (6)
C22	0.0210 (8)	0.0171 (7)	0.0122 (7)	−0.0029 (6)	−0.0026 (6)	0.0015 (5)
C23	0.0259 (8)	0.0281 (9)	0.0209 (8)	0.0081 (7)	0.0006 (7)	0.0028 (7)

Geometric parameters (Å, º) top

S1—C3	1.8162 (17)	C8—C20	1.541 (2)
S1—S2	2.0406 (6)	C8—H8	1.0000
S2—C4	1.8285 (17)	C9—C10	1.517 (2)
S3—C23	1.8014 (18)	C10—C11	1.536 (2)
S3—C22	1.8095 (16)	C10—H10A	0.9900
O1—C1	1.223 (2)	C10—H10B	0.9900
O2—C9	1.3602 (18)	C11—C12	1.543 (2)
O2—C8	1.4494 (18)	C11—H11	1.0000
O3—C9	1.199 (2)	C12—C13	1.541 (2)
O4—C11	1.4380 (17)	C12—H12	1.0000
O4—H4	0.8399 (10)	C13—C16	1.533 (2)
O5—C17	1.233 (2)	C13—C14	1.533 (2)
O6—C19	1.230 (2)	C13—H13	1.0000
N1—C1	1.338 (2)	C14—C15	1.528 (2)
N1—C12	1.4769 (18)	C14—H14A	0.9900
N1—H1	0.8797 (10)	C14—H14B	0.9900
N2—C17	1.340 (2)	C15—H15A	0.9800
N2—C2	1.4524 (19)	C15—H15B	0.9800
N2—H2	0.8798 (10)	C15—H15C	0.9800
N3—C19	1.353 (2)	C16—H16A	0.9800
N3—C18	1.4624 (18)	C16—H16B	0.9800
N3—H3	0.8799 (10)	C16—H16C	0.9800
C1—C2	1.553 (2)	C17—C18	1.529 (2)
C2—C3	1.528 (2)	C18—C21	1.540 (2)
C2—H2A	1.0000	C18—H18	1.0000
C3—H3A	0.9900	C19—C20	1.513 (2)
C3—H3B	0.9900	C20—H20A	0.9900
C4—C5	1.531 (2)	C20—H20B	0.9900
C4—H4A	0.9900	C21—C22	1.528 (2)
C4—H4B	0.9900	C21—H21A	0.9900
C5—C6	1.505 (2)	C21—H21B	0.9900
C5—H5A	0.9900	C22—H22A	0.9900
C5—H5B	0.9900	C22—H22B	0.9900
C6—C7	1.323 (2)	C23—H23A	0.9800
C6—H6	0.9500	C23—H23B	0.9800
C7—C8	1.508 (2)	C23—H23C	0.9800
C7—H7	0.9500

