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_1564798
_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 H31 Cl O4'
_chemical_formula_sum            'C23 H31 Cl O4'
_chemical_formula_weight         406.92
_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   mixed
_atom_sites_solution_primary     dual
_audit_creation_date             2019-05-13
_audit_creation_method
;
Olex2 1.2
(compiled 2018.05.29 svn.r3508 for OlexSys, GUI svn.r5506)
;
_cell_angle_alpha                90
_cell_angle_beta                 98.870(2)
_cell_angle_gamma                90
_cell_formula_units_Z            4
_cell_length_a                   6.79590(10)
_cell_length_b                   36.5395(5)
_cell_length_c                   8.75130(10)
_cell_measurement_reflns_used    11243
_cell_measurement_temperature    102(4)
_cell_measurement_theta_max      73.6620
_cell_measurement_theta_min      4.8300
_cell_volume                     2147.12(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      102(4)
_diffrn_detector                 'Pilatus3R 200K-A'
_diffrn_measured_fraction_theta_full 0.998
_diffrn_measured_fraction_theta_max 0.985
_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    -30.00  18.00   0.50    1.34    --    0.00 -82.00-150.00   96
  2  \w    -11.00  30.00   0.50    1.34    --    0.00 -82.00   0.00   82
  3  \w    -26.00   8.00   0.50    1.34    --    0.00 -82.00  60.00   68
  4  \w    -20.00  20.00   0.50    1.34    --    0.00 -82.00-180.00   80
  5  \w    -82.00 -14.00   0.50    1.34    --    0.00 -57.00 -30.00  136
  6  \w    -10.00  20.00   0.50    1.34    --    0.00 -82.00 -60.00   60
  7  \w     12.00  99.00   0.50    4.30    --   95.20 -30.00-120.00  174
  8  \w     16.00  67.00   0.50    4.30    --   95.20 -61.00   0.00  102
  9  \w      6.00  62.00   0.50    4.30    --   95.20 -82.00   0.00  112
 10  \w      8.00 118.00   0.50    4.30    --   95.20 -15.00  60.00  220
 11  \w      7.00 126.00   0.50    4.30    --   95.20 -82.00  60.00  238
 12  \w     49.00 120.00   0.50    4.30    --   95.20 -82.00-180.00  142
 13  \w      6.00  59.00   0.50    4.30    --   95.20 -15.00 -90.00  106
 14  \w     90.00 118.00   0.50    4.30    --   95.20 -15.00 -90.00   56
 15  \w     33.00 114.00   0.50    4.30    --   95.20 -45.00 150.00  162
 16  \w      8.00 114.00   0.50    4.30    --   95.20 -61.00  60.00  212
 17  \w     88.00 126.00   0.50    4.30    --   95.20 -82.00-120.00   76
 18  \w     24.00  54.00   0.50    4.30    --   95.20 -82.00-120.00   60
 19  \w     23.00  48.00   0.50    4.30    --   95.20 -82.00 -60.00   50
 20  \w     98.00 123.00   0.50    4.30    --   95.20 -82.00 -60.00   50
 21  \w     58.00 125.00   0.50    4.30    --   95.20 -82.00-150.00  134
 22  \w     67.00 100.00   0.50    4.30    --   95.20 -82.00   0.00   66
 23  \w     71.00  96.00   0.50    4.30    --   95.20 -82.00 120.00   50
 24  \w     25.00 115.00   0.50    4.30    --   95.20 -15.00 150.00  180
;
_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      0.0374652000
_diffrn_orient_matrix_UB_12      0.0412661000
_diffrn_orient_matrix_UB_13      0.0266052000
_diffrn_orient_matrix_UB_21      0.1408054000
_diffrn_orient_matrix_UB_22      -0.0084186000
_diffrn_orient_matrix_UB_23      0.1512897000
_diffrn_orient_matrix_UB_31      0.1771274000
_diffrn_orient_matrix_UB_32      -0.0019683000
_diffrn_orient_matrix_UB_33      -0.0903665000
_diffrn_radiation_monochromator  graphite
_diffrn_radiation_probe          x-ray
_diffrn_radiation_type           CuK\a
_diffrn_radiation_wavelength     1.54184
_diffrn_reflns_av_R_equivalents  0.0474
_diffrn_reflns_av_unetI/netI     0.0529
_diffrn_reflns_Laue_measured_fraction_full 0.998
