Supporting information
Crystallographic Information File (CIF) https://doi.org/10.1107/S0108270103014495/ob1130sup1.cif | |
Structure factor file (CIF format) https://doi.org/10.1107/S0108270103014495/ob1130Isup2.hkl |
CCDC reference: 205223
Peptide synthesis and crystallization: [Cha]ASC was synthesized as previously described (Hamada et al., 1985, 1987). 1H NMR spectra of [Cha]ASC were recorded using a Varian Inova 500 at 300 K in dimethyl sulfoxide-d6: δH 7.70 (1H, br, Ile-NH), 7.70 (1H, br, Cha-NH), 7.57 (2H, s, Thz-H), 7.32 (1H, br, D-Val-NH), 7.29 (1H, br, D-Val-NH), 5.20–5.25 (2H, m, D-Val-CαH), 4.90–4.97 (1H, m, Cha-CαH), 4.90–4.97 (2H, m, Oxz-CβH), 4.72–7.75 (1H, m, Ile-CαH), 4.36 (2H, d, J = 4.12 Hz, Oxz-CαH), 2.31–2.35 (2H, m, D-Val-CβH), 2.05–2.13 (1H, m, Ile-CβH), 1.81–1.95 (1H, m, Cha-CβH2), 1.65–1.79, 0.87–0.95 (11H, m Cha-C6H11), 1.52–1.56 (1H, m, Cha-CβH2), 1.49 (3H, d, J = 6.41 Hz, Oxz-CγH3), 1.47 (3H, d, J = 6.41 Hz, Oxz-CγH3), 1.43–1.53 (1H, m, Ile-Cγ2H2), 1.26–1.33 (1H, m, Ile-Cγ2H2), 1.14–1.20 (12H, m, D-Val-CγH3 × 2), 0.96 (3H, d, J = 6.86 Hz, Ile-Cγ1H3), 0.84 (3H, t, J = 7.32 Hz, Ile-CγH3). [Cha]ASC (7–8 mg) was dissolved in 0.2 ml of N,N-dimethylformamide (DMF) or N,N-dimethylacetamide (DMA), after which approximately 0.02 ml of water was added to each solution. Crystals grew from both solutions in about a week with different crystal froms, but DMF crystals were not suitable for structure determination.
Circular dichroism: CD spectra were measured at 298 K using a JASCO 500 A (JASCO, Tokyo, Japan) dichrograph. The peptide concentration was 0.04 mM and the path length was 1 cm. The spectra were scanned at a rate of 5 nm min−1, with a 0.1 nm interval uptake to a computer. Data were averaged at each 1 nm and plotted.
Cytotoxicity: the cytotoxicity of ASC analogues was evaluated using P-388 lymphocytic leukemia cells essentially as previously described, with some modification (Kohda, Ohta, Kawazoe, et al., 1989; Kohda, Ohta, Yokoyama et al., 1989). All assays were performed three times. Semilogarithmic plots were constructed from the averaged data and the effective dose of the peptide required to inhibit cell growth by 50% (ED50) was determined.
H atoms of the peptide and DMA molecules were calculated at ideal positions and were included in the refinement as riding atoms. Wayer H atoms were located in difference Fourier maps and were refined isotropically.
Data collection: SMART (Bruker, 1998); cell refinement: SMART; data reduction: SAINT-Plus (Bruker, 1998); program(s) used to solve structure: SHELXD (Sheldrick & Gould, 1996); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: PLATON (Spek, 2001); software used to prepare material for publication: PARST (Nardelli, 1983).
C39H56N8O6S2·C4H9NO·2H2O | F(000) = 988 |
Mr = 920.19 | Dx = 1.253 Mg m−3 |
Monoclinic, P21 | Mo Kα radiation, λ = 0.71073 Å |
a = 13.283 (2) Å | Cell parameters from 9020 reflections |
b = 14.153 (2) Å | θ = 2.1–28.3° |
c = 13.452 (2) Å | µ = 0.17 mm−1 |
β = 105.252 (2)° | T = 90 K |
V = 2439.8 (7) Å3 | Block, colourless |
Z = 2 | 0.40 × 0.25 × 0.20 mm |
Bruker AXS SMART APEX CCD diffractometer | 11112 independent reflections |
Radiation source: MacScience M18XCE rotating anode | 9973 reflections with I > 2σ(I) |
Graphite monochromator | Rint = 0.023 |
Detector resolution: 8.366 pixels mm-1 | θmax = 28.3°, θmin = 2.1° |
ω scans | h = −17→17 |
Absorption correction: empirical (using intensity measurements) (SADABS; Sheldrick, 1996) | k = −18→18 |
Tmin = 0.797, Tmax = 0.967 | l = −17→17 |
22268 measured reflections |
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)] = 0.051 | H atoms treated by a mixture of independent and constrained refinement |
wR(F2) = 0.137 | w = 1/[σ2(Fo2) + (0.0937P)2 + 0.2367P] where P = (Fo2 + 2Fc2)/3 |
S = 1.04 | (Δ/σ)max = 0.004 |
11112 reflections | Δρmax = 0.85 e Å−3 |
584 parameters | Δρmin = −0.35 e Å−3 |
1 restraint | Absolute structure: (Flack, 1983), 5087 Friedel pairs |
Primary atom site location: structure-invariant direct methods | Absolute structure parameter: −0.06 (6) |
C39H56N8O6S2·C4H9NO·2H2O | V = 2439.8 (7) Å3 |
Mr = 920.19 | Z = 2 |
Monoclinic, P21 | Mo Kα radiation |
a = 13.283 (2) Å | µ = 0.17 mm−1 |
b = 14.153 (2) Å | T = 90 K |
c = 13.452 (2) Å | 0.40 × 0.25 × 0.20 mm |
