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_1564797
_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 H32 O4'
_chemical_formula_sum            'C23 H32 O4'
_chemical_formula_weight         372.48
_space_group_crystal_system      monoclinic
_space_group_IT_number           4
_space_group_name_Hall           'P 2yb'
_space_group_name_H-M_alt        'P 1 21 1'
_atom_sites_solution_hydrogens   geom
_atom_sites_solution_primary     dual
_audit_creation_date             2018-11-07
_audit_creation_method
;
Olex2 1.2
(compiled 2018.05.29 svn.r3508 for OlexSys, GUI svn.r5506)
;
_cell_angle_alpha                90
_cell_angle_beta                 94.348(2)
_cell_angle_gamma                90
_cell_formula_units_Z            4
_cell_length_a                   7.6632(2)
_cell_length_b                   12.1003(3)
_cell_length_c                   21.8916(6)
_cell_measurement_reflns_used    7059
_cell_measurement_temperature    99.9(6)
_cell_measurement_theta_max      73.4470
_cell_measurement_theta_min      5.7670
_cell_volume                     2024.10(9)
_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(6)
_diffrn_detector                 'Pilatus3R 200K-A'
_diffrn_measured_fraction_theta_full 0.994
_diffrn_measured_fraction_theta_max 0.976
_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   5.00   0.50    2.00    --    0.00 -77.00 -30.00   54
  2  \w    -32.00  26.00   0.50    2.00    --    0.00 -82.00   0.00  116
  3  \w    -33.00  31.00   0.50    2.00    --    0.00 -82.00-120.00  128
  4  \w    -32.00  27.00   0.50    2.00    --    0.00 -82.00-180.00  118
  5  \w    -30.00  27.00   0.50    2.00    --    0.00 -82.00  60.00  114
  6  \w      7.00 113.00   0.50   10.00    --   95.20 -61.00  30.00  212
  7  \w     95.00 122.00   0.50   10.00    --   95.20 -82.00 -30.00   54
  8  \w      8.00 105.00   0.50   10.00    --   95.20 -15.00-120.00  194
  9  \w      6.00 119.00   0.50   10.00    --   95.20 -61.00 150.00  226
 10  \w    145.00 176.00   0.50   10.00    --   95.20  15.00 -30.00   62
 11  \w      6.00  40.00   0.50   10.00    --   95.20 -45.00-120.00   68
 12  \w     73.00 139.00   0.50   10.00    --   95.20  15.00 -30.00  132
 13  \w    108.00 184.00   0.50   10.00    --   95.20  15.00 150.00  152
 14  \w     11.00 110.00   0.50   10.00    --   95.20 -61.00 -90.00  198
 15  \w      7.00 125.00   0.50   10.00    --   95.20 -82.00 150.00  236
 16  \w      8.00 116.00   0.50   10.00    --   95.20 -82.00  30.00  216
 17  \w     70.00  95.00   0.50   10.00    --   95.20 -82.00-150.00   50
 18  \w     60.00 117.00   0.50   10.00    --   95.20 -82.00 -90.00  114
 19  \w     92.00 117.00   0.50   10.00    --   95.20  82.00-180.00   50
 20  \w     80.00 105.00   0.50   10.00    --   95.20 -82.00 -60.00   50
 21  \w     23.00 101.00   0.50   10.00    --   95.20 -15.00   0.00  156
;
_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      0.0012831000
_diffrn_orient_matrix_UB_12      0.0018702000
_diffrn_orient_matrix_UB_13      -0.0703172000
_diffrn_orient_matrix_UB_21      0.0128973000
_diffrn_orient_matrix_UB_22      0.1270574000
_diffrn_orient_matrix_UB_23      0.0014454000
_diffrn_orient_matrix_UB_31      0.2011978000
_diffrn_orient_matrix_UB_32      -0.0081942000
_diffrn_orient_matrix_UB_33      0.0057462000
_diffrn_radiation_monochromator  graphite
_diffrn_radiation_probe          x-ray
_diffrn_radiation_type           CuK\a
_diffrn_radiation_wavelength     1.54184
_diffrn_reflns_av_R_equivalents  0.0737
_diffrn_reflns_av_unetI/netI     0.0664
_diffrn_reflns_Laue_measured_fraction_full 0.994
_diffrn_reflns_Laue_measured_fraction_max 0.976
_diffrn_reflns_limit_h_max       9
_diffrn_reflns_limit_h_min       -5
_diffrn_reflns_limit_k_max       15
_diffrn_reflns_limit_k_min       -15
_diffrn_reflns_limit_l_max       26