_diffrn_reflns_Laue_measured_fraction_max 0.985
_diffrn_reflns_limit_h_max       8
_diffrn_reflns_limit_h_min       -5
_diffrn_reflns_limit_k_max       44
_diffrn_reflns_limit_k_min       -45
_diffrn_reflns_limit_l_max       9
_diffrn_reflns_limit_l_min       -10
_diffrn_reflns_number            22034
_diffrn_reflns_point_group_measured_fraction_full 0.989
_diffrn_reflns_point_group_measured_fraction_max 0.959
_diffrn_reflns_theta_full        67.684
_diffrn_reflns_theta_max         74.114
_diffrn_reflns_theta_min         4.841
_diffrn_source                   'Rotating-anode X-ray tube'
_diffrn_source_type              'MicroMax 007 (Cu) X-ray Source'
_exptl_absorpt_coefficient_mu    1.778
_exptl_absorpt_correction_T_max  1.00000
_exptl_absorpt_correction_T_min  0.75818
_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    1.259
_exptl_crystal_description       block
_exptl_crystal_F_000             872
_exptl_crystal_size_max          0.1
_exptl_crystal_size_mid          0.07
_exptl_crystal_size_min          0.05
_refine_diff_density_max         0.688
_refine_diff_density_min         -0.316
_refine_diff_density_rms         0.052
_refine_ls_abs_structure_details
;
 Flack x determined using 3126 quotients [(I+)-(I-)]/[(I+)+(I-)]
 (Parsons, Flack and Wagner, Acta Cryst. B69 (2013) 249-259).
;
_refine_ls_abs_structure_Flack   0.020(8)
_refine_ls_extinction_method     none
_refine_ls_goodness_of_fit_ref   1.056
_refine_ls_hydrogen_treatment    mixed
_refine_ls_matrix_type           full
_refine_ls_number_parameters     535
_refine_ls_number_reflns         8374
_refine_ls_number_restraints     1
_refine_ls_restrained_S_all      1.056
_refine_ls_R_factor_all          0.0540
_refine_ls_R_factor_gt           0.0479
_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^)+(0.0761P)^2^+0.4028P] where P=(Fo^2^+2Fc^2^)/3'
_refine_ls_weighting_scheme      calc
_refine_ls_wR_factor_gt          0.1279
_refine_ls_wR_factor_ref         0.1310
_reflns_Friedel_coverage         0.916
_reflns_Friedel_fraction_full    0.979
_reflns_Friedel_fraction_max     0.932
_reflns_number_gt                7474
_reflns_number_total             8374
_reflns_threshold_expression     'I > 2\s(I)'
_cod_data_source_file            jm1c01402_si_004.cif
_cod_data_source_block           luoxiaowei_as64_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 H62 Cl2 O8'
_cod_original_formula_weight         813.85
_cod_original_formula_moiety         '2(C23 H31 Cl O4)'
_cod_original_formula_units_Z            2
_cod_database_code               1564798
_shelx_shelxl_version_number     2014/7
_chemical_oxdiff_formula         'C88 H122 Cl4 N4 O16 '
_shelx_estimated_absorpt_t_max   0.916
_shelx_estimated_absorpt_t_min   0.842
_reflns_odcompleteness_completeness 99.77
_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:
 C14(H14), C18(H18), C14'(H14'), C18'(H18')
2.b Secondary CH2 refined with riding coordinates:
 C9'(H9'A,H9'B), C13(H13A,H13B), C9(H9A,H9B), C12(H12A,H12B), C13'(H13C,H13D),
 C12'(H12C,H12D), C17'(H17C,H17D), C17(H17A,H17B), C16(H16A,H16B), C16'(H16C,
 H16D)
2.c Aromatic/amide H refined with riding coordinates:
 C8'(H8'), C8(H8), C10'(H10'), C10(H10)
2.d Idealised Me refined as rotating group:
 C7'(H7'A,H7'B,H7'C), C22(H22A,H22B,H22C), C7(H7A,H7B,H7C), C20(H20A,H20B,
 H20C), C20'(H20D,H20E,H20F), C23(H23A,H23B,H23C), C23'(H23D,H23E,H23F),
 C22'(H22D,H22E,H22F)
2.e Idealised tetrahedral OH refined as rotating group:
 O2(H2), O3'(H3'), O2'(H2'), O3(H3), O4(H4), O4'(H4')
;
_shelx_res_checksum              23269
_shelx_hkl_checksum              91410
_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 1.869
_oxdiff_exptl_absorpt_empirical_full_min 0.503