β = 105.252 (2)° |
Bruker AXS SMART APEX CCD diffractometer | 11112 independent reflections |
Absorption correction: empirical (using intensity measurements) (SADABS; Sheldrick, 1996) | 9973 reflections with I > 2σ(I) |
Tmin = 0.797, Tmax = 0.967 | Rint = 0.023 |
22268 measured reflections |
R[F2 > 2σ(F2)] = 0.051 | H atoms treated by a mixture of independent and constrained refinement |
wR(F2) = 0.137 | Δρmax = 0.85 e Å−3 |
S = 1.04 | Δρmin = −0.35 e Å−3 |
11112 reflections | Absolute structure: (Flack, 1983), 5087 Friedel pairs |
584 parameters | Absolute structure parameter: −0.06 (6) |
1 restraint |
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. Data collection was carried out using a Bruker SMART APEX diffractometer at 90 K, and the primary structures were solved using the dual-space recycling method with SHELXD (Sheldrick, & Gould, 1996). The structure was refined using SHELXL97 (Sheldrick, 1997). 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. |
x | y | z | Uiso*/Ueq | ||
N_1 | 0.89187 (15) | 0.58835 (13) | 0.92788 (14) | 0.0279 (4) | |
H1_1 | 0.8403 | 0.6188 | 0.8856 | 0.033* | |
CA_1 | 0.98583 (17) | 0.56998 (15) | 0.89792 (17) | 0.0282 (4) | |
H2_1 | 1.0336 | 0.5313 | 0.9528 | 0.034* | |
CB_1 | 0.96620 (19) | 0.51659 (16) | 0.79455 (18) | 0.0315 (5) | |
H3_1 | 0.9144 | 0.5527 | 0.7418 | 0.038* | |
H4_1 | 1.0321 | 0.5157 | 0.7733 | 0.038* | |
CG_1 | 0.92741 (18) | 0.41553 (15) | 0.79457 (17) | 0.0291 (4) | |
H5_1 | 0.8575 | 0.4169 | 0.8093 | 0.035* | |
CD1_1 | 0.9145 (2) | 0.37317 (18) | 0.68779 (18) | 0.0383 (5) | |
H6_1 | 0.8621 | 0.4105 | 0.6370 | 0.046* | |
H7_1 | 0.9817 | 0.3779 | 0.6692 | 0.046* | |
CE1_1 | 0.8803 (2) | 0.2705 (2) | 0.6812 (2) | 0.0460 (6) | |
H8_1 | 0.8773 | 0.2456 | 0.6117 | 0.055* | |
H9_1 | 0.8094 | 0.2661 | 0.6917 | 0.055* | |
CZ_1 | 0.9553 (3) | 0.2108 (2) | 0.7619 (2) | 0.0536 (8) | |
H10_1 | 0.9291 | 0.1451 | 0.7591 | 0.064* | |
H11_1 | 1.0246 | 0.2095 | 0.7472 | 0.064* | |
CE2_1 | 0.9658 (3) | 0.25163 (19) | 0.8686 (2) | 0.0537 (8) | |
H12_1 | 0.8978 | 0.2469 | 0.8855 | 0.064* | |
H13_1 | 1.0172 | 0.2139 | 0.9199 | 0.064* | |
CD2_1 | 1.0003 (2) | 0.35384 (18) | 0.87605 (19) | 0.0389 (6) | |
H14_1 | 1.0719 | 0.3577 | 0.8672 | 0.047* | |
H15_1 | 1.0022 | 0.3783 | 0.9454 | 0.047* | |
C3_2 | 1.03980 (17) | 0.66093 (16) | 0.88552 (16) | 0.0277 (4) | |
N_2 | 0.99507 (15) | 0.73935 (13) | 0.86281 (14) | 0.0280 (4) | |
CA_2 | 1.07289 (17) | 0.80115 (16) | 0.83444 (18) | 0.0294 (4) | |
H16_2 | 1.0790 | 0.8622 | 0.8730 | 0.035* | |
CB_2 | 1.17626 (18) | 0.74546 (17) | 0.86825 (18) | 0.0314 (5) | |
H17_2 | 1.2105 | 0.7422 | 0.8104 | 0.038* | |
OG1_2 | 1.14100 (12) | 0.65212 (11) | 0.88943 (14) | 0.0339 (4) | |
CG2_2 | 1.2513 (2) | 0.7845 (2) | 0.9638 (2) | 0.0434 (6) | |
H18_2 | 1.3152 | 0.7465 | 0.9805 | 0.065* | |
H19_2 | 1.2190 | 0.7822 | 1.0214 | 0.065* | |
H20_2 | 1.2683 | 0.8501 | 0.9515 | 0.065* | |
C_2 | 1.04274 (17) | 0.81964 (15) | 0.71983 (18) | 0.0289 (4) | |
O_2 | 1.10290 (14) | 0.86211 (14) | 0.67997 (15) | 0.0417 (4) | |
N_3 | 0.95016 (14) | 0.78722 (14) | 0.66781 (14) | 0.0288 (4) | |
H21_3 | 0.9110 | 0.7588 | 0.7022 | 0.035* | |
CA_3 | 0.91030 (17) | 0.79633 (16) | 0.55678 (18) | 0.0299 (5) | |
H22_3 | 0.9686 | 0.8166 | 0.5274 | 0.036* | |
CB_3 | 0.82088 (18) | 0.86828 (18) | 0.52486 (19) | 0.0347 (5) | |
H23_3 | 0.7581 | 0.8416 | 0.5427 | 0.042* | |
CG1_3 | 0.8491 (2) | 0.96176 (19) | 0.5822 (2) | 0.0457 (6) | |
H24_3 | 0.8658 | 0.9504 | 0.6566 | 0.069* | |
H25_3 | 0.7899 | 1.0053 | 0.5621 | 0.069* | |
H26_3 | 0.9098 | 0.9895 | 0.5646 | 0.069* | |
CG2_3 | 0.7948 (2) | 0.8818 (2) | 0.4091 (2) | 0.0495 (7) | |
H27_3 | 0.7769 | 0.8207 | 0.3748 | 0.074* | |
H28_3 | 0.8554 | 0.9085 | 0.3902 | 0.074* | |
H29_3 | 0.7355 | 0.9251 | 0.3874 | 0.074* | |
C3_4 | 0.87402 (17) | 0.70005 (17) | 0.51550 (16) | 0.0277 (4) | |
N_4 | 0.79327 (14) | 0.65901 (14) | 0.53238 (14) | 0.0282 (4) | |
CA_4 | 0.77966 (18) | 0.57019 (16) | 0.49032 (16) | 0.0285 (4) | |
CB_4 | 0.85145 (19) | 0.54298 (19) | 0.44090 (19) | 0.0356 (5) | |
H30_4 | 0.8526 | 0.4837 | 0.4080 | 0.043* | |
SG_4 | 0.93975 (5) | 0.63203 (5) | 0.44692 (5) | 0.03871 (15) | |
C_4 | 0.69220 (18) | 0.51101 (17) | 0.50475 (17) | 0.0291 (4) | |
O_4 | 0.66503 (13) | 0.43751 (12) | 0.45794 (13) | 0.0352 (4) | |
