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_1564803
_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   geom
_atom_sites_solution_primary     dual
_audit_creation_date             2018-12-28
_audit_creation_method
;
Olex2 1.2
(compiled 2018.05.29 svn.r3508 for OlexSys, GUI svn.r5506)
;
_cell_angle_alpha                90
_cell_angle_beta                 96.963(2)
_cell_angle_gamma                90
_cell_formula_units_Z            8
_cell_length_a                   7.1951(2)
_cell_length_b                   40.1443(12)
_cell_length_c                   15.3671(4)
_cell_measurement_reflns_used    7431
_cell_measurement_temperature    99.9(8)
_cell_measurement_theta_max      72.9340
_cell_measurement_theta_min      4.3920
_cell_volume                     4405.9(2)
_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 0.999
_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    -45.00 -12.00   0.50    4.00    --    0.00 -77.00 -60.00   66
  2  \w    -17.00  87.00   0.50    4.00    --    0.00  19.00 -60.00  208
  3  \w    -31.00  22.00   0.50    4.00    --    0.00 -82.00 150.00  106
  4  \w     12.00 110.00   0.50   17.00    --   95.20 -30.00   0.00  196
  5  \w     29.00 111.00   0.50   17.00    --   95.20 -45.00 150.00  164
  6  \w      9.00  89.00   0.50   17.00    --   95.20 -45.00 -30.00  160
  7  \w    122.00 174.00   0.50   17.00    --   95.20  30.00  60.00  104
  8  \w     81.00 108.00   0.50   17.00    --   95.20  30.00  60.00   54
  9  \w     75.00 172.00   0.50   17.00    --   95.20  61.00 -60.00  194
 10  \w     18.00 112.00   0.50   17.00    --   95.20 -30.00 150.00  188
 11  \w    110.00 139.00   0.50   17.00    --   95.20  30.00  90.00   58
;
_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      0.0317267000
_diffrn_orient_matrix_UB_12      0.0207825000
_diffrn_orient_matrix_UB_13      0.0847221000
_diffrn_orient_matrix_UB_21      0.1575377000
_diffrn_orient_matrix_UB_22      0.0193439000
_diffrn_orient_matrix_UB_23      -0.0372513000
_diffrn_orient_matrix_UB_31      -0.1439137000
_diffrn_orient_matrix_UB_32      0.0258196000
_diffrn_orient_matrix_UB_33      -0.0403915000
_diffrn_radiation_monochromator  graphite
_diffrn_radiation_probe          x-ray
_diffrn_radiation_type           CuK\a
_diffrn_radiation_wavelength     1.54184
_diffrn_reflns_av_R_equivalents  0.0487
_diffrn_reflns_av_unetI/netI     0.0720
_diffrn_reflns_Laue_measured_fraction_full 0.999
_diffrn_reflns_Laue_measured_fraction_max 0.970
_diffrn_reflns_limit_h_max       8
_diffrn_reflns_limit_h_min       -8
_diffrn_reflns_limit_k_max       49
_diffrn_reflns_limit_k_min       -46
_diffrn_reflns_limit_l_max       18
_diffrn_reflns_limit_l_min       -19
_diffrn_reflns_number            23672
_diffrn_reflns_point_group_measured_fraction_full 0.797
_diffrn_reflns_point_group_measured_fraction_max 0.757
_diffrn_reflns_theta_full        67.684
_diffrn_reflns_theta_max         74.081
_diffrn_reflns_theta_min         4.395
_diffrn_source                   'Rotating-anode X-ray tube'
_diffrn_source_type              'MicroMax 007 (Cu) X-ray Source'
_exptl_absorpt_coefficient_mu    1.733
_exptl_absorpt_correction_T_max  1.00000
_exptl_absorpt_correction_T_min  0.47001
_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    1.227
_exptl_crystal_description       block
_exptl_crystal_F_000             1744
_exptl_crystal_size_max          0.05
_exptl_crystal_size_mid          0.05
_exptl_crystal_size_min          0.04
_refine_diff_density_max         1.018
_refine_diff_density_min         -0.921
_refine_diff_density_rms         0.094
_refine_ls_abs_structure_details
;
 Flack x determined using 3249 quotients [(I+)-(I-)]/[(I+)+(I-)]
 (Parsons, Flack and Wagner, Acta Cryst. B69 (2013) 249-259).
