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_1564800
_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 O5'
_chemical_formula_sum            'C23 H31 Cl O5'
_chemical_formula_weight         422.93
_space_group_crystal_system      triclinic
_space_group_IT_number           1
_space_group_name_Hall           'P 1'
_space_group_name_H-M_alt        'P 1'
_atom_sites_solution_hydrogens   geom
_atom_sites_solution_primary     dual
_audit_creation_date             2019-11-06
_audit_creation_method
;
Olex2 1.2
(compiled 2018.05.29 svn.r3508 for OlexSys, GUI svn.r5506)
;
_cell_angle_alpha                105.337(2)
_cell_angle_beta                 92.858(2)
_cell_angle_gamma                113.621(3)
_cell_formula_units_Z            8
_cell_length_a                   15.1437(4)
_cell_length_b                   17.4925(5)
_cell_length_c                   19.3925(5)
_cell_measurement_reflns_used    4983
_cell_measurement_temperature    100(1)
_cell_measurement_theta_max      73.3700
_cell_measurement_theta_min      5.2790
_cell_volume                     4467.9(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      100(1)
_diffrn_detector                 'Pilatus3R 200K-A'
_diffrn_measured_fraction_theta_full 0.988
_diffrn_measured_fraction_theta_max 0.955
_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    -18.00  25.00   0.10    0.80    --    0.00 -82.00 -60.00  430
  2  \w     -2.00  23.00   0.10    0.80    --    0.00 -77.00  30.00  250
  3  \w    -46.00 -18.00   0.10    0.80    --    0.00 -77.00   0.00  280
  4  \w    -25.00  29.00   0.10    0.80    --    0.00 -82.00  90.00  540
  5  \w    -32.00  14.00   0.10    0.80    --    0.00 -82.00-120.00  460
  6  \w    -41.00  -7.00   0.10    0.80    --    0.00 -77.00  30.00  340
  7  \w     81.00 120.00   0.10    2.50    --   95.80 -82.00 -60.00  390
  8  \w      7.00  88.00   0.10    2.50    --   95.80 -61.00 120.00  810
  9  \w     89.00 128.00   0.10    2.50    --   95.80  82.00-120.00  390
 10  \w     85.00 136.00   0.10    2.50    --   95.80  15.00  30.00  510
 11  \w    144.00 178.00   0.10    2.50    --   95.80  15.00  30.00  340
 12  \w      9.00  46.00   0.10    2.50    --   95.80 -82.00 -60.00  370
 13  \w     88.00 116.00   0.10    2.50    --   95.80 -61.00 -30.00  280
 14  \w      8.00  67.00   0.10    2.50    --   95.80 -30.00  60.00  590
 15  \w      6.00  92.00   0.10    2.50    --   95.80 -61.00-150.00  860
 16  \w     77.00 105.00   0.10    2.50    --   95.80 -82.00 120.00  280
 17  \w      8.00  63.00   0.10    2.50    --   95.80 -82.00 120.00  550
 18  \w     71.00 101.00   0.10    2.50    --   95.80 -30.00  60.00  300
 19  \w     23.00 115.00   0.10    2.50    --   95.80 -82.00  30.00  920
 20  \w     10.00 104.00   0.10    2.50    --   95.80 -61.00 -60.00  940
 21  \w     14.00 121.00   0.10    2.50    --   95.80 -82.00-150.00 1070
 22  \w     93.00 119.00   0.10    2.50    --   95.80 -82.00-120.00  260
 23  \w     33.00 112.00   0.10    2.50    --   95.80 -30.00 -90.00  790
 24  \w    106.00 132.00   0.10    2.50    --   95.80  82.00  30.00  260