N_5 | 0.64664 (14) | 0.54521 (14) | 0.57581 (15) | 0.0288 (4) | |
H31_5 | 0.6718 | 0.5965 | 0.6105 | 0.035* | |
CA_5 | 0.55692 (17) | 0.49857 (15) | 0.59574 (17) | 0.0274 (4) | |
H32_5 | 0.5123 | 0.4746 | 0.5286 | 0.033* | |
CB_5 | 0.58932 (18) | 0.41282 (16) | 0.66903 (18) | 0.0320 (5) | |
H33_5 | 0.6485 | 0.3809 | 0.6495 | 0.038* | |
CG1_5 | 0.5008 (2) | 0.34017 (18) | 0.6546 (2) | 0.0424 (6) | |
H34_5 | 0.5193 | 0.2941 | 0.7119 | 0.051* | |
H35_5 | 0.4367 | 0.3733 | 0.6596 | 0.051* | |
CG2_5 | 0.6292 (2) | 0.4428 (2) | 0.7809 (2) | 0.0432 (6) | |
H36_5 | 0.6858 | 0.4887 | 0.7874 | 0.065* | |
H37_5 | 0.6553 | 0.3874 | 0.8235 | 0.065* | |
H38_5 | 0.5722 | 0.4718 | 0.8039 | 0.065* | |
CD_5 | 0.4772 (3) | 0.2867 (2) | 0.5541 (3) | 0.0580 (8) | |
H39_5 | 0.4196 | 0.2426 | 0.5511 | 0.087* | |
H40_5 | 0.5393 | 0.2515 | 0.5494 | 0.087* | |
H41_5 | 0.4573 | 0.3314 | 0.4966 | 0.087* | |
C3_6 | 0.49518 (17) | 0.57090 (15) | 0.63623 (16) | 0.0254 (4) | |
N_6 | 0.53314 (14) | 0.64243 (13) | 0.68874 (14) | 0.0278 (4) | |
CA_6 | 0.44570 (17) | 0.69207 (15) | 0.71452 (16) | 0.0270 (4) | |
H42_6 | 0.4387 | 0.7574 | 0.6851 | 0.032* | |
CB_6 | 0.34881 (16) | 0.63329 (17) | 0.66352 (17) | 0.0297 (4) | |
H43_6 | 0.3171 | 0.6072 | 0.7174 | 0.036* | |
OG1_6 | 0.39207 (12) | 0.55590 (12) | 0.61431 (14) | 0.0334 (4) | |
CG2_6 | 0.2676 (2) | 0.68453 (19) | 0.5832 (2) | 0.0416 (6) | |
H44_6 | 0.2088 | 0.6421 | 0.5549 | 0.062* | |
H45_6 | 0.2978 | 0.7055 | 0.5279 | 0.062* | |
H46_6 | 0.2432 | 0.7396 | 0.6144 | 0.062* | |
C_6 | 0.46537 (17) | 0.69625 (16) | 0.83230 (17) | 0.0278 (4) | |
O_6 | 0.41764 (15) | 0.64814 (13) | 0.87847 (13) | 0.0419 (4) | |
N_7 | 0.54012 (14) | 0.75738 (15) | 0.87774 (14) | 0.0300 (4) | |
H47_7 | 0.5688 | 0.7932 | 0.8392 | 0.036* | |
CA_7 | 0.57512 (18) | 0.76621 (18) | 0.98862 (17) | 0.0314 (5) | |
H48_7 | 0.5135 | 0.7578 | 1.0174 | 0.038* | |
CB_7 | 0.6195 (2) | 0.86551 (18) | 1.01650 (18) | 0.0353 (5) | |
H49_7 | 0.6760 | 0.8756 | 0.9810 | 0.042* | |
CG1_7 | 0.6679 (2) | 0.8769 (2) | 1.1317 (2) | 0.0468 (6) | |
H50_7 | 0.6957 | 0.9410 | 1.1460 | 0.070* | |
H51_7 | 0.7245 | 0.8310 | 1.1546 | 0.070* | |
H52_7 | 0.6145 | 0.8659 | 1.1688 | 0.070* | |
CG2_7 | 0.5366 (3) | 0.9404 (2) | 0.9778 (2) | 0.0539 (8) | |
H53_7 | 0.5064 | 0.9324 | 0.9036 | 0.081* | |
H54_7 | 0.5683 | 1.0033 | 0.9911 | 0.081* | |
H55_7 | 0.4817 | 0.9340 | 1.0137 | 0.081* | |
C3_8 | 0.65293 (18) | 0.68950 (17) | 1.03147 (17) | 0.0307 (5) | |
N_8 | 0.72820 (14) | 0.66647 (14) | 0.99234 (14) | 0.0274 (4) | |
CA_8 | 0.78841 (18) | 0.59688 (16) | 1.04885 (17) | 0.0301 (4) | |
CB_8 | 0.7591 (2) | 0.56596 (18) | 1.1327 (2) | 0.0387 (5) | |
H56_8 | 0.7936 | 0.5184 | 1.1791 | 0.046* | |
SG_8 | 0.65077 (5) | 0.62613 (5) | 1.14128 (5) | 0.04115 (15) | |
C_8 | 0.88180 (18) | 0.55963 (15) | 1.01979 (18) | 0.0288 (4) | |
O_8 | 0.94435 (15) | 0.50875 (12) | 1.07897 (15) | 0.0393 (4) | |
O1_9 | 0.75291 (15) | 0.68878 (15) | 0.75797 (13) | 0.0367 (4) | |
H1_9 | 0.754 (2) | 0.748 (3) | 0.767 (2) | 0.034 (8)* | |
H2_9 | 0.684 (4) | 0.683 (3) | 0.740 (3) | 0.073 (12)* | |
O2_10 | 1.32160 (18) | 0.89334 (16) | 0.74102 (17) | 0.0504 (5) | |
H1_10 | 1.248 (2) | 0.880 (2) | 0.718 (2) | 0.030 (7)* | |
H2_10 | 1.326 (2) | 0.910 (2) | 0.676 (2) | 0.030 (7)* | |
O1_11 | 0.66817 (16) | 0.86930 (14) | 0.75907 (16) | 0.0466 (4) | |
C1_11 | 0.7052 (2) | 0.9453 (2) | 0.7962 (2) | 0.0429 (6) | |
N1_11 | 0.6504 (2) | 1.02515 (18) | 0.7720 (2) | 0.0501 (6) | |
C2_11 | 0.8118 (3) | 0.9481 (3) | 0.8705 (3) | 0.0661 (10) | |
H1_11 | 0.8294 | 1.0134 | 0.8924 | 0.099* | |
H2_11 | 0.8633 | 0.9235 | 0.8367 | 0.099* | |
H3_11 | 0.8120 | 0.9091 | 0.9308 | 0.099* | |
C3_11 | 0.5478 (2) | 1.0228 (3) | 0.7000 (3) | 0.0536 (7) | |
H4_11 | 0.5185 | 1.0868 | 0.6912 | 0.080* | |
H5_11 | 0.5020 | 0.9812 | 0.7267 | 0.080* | |
H6_11 | 0.5536 | 0.9989 | 0.6333 | 0.080* | |
C4_11 | 0.6817 (4) | 1.1166 (3) | 0.8187 (5) | 0.0939 (15) | |
H7_11 | 0.6283 | 1.1637 | 0.7885 | 0.141* | |
H8_11 | 0.7483 | 1.1352 | 0.8060 | 0.141* | |
H9_11 | 0.6896 | 1.1127 | 0.8931 | 0.141* |
U11 | U22 | U33 | U12 | U13 | U23 | |
N_1 | 0.0276 (9) | 0.0246 (8) | 0.0299 (9) | −0.0004 (7) | 0.0049 (7) | 0.0027 (7) |
CA_1 | 0.0285 (10) | 0.0238 (10) | 0.0307 (10) | 0.0024 (8) | 0.0050 (8) | 0.0028 (8) |