C3—S1—S2	103.96 (6)	C12—C11—H11	108.5
C4—S2—S1	104.41 (6)	N1—C12—C13	113.84 (12)
C23—S3—C22	98.63 (8)	N1—C12—C11	113.14 (12)
C9—O2—C8	118.31 (12)	C13—C12—C11	112.95 (12)
C11—O4—H4	102.9 (15)	N1—C12—H12	105.3
C1—N1—C12	125.27 (13)	C13—C12—H12	105.3
C1—N1—H1	121.5 (13)	C11—C12—H12	105.3
C12—N1—H1	111.9 (13)	C16—C13—C14	110.81 (13)
C17—N2—C2	123.82 (13)	C16—C13—C12	114.39 (13)
C17—N2—H2	117.7 (13)	C14—C13—C12	110.31 (12)
C2—N2—H2	118.4 (13)	C16—C13—H13	107.0
C19—N3—C18	118.95 (13)	C14—C13—H13	107.0
C19—N3—H3	120.1 (13)	C12—C13—H13	107.0
C18—N3—H3	120.8 (13)	C15—C14—C13	112.76 (13)
O1—C1—N1	124.65 (14)	C15—C14—H14A	109.0
O1—C1—C2	118.38 (14)	C13—C14—H14A	109.0
N1—C1—C2	116.97 (13)	C15—C14—H14B	109.0
N2—C2—C3	111.24 (12)	C13—C14—H14B	109.0
N2—C2—C1	113.92 (12)	H14A—C14—H14B	107.8
C3—C2—C1	106.69 (12)	C14—C15—H15A	109.5
N2—C2—H2A	108.3	C14—C15—H15B	109.5
C3—C2—H2A	108.3	H15A—C15—H15B	109.5
C1—C2—H2A	108.3	C14—C15—H15C	109.5
C2—C3—S1	115.69 (11)	H15A—C15—H15C	109.5
C2—C3—H3A	108.4	H15B—C15—H15C	109.5
S1—C3—H3A	108.4	C13—C16—H16A	109.5
C2—C3—H3B	108.4	C13—C16—H16B	109.5
S1—C3—H3B	108.4	H16A—C16—H16B	109.5
H3A—C3—H3B	107.4	C13—C16—H16C	109.5
C5—C4—S2	109.33 (11)	H16A—C16—H16C	109.5
C5—C4—H4A	109.8	H16B—C16—H16C	109.5
S2—C4—H4A	109.8	O5—C17—N2	123.19 (14)
C5—C4—H4B	109.8	O5—C17—C18	120.72 (13)
S2—C4—H4B	109.8	N2—C17—C18	116.05 (13)
H4A—C4—H4B	108.3	N3—C18—C17	111.75 (12)
C6—C5—C4	112.26 (13)	N3—C18—C21	110.75 (12)
C6—C5—H5A	109.2	C17—C18—C21	109.20 (12)
C4—C5—H5A	109.2	N3—C18—H18	108.4
C6—C5—H5B	109.2	C17—C18—H18	108.4
C4—C5—H5B	109.2	C21—C18—H18	108.4
H5A—C5—H5B	107.9	O6—C19—N3	121.62 (14)
C7—C6—C5	125.51 (15)	O6—C19—C20	121.58 (14)
C7—C6—H6	117.2	N3—C19—C20	116.73 (14)
C5—C6—H6	117.2	C19—C20—C8	113.10 (13)
C6—C7—C8	126.32 (14)	C19—C20—H20A	109.0
C6—C7—H7	116.8	C8—C20—H20A	109.0
C8—C7—H7	116.8	C19—C20—H20B	109.0
O2—C8—C7	106.14 (12)	C8—C20—H20B	109.0
O2—C8—C20	112.45 (12)	H20A—C20—H20B	107.8
C7—C8—C20	112.21 (13)	C22—C21—C18	114.37 (13)
O2—C8—H8	108.6	C22—C21—H21A	108.7
C7—C8—H8	108.6	C18—C21—H21A	108.7
C20—C8—H8	108.6	C22—C21—H21B	108.7
O3—C9—O2	123.95 (14)	C18—C21—H21B	108.7
O3—C9—C10	126.34 (14)	H21A—C21—H21B	107.6
O2—C9—C10	109.66 (12)	C21—C22—S3	111.34 (11)
C9—C10—C11	116.50 (12)	C21—C22—H22A	109.4
C9—C10—H10A	108.2	S3—C22—H22A	109.4
C11—C10—H10A	108.2	C21—C22—H22B	109.4
C9—C10—H10B	108.2	S3—C22—H22B	109.4
C11—C10—H10B	108.2	H22A—C22—H22B	108.0
H10A—C10—H10B	107.3	S3—C23—H23A	109.5
O4—C11—C10	111.44 (12)	S3—C23—H23B	109.5
O4—C11—C12	106.37 (11)	H23A—C23—H23B	109.5
C10—C11—C12	113.29 (12)	S3—C23—H23C	109.5
O4—C11—H11	108.5	H23A—C23—H23C	109.5
C10—C11—H11	108.5	H23B—C23—H23C	109.5