_diffrn_reflns_limit_l_min       -27
_diffrn_reflns_number            19824
_diffrn_reflns_point_group_measured_fraction_full 0.986
_diffrn_reflns_point_group_measured_fraction_max 0.949
_diffrn_reflns_theta_full        67.684
_diffrn_reflns_theta_max         74.115
_diffrn_reflns_theta_min         5.458
_diffrn_source                   'Rotating-anode X-ray tube'
_diffrn_source_type              'MicroMax 007 (Cu) X-ray Source'
_exptl_absorpt_coefficient_mu    0.653
_exptl_absorpt_correction_T_max  1.00000
_exptl_absorpt_correction_T_min  0.55777
_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 whiteish colourless'
_exptl_crystal_colour_lustre     clear
_exptl_crystal_colour_modifier   whiteish
_exptl_crystal_colour_primary    colourless
_exptl_crystal_density_diffrn    1.222
_exptl_crystal_description       needle
_exptl_crystal_F_000             808
_exptl_crystal_size_max          0.4
_exptl_crystal_size_mid          0.05
_exptl_crystal_size_min          0.03
_refine_diff_density_max         0.276
_refine_diff_density_min         -0.255
_refine_diff_density_rms         0.060
_refine_ls_abs_structure_details
;
 Flack x determined using 2432 quotients [(I+)-(I-)]/[(I+)+(I-)]
 (Parsons, Flack and Wagner, Acta Cryst. B69 (2013) 249-259).
;
_refine_ls_abs_structure_Flack   0.04(15)
_refine_ls_extinction_method     none
_refine_ls_goodness_of_fit_ref   1.080
_refine_ls_hydrogen_treatment    constr
_refine_ls_matrix_type           full
_refine_ls_number_parameters     501
_refine_ls_number_reflns         7821
_refine_ls_number_restraints     1
_refine_ls_restrained_S_all      1.080
_refine_ls_R_factor_all          0.0714
_refine_ls_R_factor_gt           0.0583
_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^)+(0.0985P)^2^+0.3280P] where P=(Fo^2^+2Fc^2^)/3'
_refine_ls_weighting_scheme      calc
_refine_ls_wR_factor_gt          0.1575
_refine_ls_wR_factor_ref         0.1739
_reflns_Friedel_coverage         0.852
_reflns_Friedel_fraction_full    0.977
_reflns_Friedel_fraction_max     0.920
_reflns_number_gt                6330
_reflns_number_total             7821
_reflns_threshold_expression     'I > 2\s(I)'
_cod_data_source_file            jm1c01402_si_008.cif
_cod_data_source_block           luoxiaowei_as5_collect
_cod_depositor_comments
;

2022-05-30
Z value and formula fixed to values more according to usual
chemical conventions.                 miguel
;
_cod_original_formula_sum            'C46 H64 O8'
_cod_original_formula_weight         744.97
_cod_original_formula_moiety         '2(C23 H32 O4)'
_cod_original_formula_units_Z            2
_cod_database_code               1564797
_shelx_shelxl_version_number     2014/7
_chemical_oxdiff_formula         'C90 H124 O18 '
_shelx_estimated_absorpt_t_max   0.981
_shelx_estimated_absorpt_t_min   0.780
_reflns_odcompleteness_completeness 99.50
_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:
 C15(H15), C15'(H15'), C19(H19), C19'(H19')
2.b Secondary CH2 refined with riding coordinates:
 C16(H16C,H16D), C16'(H16A,H16B), C12(H12C,H12D), C13'(H13A,H13B), C13(H13C,
 H13D), C9(H9A,H9B), C17(H17C,H17D), C12'(H12A,H12B), C17'(H17A,H17B), C9'(H9'A,
 H9'B)
2.c Aromatic/amide H refined with riding coordinates:
 C8'(H8'), C10(H10), C5(H5), C5'(H5'), C10'(H10'), C8(H8)
2.d Idealised Me refined as rotating group:
 C20'(H20A,H20B,H20C), C7'(H7'A,H7'B,H7'C), C7(H7A,H7B,H7C), C22(H22D,H22E,
 H22F), C23(H23D,H23E,H23F), C21'(H21A,H21B,H21C), C20(H20D,H20E,H20F),
 C22'(H22A,H22B,H22C), C21(H21D,H21E,H21F), C23'(H23A,H23B,H23C)
2.e Idealised tetrahedral OH refined as rotating group:
 O3(H3), O2'(H2'), O3'(H3'), O2(H2)
;
_shelx_res_checksum              15688
_shelx_hkl_checksum              97933
_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 2.027
_oxdiff_exptl_absorpt_empirical_full_min 0.370