CB_1 | 0.0345 (12) | 0.0284 (11) | 0.0318 (11) | −0.0008 (9) | 0.0091 (9) | 0.0018 (9) |
CG_1 | 0.0320 (11) | 0.0245 (10) | 0.0301 (10) | 0.0028 (8) | 0.0067 (8) | 0.0003 (8) |
CD1_1 | 0.0449 (14) | 0.0371 (12) | 0.0281 (11) | 0.0051 (11) | 0.0010 (10) | 0.0012 (9) |
CE1_1 | 0.0533 (16) | 0.0367 (14) | 0.0426 (14) | 0.0017 (11) | 0.0033 (12) | −0.0094 (11) |
CZ_1 | 0.088 (2) | 0.0313 (13) | 0.0411 (15) | 0.0129 (14) | 0.0165 (15) | −0.0056 (11) |
CE2_1 | 0.096 (2) | 0.0292 (13) | 0.0360 (13) | 0.0151 (14) | 0.0179 (14) | 0.0020 (11) |
CD2_1 | 0.0528 (15) | 0.0321 (12) | 0.0287 (11) | 0.0112 (11) | 0.0053 (10) | 0.0011 (9) |
C3_2 | 0.0307 (10) | 0.0283 (10) | 0.0233 (9) | −0.0006 (8) | 0.0056 (8) | −0.0009 (8) |
N_2 | 0.0302 (9) | 0.0268 (9) | 0.0279 (9) | −0.0007 (7) | 0.0094 (7) | −0.0009 (7) |
CA_2 | 0.0281 (11) | 0.0251 (10) | 0.0346 (11) | −0.0023 (8) | 0.0078 (9) | −0.0013 (8) |
CB_2 | 0.0268 (10) | 0.0318 (11) | 0.0342 (11) | −0.0021 (9) | 0.0058 (9) | 0.0044 (9) |
OG1_2 | 0.0298 (8) | 0.0270 (8) | 0.0439 (9) | 0.0002 (6) | 0.0081 (7) | 0.0055 (7) |
CG2_2 | 0.0346 (13) | 0.0499 (15) | 0.0404 (13) | −0.0094 (11) | 0.0004 (10) | 0.0041 (11) |
C_2 | 0.0279 (10) | 0.0211 (10) | 0.0377 (11) | 0.0014 (8) | 0.0086 (9) | 0.0069 (8) |
O_2 | 0.0336 (9) | 0.0452 (10) | 0.0459 (10) | −0.0060 (8) | 0.0098 (7) | 0.0190 (8) |
N_3 | 0.0265 (9) | 0.0312 (9) | 0.0294 (9) | 0.0011 (7) | 0.0086 (7) | 0.0071 (7) |
CA_3 | 0.0273 (10) | 0.0318 (11) | 0.0315 (11) | 0.0024 (8) | 0.0094 (9) | 0.0087 (9) |
CB_3 | 0.0292 (11) | 0.0336 (12) | 0.0409 (13) | 0.0044 (9) | 0.0087 (9) | 0.0081 (10) |
CG1_3 | 0.0453 (15) | 0.0319 (13) | 0.0568 (17) | 0.0025 (11) | 0.0076 (12) | 0.0075 (12) |
CG2_3 | 0.0473 (15) | 0.0548 (17) | 0.0443 (15) | 0.0196 (13) | 0.0081 (12) | 0.0142 (13) |
C3_4 | 0.0252 (10) | 0.0349 (11) | 0.0245 (10) | 0.0077 (8) | 0.0090 (8) | 0.0072 (8) |
N_4 | 0.0270 (9) | 0.0327 (10) | 0.0267 (9) | 0.0057 (7) | 0.0099 (7) | 0.0054 (7) |
CA_4 | 0.0277 (10) | 0.0327 (11) | 0.0247 (10) | 0.0073 (8) | 0.0061 (8) | 0.0035 (8) |
CB_4 | 0.0379 (12) | 0.0360 (12) | 0.0365 (12) | 0.0003 (10) | 0.0162 (10) | −0.0017 (10) |
SG_4 | 0.0353 (3) | 0.0431 (3) | 0.0451 (3) | 0.0016 (3) | 0.0237 (2) | −0.0022 (3) |
C_4 | 0.0292 (10) | 0.0331 (11) | 0.0256 (10) | 0.0079 (9) | 0.0082 (8) | 0.0044 (8) |
O_4 | 0.0374 (9) | 0.0338 (9) | 0.0360 (8) | 0.0001 (7) | 0.0127 (7) | −0.0054 (7) |
N_5 | 0.0318 (9) | 0.0265 (9) | 0.0303 (9) | 0.0001 (7) | 0.0120 (7) | −0.0009 (7) |
CA_5 | 0.0296 (11) | 0.0265 (10) | 0.0268 (10) | 0.0005 (8) | 0.0087 (8) | 0.0003 (8) |
CB_5 | 0.0306 (11) | 0.0281 (11) | 0.0393 (12) | 0.0056 (9) | 0.0126 (9) | 0.0078 (9) |
CG1_5 | 0.0420 (14) | 0.0315 (12) | 0.0597 (16) | 0.0036 (10) | 0.0242 (12) | 0.0105 (11) |
CG2_5 | 0.0442 (14) | 0.0466 (14) | 0.0372 (13) | 0.0073 (12) | 0.0080 (11) | 0.0124 (11) |
CD_5 | 0.0582 (18) | 0.0361 (14) | 0.082 (2) | −0.0075 (13) | 0.0220 (16) | −0.0040 (14) |
C3_6 | 0.0262 (10) | 0.0249 (10) | 0.0238 (9) | 0.0001 (7) | 0.0043 (8) | 0.0045 (8) |
N_6 | 0.0263 (8) | 0.0306 (9) | 0.0270 (8) | −0.0013 (7) | 0.0080 (7) | −0.0028 (7) |
CA_6 | 0.0260 (10) | 0.0263 (10) | 0.0273 (10) | 0.0020 (8) | 0.0046 (8) | −0.0010 (8) |
CB_6 | 0.0252 (10) | 0.0316 (11) | 0.0307 (10) | 0.0043 (9) | 0.0047 (8) | −0.0059 (9) |
OG1_6 | 0.0236 (7) | 0.0278 (8) | 0.0464 (9) | 0.0001 (6) | 0.0051 (7) | −0.0097 (7) |
CG2_6 | 0.0313 (12) | 0.0400 (13) | 0.0447 (14) | 0.0071 (10) | −0.0056 (10) | −0.0101 (11) |
C_6 | 0.0261 (10) | 0.0295 (10) | 0.0279 (10) | 0.0044 (8) | 0.0074 (8) | −0.0004 (8) |
O_6 | 0.0494 (10) | 0.0437 (11) | 0.0327 (8) | −0.0125 (8) | 0.0109 (7) | 0.0006 (7) |
N_7 | 0.0276 (9) | 0.0397 (10) | 0.0235 (9) | −0.0042 (8) | 0.0078 (7) | −0.0035 (7) |
CA_7 | 0.0282 (10) | 0.0444 (13) | 0.0231 (10) | −0.0009 (9) | 0.0092 (8) | −0.0052 (9) |
CB_7 | 0.0397 (12) | 0.0398 (13) | 0.0264 (11) | 0.0010 (10) | 0.0087 (9) | −0.0085 (9) |
CG1_7 | 0.0545 (16) | 0.0519 (16) | 0.0303 (12) | 0.0003 (13) | 0.0048 (11) | −0.0129 (11) |
CG2_7 | 0.0625 (19) | 0.0518 (17) | 0.0427 (15) | 0.0180 (15) | 0.0058 (13) | −0.0139 (13) |
C3_8 | 0.0327 (11) | 0.0367 (12) | 0.0233 (10) | −0.0091 (9) | 0.0087 (8) | −0.0025 (9) |
N_8 | 0.0274 (9) | 0.0301 (9) | 0.0249 (8) | −0.0032 (7) | 0.0071 (7) | −0.0010 (7) |