;
_refine_ls_abs_structure_Flack   0.083(13)
_refine_ls_extinction_method     none
_refine_ls_goodness_of_fit_ref   1.069
_refine_ls_hydrogen_treatment    constr
_refine_ls_matrix_type           full
_refine_ls_number_parameters     1037
_refine_ls_number_reflns         13519
_refine_ls_number_restraints     1
_refine_ls_restrained_S_all      1.069
_refine_ls_R_factor_all          0.1034
_refine_ls_R_factor_gt           0.0932
_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^)+(0.1148P)^2^+12.7466P] where P=(Fo^2^+2Fc^2^)/3'
_refine_ls_weighting_scheme      calc
_refine_ls_wR_factor_gt          0.2455
_refine_ls_wR_factor_ref         0.2528
_reflns_Friedel_coverage         0.539
_reflns_Friedel_fraction_full    0.589
_reflns_Friedel_fraction_max     0.538
_reflns_number_gt                11386
_reflns_number_total             13519
_reflns_threshold_expression     'I > 2\s(I)'
_cod_data_source_file            jm1c01402_si_009.cif
_cod_data_source_block           luoxiaowei_as58_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 H124 Cl4 O16'
_cod_original_formula_weight         1627.70
_cod_original_formula_moiety         '4(C23 H31 Cl O4)'
_cod_original_formula_units_Z            2
_cod_database_code               1564803
_shelx_shelxl_version_number     2014/7
_chemical_oxdiff_formula         'C209 H190 N19 O19 Cl1 '
_shelx_estimated_absorpt_t_max   0.934
_shelx_estimated_absorpt_t_min   0.918
_reflns_odcompleteness_completeness 99.89
_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), C19'(H19'), C15A(H15A), C15"(H15"), C15'(H15'), C19(H19),
 C19A(H19A), C19"(H19")
2.b Secondary CH2 refined with riding coordinates:
 C16A(H16E,H16F), C12A(H12E,H12F), C12(H12A,H12B), C9(H9A,H9B), C13(H13A,H13B),
  C12'(H12G,H12H), C13"(H13C,H13D), C9A(H9AA,H9AB), C13'(H13G,H13H), C17(H17A,
 H17B), C17'(H17G,H17H), C12"(H12C,H12D), C13A(H13E,H13F), C17A(H17E,H17F),
 C9"(H9"A,H9"B), C16'(H16G,H16H), C16(H16A,H16B), C17"(H17C,H17D), C16"(H16C,
 H16D), C9'(H9'A,H9'B)
2.c Aromatic/amide H refined with riding coordinates:
 C8A(H8A), C10"(H10"), C8"(H8"), C10(H10), C10A(H10A), C8(H8), C8'(H8'),
 C10'(H10')
2.d Idealised Me refined as rotating group:
 C7(H7A,H7B,H7C), C23A(H23G,H23H,H23I), C20'(H20J,H20K,H20L), C22'(H22J,H22K,
 H22L), C20A(H20G,H20H,H20I), C21(H21A,H21B,H21C), C7"(H7"A,H7"B,H7"C),
 C22A(H22G,H22H,H22I), C23(H23A,H23B,H23C), C20(H20A,H20B,H20C), C22(H22A,H22B,
 H22C), C7A(H7AA,H7AB,H7AC), C21A(H21G,H21H,H21I), C20"(H20D,H20E,H20F),
 C7'(H7'A,H7'B,H7'C), C21"(H21D,H21E,H21F), C21'(H21J,H21K,H21L), C23"(H23D,
 H23E,H23F), C22"(H22D,H22E,H22F), C23'(H23J,H23K,H23L)
2.e Idealised tetrahedral OH refined as rotating group:
 O2"(H2"), O3(H3), O3"(H3"), O2A(H2A), O2(H2), O3A(H3A), O2'(H2'), O3'(H3')
;
_shelx_res_checksum              9151
_shelx_hkl_checksum              64258
_shelx_fab_checksum              35066
_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 1.809
_oxdiff_exptl_absorpt_empirical_full_min 0.538