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_1564801
_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      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     iterative
_audit_creation_date             2019-07-26
_audit_creation_method
;
Olex2 1.2
(compiled 2018.05.29 svn.r3508 for OlexSys, GUI svn.r5506)
;
_cell_angle_alpha                90
_cell_angle_beta                 93.822(4)
_cell_angle_gamma                90
_cell_formula_units_Z            8
_cell_length_a                   24.8351(9)
_cell_length_b                   7.1710(2)
_cell_length_c                   25.5947(9)
_cell_measurement_reflns_used    8537
_cell_measurement_temperature    100(1)
_cell_measurement_theta_max      73.5180
_cell_measurement_theta_min      3.8400
_cell_volume                     4548.1(3)
_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    'olex2.solve (Bourhis et al., 2015)'
_diffrn_ambient_environment      N~2~
_diffrn_ambient_temperature      100(1)
_diffrn_detector                 'Pilatus3R 200K-A'
_diffrn_measured_fraction_theta_full 0.997
_diffrn_measured_fraction_theta_max 0.964
_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    -33.00   4.00   0.50    2.50    --    0.00 -82.00-150.00   74
  2  \w    -33.00  31.00   0.50    2.50    --    0.00 -82.00 -60.00  128
  3  \w    -18.00  20.00   0.50    2.50    --    0.00 -82.00   0.00   76
  4  \w    -30.00  24.00   0.50    2.50    --    0.00 -77.00  60.00  108
  5  \w     78.00 115.00   0.50   16.50    --   95.20 -61.00-150.00   74
  6  \w     87.00 170.00   0.50   16.50    --   95.20  30.00 150.00  166
  7  \w     98.00 146.00   0.50   16.50    --   95.20  45.00  90.00   96
  8  \w     35.00 127.00   0.50   16.50    --   95.20 -82.00 150.00  184
  9  \w     12.00 110.00   0.50   16.50    --   95.20 -30.00 150.00  196
 10  \w     32.00 111.00   0.50   16.50    --   95.20 -45.00 -30.00  158
 11  \w    131.00 173.00   0.50   16.50    --   95.20  82.00   0.00   84
 12  \w     74.00 114.00   0.50   16.50    --   95.20 -82.00 -60.00   80
 13  \w     11.00  46.00   0.50   16.50    --   95.20 -82.00 -60.00   70
;
_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      -0.0140366000
_diffrn_orient_matrix_UB_12      0.0564940000
_diffrn_orient_matrix_UB_13      -0.0573652000
_diffrn_orient_matrix_UB_21      0.0586056000
_diffrn_orient_matrix_UB_22      0.0644211000
_diffrn_orient_matrix_UB_23      -0.0048271000
_diffrn_orient_matrix_UB_31      0.0151600000
_diffrn_orient_matrix_UB_32      -0.1970537000
_diffrn_orient_matrix_UB_33      -0.0180768000
_diffrn_radiation_monochromator  graphite
_diffrn_radiation_probe          x-ray
_diffrn_radiation_type           CuK\a
_diffrn_radiation_wavelength     1.54184
_diffrn_reflns_av_R_equivalents  0.0422
_diffrn_reflns_av_unetI/netI     0.0650
_diffrn_reflns_Laue_measured_fraction_full 0.997
_diffrn_reflns_Laue_measured_fraction_max 0.964
_diffrn_reflns_limit_h_max       27
_diffrn_reflns_limit_h_min       -30
_diffrn_reflns_limit_k_max       4
_diffrn_reflns_limit_k_min       -8
_diffrn_reflns_limit_l_max       29
_diffrn_reflns_limit_l_min       -31
_diffrn_reflns_number            23731
_diffrn_reflns_point_group_measured_fraction_full 0.711
_diffrn_reflns_point_group_measured_fraction_max 0.676
_diffrn_reflns_theta_full        67.684
_diffrn_reflns_theta_max         74.350
_diffrn_reflns_theta_min         3.787
_diffrn_source                   'Rotating-anode X-ray tube'
_diffrn_source_type              'MicroMax 007 (Cu) X-ray Source'
_exptl_absorpt_coefficient_mu    1.732
_exptl_absorpt_correction_T_max  1.00000
_exptl_absorpt_correction_T_min  0.68364
_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    1.229
_exptl_crystal_description       needle
_exptl_crystal_F_000             1792
_exptl_crystal_size_max          0.5
_exptl_crystal_size_mid          0.03
_exptl_crystal_size_min          0.02
_refine_diff_density_max         0.436
_refine_diff_density_min         -0.269
_refine_diff_density_rms         0.053
_refine_ls_abs_structure_details
;
 Flack x determined using 2096 quotients [(I+)-(I-)]/[(I+)+(I-)]
 (Parsons, Flack and Wagner, Acta Cryst. B69 (2013) 249-259).