CA_8 | 0.0348 (11) | 0.0268 (10) | 0.0287 (10) | −0.0060 (9) | 0.0084 (9) | 0.0011 (8) |
CB_8 | 0.0463 (14) | 0.0350 (13) | 0.0358 (12) | −0.0053 (10) | 0.0125 (11) | 0.0069 (10) |
SG_8 | 0.0463 (3) | 0.0479 (3) | 0.0347 (3) | −0.0051 (3) | 0.0203 (2) | 0.0056 (3) |
C_8 | 0.0340 (11) | 0.0195 (9) | 0.0327 (11) | −0.0028 (8) | 0.0083 (9) | 0.0028 (8) |
O_8 | 0.0449 (10) | 0.0305 (8) | 0.0434 (10) | 0.0047 (7) | 0.0130 (8) | 0.0146 (7) |
O1_9 | 0.0326 (10) | 0.0447 (11) | 0.0320 (8) | 0.0051 (7) | 0.0071 (7) | −0.0017 (7) |
O2_10 | 0.0497 (12) | 0.0569 (13) | 0.0441 (11) | 0.0023 (10) | 0.0113 (9) | −0.0003 (10) |
O1_11 | 0.0448 (10) | 0.0379 (10) | 0.0559 (12) | −0.0040 (8) | 0.0112 (9) | 0.0020 (9) |
C1_11 | 0.0395 (14) | 0.0531 (16) | 0.0378 (13) | −0.0101 (12) | 0.0132 (11) | 0.0008 (12) |
N1_11 | 0.0467 (13) | 0.0450 (13) | 0.0583 (15) | −0.0099 (11) | 0.0132 (11) | −0.0170 (11) |
C2_11 | 0.0407 (16) | 0.101 (3) | 0.0539 (18) | −0.0200 (18) | 0.0068 (14) | −0.0003 (19) |
C3_11 | 0.0490 (16) | 0.0567 (18) | 0.0520 (17) | 0.0061 (14) | 0.0075 (13) | −0.0037 (14) |
C4_11 | 0.087 (3) | 0.061 (2) | 0.130 (4) | −0.022 (2) | 0.022 (3) | −0.046 (3) |
N_1—C_8 | 1.341 (3) | CA_5—H32_5 | 1.0000 |
N_1—CA_1 | 1.433 (3) | CB_5—CG2_5 | 1.518 (4) |
N_1—H1_1 | 0.8800 | CB_5—CG1_5 | 1.535 (3) |
CA_1—C3_2 | 1.504 (3) | CB_5—H33_5 | 1.0000 |
CA_1—CB_1 | 1.543 (3) | CG1_5—CD_5 | 1.508 (5) |
CA_1—H2_1 | 1.0000 | CG1_5—H34_5 | 0.9900 |
CB_1—CG_1 | 1.520 (3) | CG1_5—H35_5 | 0.9900 |
CB_1—H3_1 | 0.9900 | CG2_5—H36_5 | 0.9800 |
CB_1—H4_1 | 0.9900 | CG2_5—H37_5 | 0.9800 |
CG_1—CD1_1 | 1.524 (3) | CG2_5—H38_5 | 0.9800 |
CG_1—CD2_1 | 1.531 (3) | CD_5—H39_5 | 0.9800 |
CG_1—H5_1 | 1.0000 | CD_5—H40_5 | 0.9800 |
CD1_1—CE1_1 | 1.518 (4) | CD_5—H41_5 | 0.9800 |
CD1_1—H6_1 | 0.9900 | C3_6—N_6 | 1.261 (3) |
CD1_1—H7_1 | 0.9900 | C3_6—OG1_6 | 1.340 (3) |
CE1_1—CZ_1 | 1.522 (4) | N_6—CA_6 | 1.475 (3) |
CE1_1—H8_1 | 0.9900 | CA_6—CB_6 | 1.534 (3) |
CE1_1—H9_1 | 0.9900 | CA_6—C_6 | 1.538 (3) |
CZ_1—CE2_1 | 1.520 (4) | CA_6—H42_6 | 1.0000 |
CZ_1—H10_1 | 0.9900 | CB_6—OG1_6 | 1.473 (3) |
CZ_1—H11_1 | 0.9900 | CB_6—CG2_6 | 1.497 (3) |
CE2_1—CD2_1 | 1.513 (4) | CB_6—H43_6 | 1.0000 |
CE2_1—H12_1 | 0.9900 | CG2_6—H44_6 | 0.9800 |
CE2_1—H13_1 | 0.9900 | CG2_6—H45_6 | 0.9800 |
CD2_1—H14_1 | 0.9900 | CG2_6—H46_6 | 0.9800 |
CD2_1—H15_1 | 0.9900 | C_6—O_6 | 1.208 (3) |
C3_2—N_2 | 1.258 (3) | C_6—N_7 | 1.337 (3) |
C3_2—OG1_2 | 1.337 (3) | N_7—CA_7 | 1.446 (3) |
N_2—CA_2 | 1.479 (3) | N_7—H47_7 | 0.8800 |
CA_2—C_2 | 1.510 (3) | CA_7—C3_8 | 1.505 (3) |
CA_2—CB_2 | 1.544 (3) | CA_7—CB_7 | 1.532 (4) |
CA_2—H16_2 | 1.0000 | CA_7—H48_7 | 1.0000 |
CB_2—OG1_2 | 1.455 (3) | CB_7—CG2_7 | 1.519 (4) |
CB_2—CG2_2 | 1.508 (3) | CB_7—CG1_7 | 1.522 (3) |
CB_2—H17_2 | 1.0000 | CB_7—H49_7 | 1.0000 |
CG2_2—H18_2 | 0.9800 | CG1_7—H50_7 | 0.9800 |
CG2_2—H19_2 | 0.9800 | CG1_7—H51_7 | 0.9800 |
CG2_2—H20_2 | 0.9800 | CG1_7—H52_7 | 0.9800 |
C_2—O_2 | 1.230 (3) | CG2_7—H53_7 | 0.9800 |
C_2—N_3 | 1.327 (3) | CG2_7—H54_7 | 0.9800 |
N_3—CA_3 | 1.453 (3) | CG2_7—H55_7 | 0.9800 |
N_3—H21_3 | 0.8800 | C3_8—N_8 | 1.288 (3) |
CA_3—C3_4 | 1.502 (3) | C3_8—SG_8 | 1.735 (2) |
CA_3—CB_3 | 1.537 (3) | N_8—CA_8 | 1.367 (3) |
CA_3—H22_3 | 1.0000 | CA_8—CB_8 | 1.358 (3) |
CB_3—CG2_3 | 1.516 (4) | CA_8—C_8 | 1.492 (3) |
CB_3—CG1_3 | 1.528 (4) | CB_8—SG_8 | 1.702 (3) |
CB_3—H23_3 | 1.0000 | CB_8—H56_8 | 0.9500 |
CG1_3—H24_3 | 0.9800 | C_8—O_8 | 1.223 (3) |
CG1_3—H25_3 | 0.9800 | O1_9—H1_9 | 0.84 (4) |
CG1_3—H26_3 | 0.9800 | O1_9—H2_9 | 0.88 (5) |
CG2_3—H27_3 | 0.9800 | O2_10—H1_10 | 0.96 (3) |
CG2_3—H28_3 | 0.9800 | O2_10—H2_10 | 0.93 (3) |
CG2_3—H29_3 | 0.9800 | O1_11—C1_11 | 1.232 (4) |
C3_4—N_4 | 1.291 (3) | C1_11—N1_11 | 1.337 (4) |
C3_4—SG_4 | 1.722 (2) | C1_11—C2_11 | 1.504 (4) |
N_4—CA_4 | 1.371 (3) | N1_11—C3_11 | 1.451 (4) |
CA_4—CB_4 | 1.354 (3) | N1_11—C4_11 | 1.451 (4) |
CA_4—C_4 | 1.486 (3) | C2_11—H1_11 | 0.9800 |
CB_4—SG_4 | 1.709 (3) | C2_11—H2_11 | 0.9800 |
CB_4—H30_4 | 0.9500 | C2_11—H3_11 | 0.9800 |
C_4—O_4 | 1.220 (3) | C3_11—H4_11 | 0.9800 |
C_4—N_5 | 1.349 (3) | C3_11—H5_11 | 0.9800 |
N_5—CA_5 | 1.448 (3) | C3_11—H6_11 | 0.9800 |
N_5—H31_5 | 0.8800 | C4_11—H7_11 | 0.9800 |
CA_5—C3_6 | 1.501 (3) | C4_11—H8_11 | 0.9800 |
CA_5—CB_5 | 1.551 (3) | C4_11—H9_11 | 0.9800 |
C_8—N_1—CA_1 | 120.66 (18) | N_5—CA_5—CB_5 | 111.72 (18) |
