Exploring Marine-Derived Ascochlorins as Novel Human Dihydroorotate Dehydrogenase Inhibitors for Treatment of Triple-Negative Breast Cancer.
Luo, Xiaowei; Cai, Guodi; Guo, Yinfeng; Gao, Chenghai; Huang, Weifeng; Zhang, Zhenhua; Lu, Humu; Liu, Kai; Chen, Jianghe; Xiong, Xiaofeng; Lei, Jinping; Zhou, Xuefeng; Wang, Junjian; Liu, Yonghong; Journal of medicinal chemistry 64 (2021) 13918–13932; doi:10.1021/acs.jmedchem.1c01402

data_1564802
_publ_section_title
;
 Exploring Marine-Derived Ascochlorins as Novel Human Dihydroorotate
 Dehydrogenase Inhibitors for Treatment of Triple-Negative Breast Cancer.
;
_journal_issue                   18
_journal_name_full               'Journal of medicinal chemistry'
_journal_page_first              13918
_journal_page_last               13932
_journal_paper_doi               10.1021/acs.jmedchem.1c01402
_journal_volume                  64
_journal_year                    2021
_chemical_absolute_configuration ad
_chemical_formula_moiety         'C23 H29 Cl O5'
_chemical_formula_sum            'C23 H29 Cl O5'
_chemical_formula_weight         420.91
_space_group_crystal_system      triclinic
_space_group_IT_number           1
_space_group_name_Hall           'P 1'
_space_group_name_H-M_alt        'P 1'
_atom_sites_solution_hydrogens   geom
_atom_sites_solution_primary     dual
_audit_creation_date             2018-11-28
_audit_creation_method
;
Olex2 1.2
(compiled 2018.05.29 svn.r3508 for OlexSys, GUI svn.r5506)
;
_cell_angle_alpha                90.884(2)
_cell_angle_beta                 100.853(2)
_cell_angle_gamma                93.813(3)
_cell_formula_units_Z            2
_cell_length_a                   6.1316(2)
_cell_length_b                   11.2090(3)
_cell_length_c                   16.0507(3)
_cell_measurement_reflns_used    9364
_cell_measurement_temperature    99.9(8)
_cell_measurement_theta_max      73.4980
_cell_measurement_theta_min      4.7680
_cell_volume                     1080.58(5)
_computing_cell_refinement       'CrysAlisPro 1.171.39.33c (Rigaku OD, 2017)'
_computing_data_collection       'CrysAlisPro 1.171.39.33c (Rigaku OD, 2017)'
_computing_data_reduction        'CrysAlisPro 1.171.39.33c (Rigaku OD, 2017)'
_computing_molecular_graphics    'Olex2 (Dolomanov et al., 2009)'
_computing_publication_material  'Olex2 (Dolomanov et al., 2009)'
_computing_structure_refinement  'ShelXL (Sheldrick, 2015)'
_computing_structure_solution    'ShelXT (Sheldrick, 2015)'
_diffrn_ambient_environment      N~2~
_diffrn_ambient_temperature      99.9(8)
_diffrn_detector                 'Pilatus3R 200K-A'
_diffrn_measured_fraction_theta_full 0.993
_diffrn_measured_fraction_theta_max 0.970
_diffrn_measurement_details
;
List of Runs (angles in degrees, time in seconds):

  # Type    Start    End  Width  t~exp~   \w     \q     \k     \f   Frames
--------------------------------------------------------------------------
  1  \w    -22.00  86.00   0.50    1.80    --    0.00  57.00 -90.00  216
  2  \w     64.00  91.00   0.50    1.80    --   40.00  69.00  91.81   54
  3  \w     14.00  57.00   0.50    1.80    --   40.00  69.00  91.81   86
  4  \w     17.00  49.00   0.50    1.80    --   44.00  72.00 -59.60   64
  5  \w    -34.00  68.00   0.50    6.00    --   48.00 -52.00 112.97  204
  6  \w     32.00  83.00   0.50    6.00    --   56.00  75.00 -35.03  102
  7  \w     31.00  56.00   0.50    6.00    --   56.00  70.00 132.27   50
  8  \w     75.00 117.00   0.50    6.00    --   56.00  73.00  22.13   84
  9  \w     29.00  55.00   0.50    6.00    --   56.00  73.00  22.13   52
 10  \w     32.00  59.00   0.50    6.00    --   56.00  75.00 142.88   54
 11  \w     86.00 115.00   0.50    6.00    --   56.00  75.00 -35.03   58
 12  \w     33.00  58.00   0.50    6.00    --   60.00  74.00  69.46   50
 13  \w     39.00  70.00   0.50    6.00    --   64.00  75.00 -85.91   62
 14  \w     36.00  75.00   0.50    6.00    --   64.00  74.00 171.73   78
 15  \w    103.00 133.00   0.50    6.00    --   64.00  75.00-161.53   60
 16  \w     37.00  74.00   0.50    6.00    --   64.00  75.00-161.53   74
 17  \w     43.00  70.00   0.50    6.00    --   68.00  73.00  79.07   54
 18  \w     42.00  78.00   0.50    6.00    --   68.00  73.00 127.03   72
 19  \w     40.00  80.00   0.50    6.00    --   68.00  75.00-137.52   80
 20  \w     45.00  79.00   0.50    6.00    --   72.00  75.00  19.15   68