C3—S1—S2—C4	−79.45 (8)	O4—C11—C12—N1	−164.12 (12)
C12—N1—C1—O1	−4.2 (2)	C10—C11—C12—N1	−41.37 (17)
C12—N1—C1—C2	175.04 (13)	O4—C11—C12—C13	64.71 (15)
C17—N2—C2—C3	−143.88 (14)	C10—C11—C12—C13	−172.53 (12)
C17—N2—C2—C1	95.49 (16)	N1—C12—C13—C16	−61.27 (17)
O1—C1—C2—N2	161.20 (14)	C11—C12—C13—C16	69.54 (16)
N1—C1—C2—N2	−18.11 (19)	N1—C12—C13—C14	64.44 (16)
O1—C1—C2—C3	38.06 (19)	C11—C12—C13—C14	−164.75 (12)
N1—C1—C2—C3	−141.25 (14)	C16—C13—C14—C15	−71.70 (17)
N2—C2—C3—S1	61.75 (15)	C12—C13—C14—C15	160.60 (13)
C1—C2—C3—S1	−173.45 (10)	C2—N2—C17—O5	0.9 (2)
S2—S1—C3—C2	−79.42 (12)	C2—N2—C17—C18	178.86 (12)
S1—S2—C4—C5	138.27 (10)	C19—N3—C18—C17	57.26 (17)
S2—C4—C5—C6	−67.15 (16)	C19—N3—C18—C21	179.24 (13)
C4—C5—C6—C7	141.33 (16)	O5—C17—C18—N3	−152.25 (13)
C5—C6—C7—C8	178.20 (15)	N2—C17—C18—N3	29.76 (18)
C9—O2—C8—C7	−160.50 (12)	O5—C17—C18—C21	84.87 (16)
C9—O2—C8—C20	76.45 (16)	N2—C17—C18—C21	−93.11 (15)
C6—C7—C8—O2	16.4 (2)	C18—N3—C19—O6	−1.4 (2)
C6—C7—C8—C20	139.65 (16)	C18—N3—C19—C20	−178.68 (12)
C8—O2—C9—O3	−9.1 (2)	O6—C19—C20—C8	−97.53 (17)
C8—O2—C9—C10	168.50 (12)	N3—C19—C20—C8	79.73 (16)
O3—C9—C10—C11	−58.7 (2)	O2—C8—C20—C19	47.62 (17)
O2—C9—C10—C11	123.75 (13)	C7—C8—C20—C19	−71.95 (17)
C9—C10—C11—O4	71.69 (16)	N3—C18—C21—C22	62.21 (16)
C9—C10—C11—C12	−48.21 (17)	C17—C18—C21—C22	−174.33 (13)
C1—N1—C12—C13	84.41 (18)	C18—C21—C22—S3	64.71 (15)
C1—N1—C12—C11	−46.31 (19)	C23—S3—C22—C21	179.27 (12)

Hydrogen-bond geometry (Å, º) top

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)

Symmetry codes: (i) −x+2, y−1/2, −z+3/2; (ii) −x+3/2, −y, z−1/2.

Experimental details

Crystal data
Chemical formula	C₂₃H₃₇N₃O₆S₃
M_r	547.74
Crystal system, space group	Orthorhombic, P2₁2₁2₁
Temperature (K)	100
a, b, c (Å)	12.7747 (3), 13.2926 (3), 15.4218 (4)
V (Å³)	2618.76 (11)
Z	4
Radiation type	Cu Kα
µ (mm⁻¹)	2.96
Crystal size (mm)	0.45 × 0.42 × 0.38

Data collection
Diffractometer	Bruker SMART APEXII area-detector diffractometer
Absorption correction	Multi-scan (SADABS; Bruker, 2007)
T_min, T_max	0.352, 0.403
No. of measured, independent and observed [I > 2σ(I)] reflections	34598, 4990, 4981
R_int	0.025
(sin θ/λ)_max (Å⁻¹)	0.616

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.027, 0.071, 1.05
No. of reflections	4990
No. of parameters	326
No. of restraints	4
H-atom treatment	H atoms treated by a mixture of independent and constrained refinement
Δρ_max, Δρ_min (e Å⁻³)	0.35, −0.36
Absolute structure	Flack (1983), ???? Friedel pairs
Absolute structure parameter	0.000 (9)

Computer programs: APEX2 (Bruker, 2007), SAINT (Bruker, 2007), SHELXTL (Sheldrick, 2008) and OLEX2 (Dolomanov et al., 2009), SHELXTL.

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
O4—H4···O5ⁱ	0.8399 (10)	1.901 (2)	2.7394 (15)	176 (2)
N1—H1···O6	0.8797 (10)	2.059 (5)	2.9203 (17)	166.1 (18)
N2—H2···S2	0.8798 (10)	2.833 (19)	3.2491 (13)	110.7 (15)
N3—H3···O4ⁱⁱ	0.8799 (10)	2.334 (9)	3.1534 (16)	155.0 (18)

Symmetry codes: (i) −x+2, y−1/2, −z+3/2; (ii) −x+3/2, −y, z−1/2.

Acknowledgements

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.

References

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