C_8—N_1—H1_1 | 119.7 | C3_6—CA_5—CB_5 | 112.94 (18) |
CA_1—N_1—H1_1 | 119.7 | N_5—CA_5—H32_5 | 108.0 |
N_1—CA_1—C3_2 | 110.60 (18) | C3_6—CA_5—H32_5 | 108.0 |
N_1—CA_1—CB_1 | 112.90 (18) | CB_5—CA_5—H32_5 | 108.0 |
C3_2—CA_1—CB_1 | 106.96 (18) | CG2_5—CB_5—CG1_5 | 111.6 (2) |
N_1—CA_1—H2_1 | 108.8 | CG2_5—CB_5—CA_5 | 112.1 (2) |
C3_2—CA_1—H2_1 | 108.8 | CG1_5—CB_5—CA_5 | 111.62 (19) |
CB_1—CA_1—H2_1 | 108.8 | CG2_5—CB_5—H33_5 | 107.0 |
CG_1—CB_1—CA_1 | 115.94 (19) | CG1_5—CB_5—H33_5 | 107.0 |
CG_1—CB_1—H3_1 | 108.3 | CA_5—CB_5—H33_5 | 107.0 |
CA_1—CB_1—H3_1 | 108.3 | CD_5—CG1_5—CB_5 | 114.9 (2) |
CG_1—CB_1—H4_1 | 108.3 | CD_5—CG1_5—H34_5 | 108.5 |
CA_1—CB_1—H4_1 | 108.3 | CB_5—CG1_5—H34_5 | 108.5 |
H3_1—CB_1—H4_1 | 107.4 | CD_5—CG1_5—H35_5 | 108.5 |
CB_1—CG_1—CD1_1 | 108.91 (19) | CB_5—CG1_5—H35_5 | 108.5 |
CB_1—CG_1—CD2_1 | 112.7 (2) | H34_5—CG1_5—H35_5 | 107.5 |
CD1_1—CG_1—CD2_1 | 110.10 (19) | CB_5—CG2_5—H36_5 | 109.5 |
CB_1—CG_1—H5_1 | 108.3 | CB_5—CG2_5—H37_5 | 109.5 |
CD1_1—CG_1—H5_1 | 108.3 | H36_5—CG2_5—H37_5 | 109.5 |
CD2_1—CG_1—H5_1 | 108.3 | CB_5—CG2_5—H38_5 | 109.5 |
CE1_1—CD1_1—CG_1 | 112.9 (2) | H36_5—CG2_5—H38_5 | 109.5 |
CE1_1—CD1_1—H6_1 | 109.0 | H37_5—CG2_5—H38_5 | 109.5 |
CG_1—CD1_1—H6_1 | 109.0 | CG1_5—CD_5—H39_5 | 109.5 |
CE1_1—CD1_1—H7_1 | 109.0 | CG1_5—CD_5—H40_5 | 109.5 |
CG_1—CD1_1—H7_1 | 109.0 | H39_5—CD_5—H40_5 | 109.5 |
H6_1—CD1_1—H7_1 | 107.8 | CG1_5—CD_5—H41_5 | 109.5 |
CD1_1—CE1_1—CZ_1 | 111.1 (2) | H39_5—CD_5—H41_5 | 109.5 |
CD1_1—CE1_1—H8_1 | 109.4 | H40_5—CD_5—H41_5 | 109.5 |
CZ_1—CE1_1—H8_1 | 109.4 | N_6—C3_6—OG1_6 | 119.0 (2) |
CD1_1—CE1_1—H9_1 | 109.4 | N_6—C3_6—CA_5 | 125.07 (19) |
CZ_1—CE1_1—H9_1 | 109.4 | OG1_6—C3_6—CA_5 | 115.89 (18) |
H8_1—CE1_1—H9_1 | 108.0 | C3_6—N_6—CA_6 | 106.89 (18) |
CE2_1—CZ_1—CE1_1 | 110.0 (2) | N_6—CA_6—CB_6 | 104.86 (17) |
CE2_1—CZ_1—H10_1 | 109.7 | N_6—CA_6—C_6 | 109.26 (17) |
CE1_1—CZ_1—H10_1 | 109.7 | CB_6—CA_6—C_6 | 112.13 (18) |
CE2_1—CZ_1—H11_1 | 109.7 | N_6—CA_6—H42_6 | 110.2 |
CE1_1—CZ_1—H11_1 | 109.7 | CB_6—CA_6—H42_6 | 110.2 |
H10_1—CZ_1—H11_1 | 108.2 | C_6—CA_6—H42_6 | 110.2 |
CD2_1—CE2_1—CZ_1 | 112.2 (2) | OG1_6—CB_6—CG2_6 | 109.15 (18) |
CD2_1—CE2_1—H12_1 | 109.2 | OG1_6—CB_6—CA_6 | 102.92 (16) |
CZ_1—CE2_1—H12_1 | 109.2 | CG2_6—CB_6—CA_6 | 114.8 (2) |
CD2_1—CE2_1—H13_1 | 109.2 | OG1_6—CB_6—H43_6 | 109.9 |
CZ_1—CE2_1—H13_1 | 109.2 | CG2_6—CB_6—H43_6 | 109.9 |
H12_1—CE2_1—H13_1 | 107.9 | CA_6—CB_6—H43_6 | 109.9 |
CE2_1—CD2_1—CG_1 | 112.0 (2) | C3_6—OG1_6—CB_6 | 106.28 (17) |
CE2_1—CD2_1—H14_1 | 109.2 | CB_6—CG2_6—H44_6 | 109.5 |
CG_1—CD2_1—H14_1 | 109.2 | CB_6—CG2_6—H45_6 | 109.5 |
CE2_1—CD2_1—H15_1 | 109.2 | H44_6—CG2_6—H45_6 | 109.5 |
CG_1—CD2_1—H15_1 | 109.2 | CB_6—CG2_6—H46_6 | 109.5 |
H14_1—CD2_1—H15_1 | 107.9 | H44_6—CG2_6—H46_6 | 109.5 |
N_2—C3_2—OG1_2 | 119.8 (2) | H45_6—CG2_6—H46_6 | 109.5 |
N_2—C3_2—CA_1 | 125.0 (2) | O_6—C_6—N_7 | 123.8 (2) |
OG1_2—C3_2—CA_1 | 114.80 (19) | O_6—C_6—CA_6 | 122.6 (2) |
C3_2—N_2—CA_2 | 105.48 (19) | N_7—C_6—CA_6 | 113.60 (19) |
N_2—CA_2—C_2 | 110.51 (18) | C_6—N_7—CA_7 | 121.7 (2) |
N_2—CA_2—CB_2 | 104.47 (17) | C_6—N_7—H47_7 | 119.1 |
C_2—CA_2—CB_2 | 111.43 (19) | CA_7—N_7—H47_7 | 119.1 |
N_2—CA_2—H16_2 | 110.1 | N_7—CA_7—C3_8 | 109.55 (19) |
C_2—CA_2—H16_2 | 110.1 | N_7—CA_7—CB_7 | 109.3 (2) |
CB_2—CA_2—H16_2 | 110.1 | C3_8—CA_7—CB_7 | 112.74 (19) |
OG1_2—CB_2—CG2_2 | 109.9 (2) | N_7—CA_7—H48_7 | 108.4 |
OG1_2—CB_2—CA_2 | 102.35 (17) | C3_8—CA_7—H48_7 | 108.4 |
CG2_2—CB_2—CA_2 | 113.6 (2) | CB_7—CA_7—H48_7 | 108.4 |
OG1_2—CB_2—H17_2 | 110.2 | CG2_7—CB_7—CG1_7 | 110.4 (2) |
CG2_2—CB_2—H17_2 | 110.2 | CG2_7—CB_7—CA_7 | 111.0 (2) |
CA_2—CB_2—H17_2 | 110.2 | CG1_7—CB_7—CA_7 | 112.2 (2) |
C3_2—OG1_2—CB_2 | 106.25 (17) | CG2_7—CB_7—H49_7 | 107.6 |
CB_2—CG2_2—H18_2 | 109.5 | CG1_7—CB_7—H49_7 | 107.6 |
CB_2—CG2_2—H19_2 | 109.5 | CA_7—CB_7—H49_7 | 107.6 |
H18_2—CG2_2—H19_2 | 109.5 | CB_7—CG1_7—H50_7 | 109.5 |
CB_2—CG2_2—H20_2 | 109.5 | CB_7—CG1_7—H51_7 | 109.5 |
H18_2—CG2_2—H20_2 | 109.5 | H50_7—CG1_7—H51_7 | 109.5 |
H19_2—CG2_2—H20_2 | 109.5 | CB_7—CG1_7—H52_7 | 109.5 |
O_2—C_2—N_3 | 123.9 (2) | H50_7—CG1_7—H52_7 | 109.5 |
O_2—C_2—CA_2 | 120.1 (2) | H51_7—CG1_7—H52_7 | 109.5 |
N_3—C_2—CA_2 | 116.01 (19) | CB_7—CG2_7—H53_7 | 109.5 |
C_2—N_3—CA_3 | 123.23 (19) | CB_7—CG2_7—H54_7 | 109.5 |