 21  \w     94.00 134.00   0.50    6.00    --   80.00  71.00 -61.22   80
 22  \w     54.00  95.00   0.50    6.00    --   80.00  74.00  95.52   82
 23  \w     54.00  83.00   0.50    6.00    --   80.00  71.00 -61.22   58
 24  \w    136.00 169.00   0.50    6.00    --   80.00  74.00  95.52   66
 25  \w    113.00 180.00   0.50    6.00    --   92.00  69.00 -37.62  134
 26  \w     66.00 106.00   0.50    6.00    --   92.00  69.00 -37.62   80
 27  \w     13.00  58.00   0.50    6.00    --   95.20 -82.00 150.00   90
 28  \w      6.00 126.00   0.50    6.00    --   95.20 -82.00   0.00  240
 29  \w     82.00 185.00   0.50    6.00    --   95.20  45.00  90.00  206
 30  \w     73.00 110.00   0.50    6.00    --   95.20  61.00-180.00   74
 31  \w     13.00 100.00   0.50    6.00    --   95.20 -82.00 -90.00  174
 32  \w    152.00 180.00   0.50    6.00    --   95.20  61.00 150.00   56
 33  \w     72.00 184.00   0.50    6.00    --   95.20  61.00-120.00  224
 34  \w     73.00 145.00   0.50    6.00    --   95.20  61.00 150.00  144
 35  \w     60.00 126.00   0.50    6.00    --   95.20 -82.00  90.00  132
 36  \w     29.00 126.00   0.50    6.00    --   95.20 -82.00 -60.00  194
 37  \w     76.00 122.00   0.50    6.00    --   95.20  61.00  30.00   92
 38  \w    129.00 154.00   0.50    6.00    --   95.20  61.00 120.00   50
 39  \w     75.00 104.00   0.50    6.00    --   95.20  61.00 120.00   58
 40  \w     66.00  92.00   0.50    6.00    --   95.20 -61.00  30.00   52
 41  \w    130.00 184.00   0.50    6.00    --   95.20  70.00   3.66  108
 42  \w     29.00  57.00   0.50    6.00    --   95.20 -61.00  30.00   56
 43  \w     72.00 100.00   0.50    6.00    --   95.20  70.00   3.66   56
 44  \w    129.00 183.00   0.50    6.00    --   95.20  73.00 148.72  108
 45  \w     77.00 183.00   0.50    6.00    --   95.20  60.00 -65.41  212
 46  \w    133.00 158.00   0.50    6.00    --   95.20  74.00-106.58   50
 47  \w     68.00 125.00   0.50    6.00    --   95.20  74.00-106.58  114
 48  \w     69.00  96.00   0.50    6.00    --   95.20  73.00 148.72   54
 49  \w    117.00 167.00   0.50    6.00    --   95.20  61.00  60.00  100
 50  \w     72.00 113.00   0.50    6.00    --   95.20  61.00  60.00   82
 51  \w     67.00 175.00   0.50    6.00    --   95.20  74.00 -18.79  216
 52  \w     72.00 178.00   0.50    6.00    --   95.20  61.00-150.00  212
 53  \w     91.00 118.00   0.50    6.00    --   95.20 -82.00 150.00   54
;
_diffrn_measurement_device       'four-circle diffractometer'
_diffrn_measurement_device_type  'XtaLAB Pro: Kappa single'
_diffrn_measurement_method       '\w scans'
_diffrn_orient_matrix_type
'CrysAlisPro convention (1999,Acta A55,543-557)'
_diffrn_orient_matrix_UB_11      -0.1154991000
_diffrn_orient_matrix_UB_12      0.1182931000
_diffrn_orient_matrix_UB_13      -0.0046259000
_diffrn_orient_matrix_UB_21      0.0476327000
_diffrn_orient_matrix_UB_22      0.0184577000
_diffrn_orient_matrix_UB_23      -0.0899670000
_diffrn_orient_matrix_UB_31      -0.2239761000
_diffrn_orient_matrix_UB_32      -0.0682280000
_diffrn_orient_matrix_UB_33      -0.0379902000
_diffrn_radiation_monochromator  graphite
_diffrn_radiation_probe          x-ray
_diffrn_radiation_type           CuK\a
_diffrn_radiation_wavelength     1.54184
_diffrn_reflns_av_R_equivalents  0.0574
_diffrn_reflns_av_unetI/netI     0.0631
_diffrn_reflns_Laue_measured_fraction_full 0.993
_diffrn_reflns_Laue_measured_fraction_max 0.970
_diffrn_reflns_limit_h_max       7
_diffrn_reflns_limit_h_min       -7
_diffrn_reflns_limit_k_max       13
_diffrn_reflns_limit_k_min       -13
_diffrn_reflns_limit_l_max       19
_diffrn_reflns_limit_l_min       -19
_diffrn_reflns_number            22591
_diffrn_reflns_point_group_measured_fraction_full 0.964
_diffrn_reflns_point_group_measured_fraction_max 0.919
_diffrn_reflns_theta_full        67.684
_diffrn_reflns_theta_max         74.306
_diffrn_reflns_theta_min         3.954
_diffrn_source                   'Rotating-anode X-ray tube'
_diffrn_source_type              'MicroMax 007 (Cu) X-ray Source'
_exptl_absorpt_coefficient_mu    1.822
_exptl_absorpt_correction_T_max  1.00000
_exptl_absorpt_correction_T_min  0.57227
_exptl_absorpt_correction_type   multi-scan
_exptl_absorpt_process_details
;
CrysAlisPro 1.171.39.33c (Rigaku Oxford Diffraction, 2017)
Empirical absorption correction using spherical harmonics,
 implemented in SCALE3 ABSPACK scaling algorithm.