 25  \w     98.00 158.00   0.10    2.50    --   95.80  82.00-150.00  600
;
_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      0.0202701000
_diffrn_orient_matrix_UB_12      0.0175499000
_diffrn_orient_matrix_UB_13      0.0826636000
_diffrn_orient_matrix_UB_21      0.0359640000
_diffrn_orient_matrix_UB_22      0.0991618000
_diffrn_orient_matrix_UB_23      0.0123104000
_diffrn_orient_matrix_UB_31      -0.1049743000
_diffrn_orient_matrix_UB_32      -0.0093340000
_diffrn_orient_matrix_UB_33      0.0043193000
_diffrn_radiation_monochromator  graphite
_diffrn_radiation_probe          x-ray
_diffrn_radiation_type           CuK\a
_diffrn_radiation_wavelength     1.54184
_diffrn_reflns_av_R_equivalents  0.0629
_diffrn_reflns_av_unetI/netI     0.0959
_diffrn_reflns_Laue_measured_fraction_full 0.988
_diffrn_reflns_Laue_measured_fraction_max 0.955
_diffrn_reflns_limit_h_max       11
_diffrn_reflns_limit_h_min       -18
_diffrn_reflns_limit_k_max       21
_diffrn_reflns_limit_k_min       -21
_diffrn_reflns_limit_l_max       23
_diffrn_reflns_limit_l_min       -24
_diffrn_reflns_number            43546
_diffrn_reflns_point_group_measured_fraction_full 0.627
_diffrn_reflns_point_group_measured_fraction_max 0.599
_diffrn_reflns_theta_full        67.684
_diffrn_reflns_theta_max         74.321
_diffrn_reflns_theta_min         3.674
_diffrn_source                   'Rotating-anode X-ray tube'
_diffrn_source_type              'MicroMax 007 (Cu) X-ray Source'
_exptl_absorpt_coefficient_mu    1.763
_exptl_absorpt_correction_T_max  1.00000
_exptl_absorpt_correction_T_min  0.79792
_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    1.257
_exptl_crystal_description       plate
_exptl_crystal_F_000             1808
_exptl_crystal_size_max          0.2
_exptl_crystal_size_mid          0.2
_exptl_crystal_size_min          0.03
_refine_diff_density_max         0.692
_refine_diff_density_min         -0.397
_refine_diff_density_rms         0.064
_refine_ls_abs_structure_details
;
 Classical Flack method preferred over Parsons because s.u. lower.
;
_refine_ls_abs_structure_Flack   0.030(15)
_refine_ls_extinction_method     none
_refine_ls_goodness_of_fit_ref   0.868
_refine_ls_hydrogen_treatment    constr
_refine_ls_matrix_type           full
_refine_ls_number_parameters     2153
_refine_ls_number_reflns         21824
_refine_ls_number_restraints     3
_refine_ls_restrained_S_all      0.868
_refine_ls_R_factor_all          0.1896
_refine_ls_R_factor_gt           0.0632
_refine_ls_shift/su_max          1.531
_refine_ls_shift/su_mean         0.209
_refine_ls_structure_factor_coef Fsqd
_refine_ls_weighting_details
'w=1/[\s^2^(Fo^2^)+(0.1256P)^2^] where P=(Fo^2^+2Fc^2^)/3'
_refine_ls_weighting_scheme      calc
_refine_ls_wR_factor_gt          0.1789
_refine_ls_wR_factor_ref         0.2678
_reflns_Friedel_coverage         0.255
_reflns_Friedel_fraction_full    0.266
_reflns_Friedel_fraction_max     0.244
_reflns_number_gt                5061
_reflns_number_total             21824
_reflns_threshold_expression     'I > 2\s(I)'