C_2—N_3—H21_3 | 118.4 | H53_7—CG2_7—H54_7 | 109.5 |
CA_3—N_3—H21_3 | 118.4 | CB_7—CG2_7—H55_7 | 109.5 |
N_3—CA_3—C3_4 | 107.10 (17) | H53_7—CG2_7—H55_7 | 109.5 |
N_3—CA_3—CB_3 | 113.06 (19) | H54_7—CG2_7—H55_7 | 109.5 |
C3_4—CA_3—CB_3 | 110.39 (18) | N_8—C3_8—CA_7 | 123.7 (2) |
N_3—CA_3—H22_3 | 108.7 | N_8—C3_8—SG_8 | 113.93 (18) |
C3_4—CA_3—H22_3 | 108.7 | CA_7—C3_8—SG_8 | 122.38 (17) |
CB_3—CA_3—H22_3 | 108.7 | C3_8—N_8—CA_8 | 111.01 (19) |
CG2_3—CB_3—CG1_3 | 111.6 (2) | CB_8—CA_8—N_8 | 116.1 (2) |
CG2_3—CB_3—CA_3 | 108.7 (2) | CB_8—CA_8—C_8 | 122.9 (2) |
CG1_3—CB_3—CA_3 | 111.3 (2) | N_8—CA_8—C_8 | 120.96 (19) |
CG2_3—CB_3—H23_3 | 108.4 | CA_8—CB_8—SG_8 | 109.10 (19) |
CG1_3—CB_3—H23_3 | 108.4 | CA_8—CB_8—H56_8 | 125.5 |
CA_3—CB_3—H23_3 | 108.4 | SG_8—CB_8—H56_8 | 125.5 |
CB_3—CG1_3—H24_3 | 109.5 | CB_8—SG_8—C3_8 | 89.84 (12) |
CB_3—CG1_3—H25_3 | 109.5 | O_8—C_8—N_1 | 124.3 (2) |
H24_3—CG1_3—H25_3 | 109.5 | O_8—C_8—CA_8 | 120.5 (2) |
CB_3—CG1_3—H26_3 | 109.5 | N_1—C_8—CA_8 | 115.21 (19) |
H24_3—CG1_3—H26_3 | 109.5 | H1_9—O1_9—H2_9 | 96 (4) |
H25_3—CG1_3—H26_3 | 109.5 | H1_10—O2_10—H2_10 | 93 (2) |
CB_3—CG2_3—H27_3 | 109.5 | O1_11—C1_11—N1_11 | 120.4 (2) |
CB_3—CG2_3—H28_3 | 109.5 | O1_11—C1_11—C2_11 | 119.8 (3) |
H27_3—CG2_3—H28_3 | 109.5 | N1_11—C1_11—C2_11 | 119.8 (3) |
CB_3—CG2_3—H29_3 | 109.5 | C1_11—N1_11—C3_11 | 119.9 (3) |
H27_3—CG2_3—H29_3 | 109.5 | C1_11—N1_11—C4_11 | 125.0 (3) |
H28_3—CG2_3—H29_3 | 109.5 | C3_11—N1_11—C4_11 | 114.9 (3) |
N_4—C3_4—CA_3 | 122.9 (2) | C1_11—C2_11—H1_11 | 109.5 |
N_4—C3_4—SG_4 | 113.86 (18) | C1_11—C2_11—H2_11 | 109.5 |
CA_3—C3_4—SG_4 | 123.14 (17) | H1_11—C2_11—H2_11 | 109.5 |
C3_4—N_4—CA_4 | 111.44 (19) | C1_11—C2_11—H3_11 | 109.5 |
CB_4—CA_4—N_4 | 115.5 (2) | H1_11—C2_11—H3_11 | 109.5 |
CB_4—CA_4—C_4 | 125.4 (2) | H2_11—C2_11—H3_11 | 109.5 |
N_4—CA_4—C_4 | 119.07 (19) | N1_11—C3_11—H4_11 | 109.5 |
CA_4—CB_4—SG_4 | 109.3 (2) | N1_11—C3_11—H5_11 | 109.5 |
CA_4—CB_4—H30_4 | 125.4 | H4_11—C3_11—H5_11 | 109.5 |
SG_4—CB_4—H30_4 | 125.4 | N1_11—C3_11—H6_11 | 109.5 |
CB_4—SG_4—C3_4 | 89.96 (12) | H4_11—C3_11—H6_11 | 109.5 |
O_4—C_4—N_5 | 123.0 (2) | H5_11—C3_11—H6_11 | 109.5 |
O_4—C_4—CA_4 | 123.3 (2) | N1_11—C4_11—H7_11 | 109.5 |
N_5—C_4—CA_4 | 113.7 (2) | N1_11—C4_11—H8_11 | 109.5 |
C_4—N_5—CA_5 | 120.83 (19) | H7_11—C4_11—H8_11 | 109.5 |
C_4—N_5—H31_5 | 119.6 | N1_11—C4_11—H9_11 | 109.5 |
CA_5—N_5—H31_5 | 119.6 | H7_11—C4_11—H9_11 | 109.5 |
N_5—CA_5—C3_6 | 108.14 (18) | H8_11—C4_11—H9_11 | 109.5 |
D—H···A | D—H | H···A | D···A | D—H···A |
N_1—H1_1···O1_9 | 0.88 | 2.06 | 2.904 (2) | 162 |
O1_9—H1_9···O1_11 | 0.85 (4) | 2.05 (4) | 2.793 (3) | 147 (4) |
O1_9—H2_9···N_6 | 0.89 (5) | 2.02 (5) | 2.896 (3) | 168 (5) |
O2_10—H1_10···O_2 | 0.96 (3) | 1.88 (3) | 2.838 (3) | 175 (3) |
CB_4—H30_4···O_2i | 0.95 | 2.25 | 3.175 (3) | 163 |
CA_2—H16_2···O_8ii | 1.00 | 2.22 | 3.191 (3) | 164 |
O2_10—H2_10···O_4iii | 0.92 (3) | 1.89 (3) | 2.799 (3) | 177 (2) |
Symmetry codes: (i) −x+2, y−1/2, −z+1; (ii) −x+2, y+1/2, −z+2; (iii) −x+2, y+1/2, −z+1. |
Experimental details
Crystal data | |
Chemical formula | C39H56N8O6S2·C4H9NO·2H2O |
Mr | 920.19 |
Crystal system, space group | Monoclinic, P21 |
Temperature (K) | 90 |
a, b, c (Å) | 13.283 (2), 14.153 (2), 13.452 (2) |
β (°) | 105.252 (2) |
V (Å3) | 2439.8 (7) |
Z | 2 |
Radiation type | Mo Kα |
µ (mm−1) | 0.17 |
Crystal size (mm) | 0.40 × 0.25 × 0.20 |
Data collection | |
Diffractometer | Bruker AXS SMART APEX CCD diffractometer |
Absorption correction | Empirical (using intensity measurements) (SADABS; Sheldrick, 1996) |
Tmin, Tmax | 0.797, 0.967 |
No. of measured, independent and observed [I > 2σ(I)] reflections | 22268, 11112, 9973 |
Rint | 0.023 |
(sin θ/λ)max (Å−1) | 0.667 |
Refinement | |
R[F2 > 2σ(F2)], wR(F2), S | 0.051, 0.137, 1.04 |
No. of reflections | 11112 |
No. of parameters | 584 |
No. of restraints | 1 |
H-atom treatment | H atoms treated by a mixture of independent and constrained refinement |
Δρmax, Δρmin (e Å−3) | 0.85, −0.35 |
Absolute structure | (Flack, 1983), 5087 Friedel pairs |
Absolute structure parameter | −0.06 (6) |
Computer programs: SMART (Bruker, 1998), SMART, SAINT-Plus (Bruker, 1998), SHELXD (Sheldrick & Gould, 1996), SHELXL97 (Sheldrick, 1997), PLATON (Spek, 2001), PARST (Nardelli, 1983).