;
_exptl_crystal_colour            'clear light colourless'
_exptl_crystal_colour_lustre     clear
_exptl_crystal_colour_modifier   light
_exptl_crystal_colour_primary    colourless
_exptl_crystal_density_diffrn    1.294
_exptl_crystal_description       needle
_exptl_crystal_F_000             448
_exptl_crystal_size_max          0.2
_exptl_crystal_size_mid          0.05
_exptl_crystal_size_min          0.05
_refine_diff_density_max         0.475
_refine_diff_density_min         -0.516
_refine_diff_density_rms         0.060
_refine_ls_abs_structure_details
;
 Flack x determined using 2710 quotients [(I+)-(I-)]/[(I+)+(I-)]
 (Parsons, Flack and Wagner, Acta Cryst. B69 (2013) 249-259).
;
_refine_ls_abs_structure_Flack   0.022(11)
_refine_ls_extinction_method     none
_refine_ls_goodness_of_fit_ref   1.051
_refine_ls_hydrogen_treatment    constr
_refine_ls_matrix_type           full
_refine_ls_number_parameters     537
_refine_ls_number_reflns         8105
_refine_ls_number_restraints     3
_refine_ls_restrained_S_all      1.051
_refine_ls_R_factor_all          0.0647
_refine_ls_R_factor_gt           0.0527
_refine_ls_shift/su_max          0.000
_refine_ls_shift/su_mean         0.000
_refine_ls_structure_factor_coef Fsqd
_refine_ls_weighting_details
'w=1/[\s^2^(Fo^2^)+(0.0915P)^2^] where P=(Fo^2^+2Fc^2^)/3'
_refine_ls_weighting_scheme      calc
_refine_ls_wR_factor_gt          0.1373
_refine_ls_wR_factor_ref         0.1462
_reflns_Friedel_coverage         0.895
_reflns_Friedel_fraction_full    0.935
_reflns_Friedel_fraction_max     0.868
_reflns_number_gt                6767
_reflns_number_total             8105
_reflns_threshold_expression     'I > 2\s(I)'
_cod_data_source_file            jm1c01402_si_010.cif
_cod_data_source_block           luoxiaowei_lxw_as41_collect2
_cod_database_code               1564802
_shelx_shelxl_version_number     2014/7
_shelx_estimated_absorpt_t_max   0.914
_shelx_estimated_absorpt_t_min   0.712
_reflns_odcompleteness_completeness 99.48
_reflns_odcompleteness_iscentric 1
_reflns_odcompleteness_theta     66.97
_olex2_refinement_description
;
1. Fixed Uiso
 At 1.2 times of:
  All C(H) groups, All C(H,H) groups
 At 1.5 times of:
  All C(H,H,H) groups, All O(H) groups
2.a Ternary CH refined with riding coordinates:
 C16'(H16'), C16(H16)
2.b Secondary CH2 refined with riding coordinates:
 C9'(H9'A,H9'B), C17'(H17C,H17D), C13'(H13C,H13D), C12(H12A,H12B), C12'(H12C,
 H12D), C17(H17A,H17B), C13(H13A,H13B), C9(H9A,H9B)
2.c Aromatic/amide H refined with riding coordinates:
 C10(H10), C14(H14), C8'(H8'), C10'(H10'), C8(H8), C14'(H14')
2.d Idealised Me refined as rotating group:
 C7(H7A,H7B,H7C), C23(H23A,H23B,H23C), C20(H20A,H20B,H20C), C20'(H20D,H20E,
 H20F), C23'(H23D,H23E,H23F), C7'(H7'A,H7'B,H7'C), C22(H22A,H22B,H22C),
 C21(H21A,H21B,H21C), C21'(H21D,H21E,H21F), C22'(H22D,H22E,H22F)
2.e Idealised tetrahedral OH refined as rotating group:
 O2(H2), O3(H3), O3'(H3'), O2'(H2')
;
_shelx_res_checksum              76895
_shelx_hkl_checksum              41140
_olex2_submission_special_instructions 'No special instructions were received'
_oxdiff_exptl_absorpt_empirical_details
;
Empirical correction (ABSPACK) includes:
- Absorption correction using spherical harmonics
- Frame scaling
;
_oxdiff_exptl_absorpt_empirical_full_max 2.021
_oxdiff_exptl_absorpt_empirical_full_min 0.436