_cod_data_source_file            jm1c01402_si_005.cif
_cod_data_source_block           luoxiaowei_as82a_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            'C184 H248 Cl8 O40'
_cod_original_formula_weight         3383.41
_cod_original_formula_moiety         '8(C23 H31 Cl O5)'
_cod_original_formula_units_Z            1
_cod_database_code               1564800
_shelx_shelxl_version_number     2014/7
_shelx_estimated_absorpt_t_max   0.949
_shelx_estimated_absorpt_t_min   0.719
_reflns_odcompleteness_completeness 98.90
_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:
 C02J(H02J), C038(H038), C03K(H03P), C03N(H03N), C03P(H9BA), C03S(H9AA),
 C04L(H04M), C04W(H04W)
2.b Secondary CH2 refined with riding coordinates:
 C01U(H01F,H01G), C01W(H01C,H01E), C01Z(H01A,H01B), C021(H02R,H02S), C022(H02A,
 H02B), C025(H02E,H02F), C02E(H02I,H02K), C02H(H02C,H02D), C02U(H02G,H02H),
 C02Z(H02U,H02V), C030(H6AA,H), C032(H03A,H03B), C034(H03M,H03O), C035(H7AA,HA),
  C03A(H7BA,HD), C03I(H03K,H03L), C03M(H03I,H03J), C03O(H03,HG), C03X(H03U,
 H03V), C041(H04V,H04X), C042(H04H,H04I), C045(H1BA,HJ), C04E(H04Y,HM),
 C04H(H04N,H04O), C04R(H04Z,HP), C04T(H04Q,H04R), C04V(H2AA,HS), C050(H05P,
 H05Q), C053(H4BA,HV), C056(H05U,H05V), C059(H05W,H05X), C05B(H05,H7CA),
 C065(H06N,H06O), C067(H06D,H06E), C068(H4CA,H5EA), C06A(H06Z,H8EA), C06C(H06F,
 H06G), C06E(H06,H9EA), C06F(H06S,H06T), C06G(H6CA,H0FA)
2.c Aromatic/amide H refined with riding coordinates:
 C01D(H01D), C01H(H01H), C02A(H02T), C02W(H02W), C02X(H02X), C033(H033),
 C036(H036), C03G(H8AA), C03Q(H1AA), C03T(H03T), C043(H043), C046(H046),
 C049(H049), C04D(H04D), C04N(H04P), C04Y(H1CA)
2.d Idealised Me refined as rotating group:
 C020(H02L,H02M,H02N), C02Y(H02O,H02P,H02Q), C031(H03C,H03D,H03E), C037(H03Z,
 HB,HC), C03F(H03F,H03G,H03H), C03H(H8BA,HE,HF), C03L(H03Q,H03R,H03S),
 C03Y(H0BA,HH,HI), C03Z(H03W,H03X,H03Y), C047(H04J,H04K,H04L), C04A(H2BA,HK,HL),
  C04B(H04A,H04B,H04C), C04P(H0CA,HN,HO), C04S(H04,HQ,HR), C04U(H04S,H04T,H04U),
  C04X(H04E,H04F,H04G), C04Z(H3BA,HT,HU), C052(H05R,H05S,H05T), C054(H3AA,HW,
 HX), C057(H05A,H05B,H05C), C05A(H05Y,HY,HZ), C05C(H4AA,H8CA,H9CA), C05E(H5AA,
 H0DA,H1DA), C05F(H05D,H05E,H05F), C05G(H5BA,H2DA,H3DA), C05H(H0AA,H4DA,H5DA),
 C05K(H05Z,H6DA,H7DA), C05M(H6BA,H8DA,H9DA), C05O(H05G,H05H,H05I), C05T(H05J,
 H05K,H05L), C05V(H05M,H05N,H05O), C05Y(H2CA,H0EA,H1EA), C061(H06K,H06L,H06M),
 C062(H3CA,H2EA,H3EA), C063(H06A,H06B,H06C), C064(H06U,H06V,H06W), C066(H06X,
 H06Y,H4EA), C069(H5CA,H6EA,H7EA), C06B(H06P,H06Q,H06R), C06D(H06H,H06I,H06J)
2.e Idealised tetrahedral OH refined as rotating group:
 O00C(H00C), O00E(H00E), O00F(H00F), O00H(H00H), O00I(H00I), O00J(H00J),
 O00K(H00K), O00L(H00L), O00M(H00M), O00N(H00N), O00R(H00R), O00S(H00S),
 O00T(H00T), O00U(H00U), O00V(H00V), O00W(H00W), O00X(H00X), O00Y(H00Y),
 O00Z(H00Z), O010(H010), O011(H011), O012(H012), O014(H014), O015(H015)
;
_shelx_res_checksum              12941
_shelx_hkl_checksum              85567
_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 1.545
_oxdiff_exptl_absorpt_empirical_full_min 0.750