;
_refine_ls_abs_structure_Flack   0.042(11)
_refine_ls_extinction_method     none
_refine_ls_goodness_of_fit_ref   0.949
_refine_ls_hydrogen_treatment    mixed
_refine_ls_matrix_type           full
_refine_ls_number_parameters     1076
_refine_ls_number_reflns         12511
_refine_ls_number_restraints     1
_refine_ls_restrained_S_all      0.949
_refine_ls_R_factor_all          0.0613
_refine_ls_R_factor_gt           0.0466
_refine_ls_shift/su_max          0.009
_refine_ls_shift/su_mean         0.000
_refine_ls_structure_factor_coef Fsqd
_refine_ls_weighting_details
'w=1/[\s^2^(Fo^2^)+(0.0737P)^2^] where P=(Fo^2^+2Fc^2^)/3'
_refine_ls_weighting_scheme      calc
_refine_ls_wR_factor_gt          0.1133
_refine_ls_wR_factor_ref         0.1194
_reflns_Friedel_coverage         0.294
_reflns_Friedel_fraction_full    0.371
_reflns_Friedel_fraction_max     0.335
_reflns_number_gt                9783
_reflns_number_total             12511
_reflns_threshold_expression     'I > 2\s(I)'
_cod_data_source_file            jm1c01402_si_006.cif
_cod_data_source_block           luoxiaowei_as66_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            'C92 H116 Cl4 O20'
_cod_original_formula_weight         1683.64
_cod_original_formula_moiety         '4(C23 H29 Cl O5)'
_cod_original_formula_units_Z            2
_cod_database_code               1564801
_shelx_shelxl_version_number     2014/7
_chemical_oxdiff_formula         'C220 H200 N20 O20 Cl1 '
_shelx_estimated_absorpt_t_max   0.966
_shelx_estimated_absorpt_t_min   0.478
_reflns_odcompleteness_completeness 99.71
_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:
 C10B(H10B), C19(H19), C10(H10), C10C(H10C), C15B(H15B), C19B(H19B),
 C15C(H15C), C15(H15), C19A(H19A), C15A(H15A), C19C(H19C), C10A(H10A)
2.b Secondary CH2 refined with riding coordinates:
 C16B(H16G,H16H), C9B(H9BA,H9BB), C17B(H17G,H17H), C16C(H16A,H16B), C17A(H17E,
 H17F), C9C(H9CA,H9CB), C17(H17C,H17D), C9(H9A,H9B), C16(H16C,H16D), C17C(H17A,
 H17B), C16A(H16E,H16F), C9A(H9AA,H9AB)
2.c Aromatic/amide H refined with riding coordinates:
 C13C(H13C), C8(H8), C12B(H12B), C13B(H13B), C12C(H12C), C12(H12), C13(H13),
 C13A(H13A), C8B(H8B), C8A(H8A), C8C(H8C), C12A(H12A)
2.d X=CH2 refined with riding coordinates:
 C23B(H23G,H23H), C23(H23C,H23D), C23C(H23A,H23B), C23A(H23E,H23F)
2.e Idealised Me refined as rotating group:
 C21B(H21J,H21K,H21L), C20B(H20J,H20K,H20L), C22(H22D,H22E,H22F), C20C(H20A,
 H20B,H20C), C20A(H20G,H20H,H20I), C22A(H22G,H22H,H22I), C21C(H21A,H21B,H21C),
 C7A(H7AA,H7AB,H7AC), C7C(H7CA,H7CB,H7CC), C21A(H21G,H21H,H21I), C7(H7A,H7B,
 H7C), C20(H20D,H20E,H20F), C22B(H22J,H22K,H22L), C22C(H22A,H22B,H22C),
 C7B(H7BA,H7BB,H7BC), C21(H21D,H21E,H21F)
2.f Idealised tetrahedral OH refined as rotating group:
 O5B(H5B), O3B(H3B), O5(H5), O3(H3), O2(H2), O2C(H2C), O3A(H3A), O2A(H2A),
 O2B(H2B), O5C(H5C), O5A(H5A)
;
_shelx_res_checksum              2657
_shelx_hkl_checksum              25560
_shelx_fab_checksum              97604
_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 1.751
_oxdiff_exptl_absorpt_empirical_full_min 0.692