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_1564799
_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 H33 Cl O5'
_chemical_formula_sum            'C23 H33 Cl O5'
_chemical_formula_weight         424.94
_space_group_crystal_system      trigonal
_space_group_IT_number           154
_space_group_name_Hall           'P 32 2"'
_space_group_name_H-M_alt        'P 32 2 1'
_atom_sites_solution_hydrogens   mixed
_atom_sites_solution_primary     dual
_audit_creation_date             2019-06-13
_audit_creation_method
;
Olex2 1.2
(compiled 2018.05.29 svn.r3508 for OlexSys, GUI svn.r5506)
;
_cell_angle_alpha                90
_cell_angle_beta                 90
_cell_angle_gamma                120
_cell_formula_units_Z            6
_cell_length_a                   11.45880(10)
_cell_length_b                   11.45880(10)
_cell_length_c                   28.4455(2)
_cell_measurement_reflns_used    9392
_cell_measurement_temperature    108(3)
_cell_measurement_theta_max      73.7110
_cell_measurement_theta_min      4.6690
_cell_volume                     3234.61(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      108(3)
_diffrn_detector                 'Pilatus3R 200K-A'
_diffrn_measured_fraction_theta_full 1.000
_diffrn_measured_fraction_theta_max 0.979
_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    -32.00  28.00   0.30    0.32    --    0.00 -82.00  90.00  200
  2  \w    -22.00   4.10   0.30    0.32    --    0.00 -82.00-180.00   87
  3  \w    -31.00   5.00   0.30    0.32    --    0.00 -82.00 -60.00  120
  4  \w     11.00 102.20   0.30    1.28    --   95.20 -77.00 150.00  304
  5  \w    100.00 172.90   0.30    1.28    --   95.20  82.00-120.00  243
  6  \w     17.00  50.00   0.30    1.28    --   95.20 -30.00-120.00  110
  7  \w    123.00 171.00   0.30    1.28    --   95.20  82.00  30.00  160
  8  \w     82.00 178.00   0.30    1.28    --   95.20  30.00   0.00  320
;
_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      -0.1209573000
_diffrn_orient_matrix_UB_12      -0.1422542000
_diffrn_orient_matrix_UB_13      0.0081235000
_diffrn_orient_matrix_UB_21      -0.0497170000
_diffrn_orient_matrix_UB_22      0.0548584000
_diffrn_orient_matrix_UB_23      0.0400195000
_diffrn_orient_matrix_UB_31      -0.0835951000
_diffrn_orient_matrix_UB_32      0.0291329000
_diffrn_orient_matrix_UB_33      -0.0355949000
_diffrn_radiation_monochromator  graphite
_diffrn_radiation_probe          x-ray
_diffrn_radiation_type           CuK\a
_diffrn_radiation_wavelength     1.54184
_diffrn_reflns_av_R_equivalents  0.0271
_diffrn_reflns_av_unetI/netI     0.0265
_diffrn_reflns_Laue_measured_fraction_full 1.000
_diffrn_reflns_Laue_measured_fraction_max 0.979
_diffrn_reflns_limit_h_max       11
_diffrn_reflns_limit_h_min       -12
_diffrn_reflns_limit_k_max       14
_diffrn_reflns_limit_k_min       -10
_diffrn_reflns_limit_l_max       34
_diffrn_reflns_limit_l_min       -34
_diffrn_reflns_number            11377
_diffrn_reflns_point_group_measured_fraction_full 1.000
_diffrn_reflns_point_group_measured_fraction_max 0.967
_diffrn_reflns_theta_full        67.684
_diffrn_reflns_theta_max         73.905
_diffrn_reflns_theta_min         4.456
_diffrn_source                   'Rotating-anode X-ray tube'
_diffrn_source_type              'MicroMax 007 (Cu) X-ray Source'
_exptl_absorpt_coefficient_mu    1.827
_exptl_absorpt_correction_T_max  1.00000
_exptl_absorpt_correction_T_min  0.75177
_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 brownish colourless'
_exptl_crystal_colour_lustre     clear
_exptl_crystal_colour_modifier   brownish
_exptl_crystal_colour_primary    colourless
_exptl_crystal_density_diffrn    1.309
_exptl_crystal_description       block
_exptl_crystal_F_000             1368
_exptl_crystal_size_max          0.15
_exptl_crystal_size_mid          0.1
_exptl_crystal_size_min          0.08
_refine_diff_density_max         0.270
_refine_diff_density_min         -0.272
_refine_diff_density_rms         0.047
_refine_ls_abs_structure_details
;
 Flack x determined using 1730 quotients [(I+)-(I-)]/[(I+)+(I-)]
 (Parsons, Flack and Wagner, Acta Cryst. B69 (2013) 249-259).
;
_refine_ls_abs_structure_Flack   0.009(5)
_refine_ls_extinction_method     none
_refine_ls_goodness_of_fit_ref   1.052
_refine_ls_hydrogen_treatment    mixed
_refine_ls_matrix_type           full
_refine_ls_number_parameters     277
_refine_ls_number_reflns         4254
_refine_ls_number_restraints     0
_refine_ls_restrained_S_all      1.052
_refine_ls_R_factor_all          0.0302
_refine_ls_R_factor_gt           0.0299
_refine_ls_shift/su_max          0.001
_refine_ls_shift/su_mean         0.000
_refine_ls_structure_factor_coef Fsqd
_refine_ls_weighting_details
'w=1/[\s^2^(Fo^2^)+(0.0493P)^2^+0.6200P] where P=(Fo^2^+2Fc^2^)/3'
_refine_ls_weighting_scheme      calc
_refine_ls_wR_factor_gt          0.0793
_refine_ls_wR_factor_ref         0.0798
_reflns_Friedel_coverage         0.715
_reflns_Friedel_fraction_full    0.999
_reflns_Friedel_fraction_max     0.951
_reflns_number_gt                4194
_reflns_number_total             4254
_reflns_threshold_expression     'I > 2\s(I)'
_cod_data_source_file            jm1c01402_si_007.cif
_cod_data_source_block           luoxiaowei_as77_collect
_cod_original_cell_volume        3234.61(6)
_cod_database_code               1564799
_shelx_shelxl_version_number     2014/7
_chemical_oxdiff_formula         'C138 H198 Cl6 O30 '
_shelx_estimated_absorpt_t_max   0.868
_shelx_estimated_absorpt_t_min   0.771
_reflns_odcompleteness_completeness 99.91
_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:
 C10(H10), C14(H14), C18(H18)
2.b Secondary CH2 refined with riding coordinates:
 C9(H9A,H9B), C17(H17A,H17B), C16(H16A,H16B), C13(H13A,H13B), C12(H12A,H12B)
2.c Aromatic/amide H refined with riding coordinates:
 C8(H8)
2.d Idealised Me refined as rotating group:
 C21(H21A,H21B,H21C), C20(H20A,H20B,H20C), C22(H22A,H22B,H22C), C23(H23A,H23B,
 H23C), C7(H7A,H7B,H7C)
2.e Idealised tetrahedral OH refined as rotating group:
 O3(H3), O2(H2)
;
_shelx_res_checksum              20541
_shelx_hkl_checksum              70071
_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 1.436
_oxdiff_exptl_absorpt_empirical_full_min 0.731