D—H···A | D—H | H···A | D···A | D—H···A |
N_1—H1_1···O1_9 | 0.879 | 2.056 | 2.904 (2) | 161.6 |
O1_9—H1_9···O1_11 | 0.85 (4) | 2.05 (4) | 2.793 (3) | 147 (4) |
O1_9—H2_9···N_6 | 0.89 (5) | 2.02 (5) | 2.896 (3) | 168 (5) |
O2_10—H1_10···O_2 | 0.96 (3) | 1.88 (3) | 2.838 (3) | 175 (3) |
CB_4—H30_4···O_2i | 0.951 | 2.254 | 3.175 (3) | 163.1 |
CA_2—H16_2···O_8ii | 1.000 | 2.218 | 3.191 (3) | 163.8 |
O2_10—H2_10···O_4iii | 0.92 (3) | 1.89 (3) | 2.799 (3) | 177 (2) |
Symmetry codes: (i) −x+2, y−1/2, −z+1; (ii) −x+2, y+1/2, −z+2; (iii) −x+2, y+1/2, −z+1. |
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Ascidiacyclamide (ASC), cyclo(–L-Ile-L-Oxz-D-Val-Thz-)2, is a cytotoxic cyclic peptide isolated from tunicate that contains the unusual amino acids oxazoline (Oxz) and thiazole (Thz) (Hamamoto et al., 1983). X-Ray diffraction analyses have revealed ASC and its analogues to have either square or folded structures (Ishida et al., 1987, 1988, 1992; Schmitz et al., 1989; In et al., 1993). In this regard, our findings suggest that substitution of an amino acid that disturbs the C2-symmetry can affect the structure of the resultant ASC analogue, viz. the folding of the peptide is seen to be related to the bulkiness of the incorporated amino acid (Asano, Doi et al., 2001; Doi et al., 2001; Asano, Yamada et al., 2002). On the other hand, incorporation of an amino acid of appropriate size results in a square structure and associated strong cytotoxicity (Asano, Minoura et al., 2002). One exception is the phenylalanine-incorporated analogue ([Phe]ASC), cyclo(–Phe-Oxz-D-Val-Thz-Ile-Oxz-D-Val-Thz-), in which cytotoxicity is conserved in the folded configuration (Doi et al., 1999). This is notable, as [Phe]ASC contains one the bulkiest of amino acids, and it is the only analogue containing an aromatic amino acid. Therefore, to better understand the determinants of the structure and cytotoxicity of ASC analogues, we incorporated a cyclohexylalanine, which has an aliphatic six-membered ring, into ASC.
The CD spectra of [Phe]ASC and [Cha]ASC, which were measured by titration using two solvents, acetonitril (MeCN) and 2,2,2-trifluoroethanol (TFE), were found to be similar (Fig. 1). Addition of TFE provides a special environment, different from that provided by MeCN (Fioroni et al., 2000). Nevertheless, addition of TFE elicited no drastic change in the spectrum. It is known that in the square form, ASC analogues show small negative cottons at about 250 nm (Asano, Minoura et al., 2002). Since positive cottons in the range of 200–300 nm can be a sign of folding, these CD spectra imply that both [Phe]ASC and [Cha]ASC are in a folded state in solution. Indeed, the crystal structure of [Phe]ASC is known to be folded (Doi et al., 1999).
The crystal structure of [Cha]ASC is shown in Fig. 2. There are two water molecules (W9 and W10) and one N,N-dimethylacetamide molecule (DMA11) in the asymmetric unit. Contrast to the suggestion of the CD spectra, the peptide ring shows a square form similar to previously described structures (Ishida et al., 1987), and the peptide and solvent molecules interact via hydrogen bonds (Table 1). The water molecule W9 (O1_9) is hydrogen bonded to N_1 (Cha1) and N_6 (Oxz6), as well as to O1_11 (DMA11). It was finally located at a deep position within the opened peptide ring, which is reminiscent of the anchored water molecule observed in the ethanol- and water-solvated ASC crystal (In et al., 1994). The other water molecule, viz. W10 (O2_10), bridges two adjacent peptide molecules (O_2 and O_4), which also interact through C—H···O hydrogen bonds (CB_4···O_2 and CA_2···O_8). This type of interaction was also observed in the dimeric ASC (Asano, Taniguchi et al., 2001), but this is the first observation in an ASC analogue.
The ED50 for the toxicity of [Cha]ASC in P388 lymphocytic leukemia cells was 5.6 µg ml−1. This is the strongest toxicity yet reported for an ASC analogue (Doi et al., 1999; Asano, Minoura et al., 2002), and is approximately two times stronger than natural ASC (ED50 = 10.5 µg ml−1) or [Phe]ASC (ED50 = 11.8 µg ml−1). That the square structure of [Cha]ASC is the most cytotoxic strongly supports the association between the square form and cytotoxicity.
We did not determine the cause of the discrepancy between the structures of [Cha]ASC in solid and solution states, though a similar discrepancy was previously seen with the Leu-incorporated analogue ([Leu]ASC), cyclo(–Leu-Oxz-D-Val-Thz-Ile-Oxz-D-Val-Thz-) (Asano, Minoura et al., 2002). The number of C atoms in Cha is the same as in Phe, making the aromaticity of the latter the only difference between [Cha]ASC and [Phe]ASC. It therefore appears likely that it is this aromaticity that accounts for the cytotoxicity of the folded structure of [Phe]ASC.