Identification, Structure–Activity Relationships of Marine-Derived Indolocarbazoles, and a Dual PKCθ/δ Inhibitor with Potent Antipancreatic Cancer Efficacy
Wang, Jinhui; Jin, Weiyang; Zhou, Xiaoxin; Li, Jiaqi; Xu, Chengdong; Ma, Zhongjun; Wang, Jianan; Qin, Lele; Zhou, Biao; Ding, Wanjing; Gao, Tingting; Yao, Hangping; Chen, Zhe; Journal of Medicinal Chemistry  (2020) –; doi:10.1021/acs.jmedchem.0c01271

data_1559412
_publ_section_title
;
 Identification, Structure--Activity Relationships of Marine-Derived
 Indolocarbazoles, and a Dual PKC\q/\d Inhibitor with Potent
 Antipancreatic Cancer Efficacy
;
_journal_name_full               'Journal of Medicinal Chemistry'
_journal_paper_doi               10.1021/acs.jmedchem.0c01271
_journal_year                    2020
_chemical_absolute_configuration ukn
_chemical_formula_moiety         'C31 H28 N4 O5'
_chemical_formula_sum            'C31 H28 N4 O5'
_chemical_formula_weight         536.57
_space_group_crystal_system      trigonal
_space_group_IT_number           146
_space_group_name_Hall           'R 3'
_space_group_name_H-M_alt        'R 3 :H'
_atom_sites_solution_hydrogens   geom
_audit_creation_date             2017-11-23
_audit_creation_method
;
Olex2 1.2
(compiled 2017.08.10 svn.r3458 for OlexSys, GUI svn.r5381)
;
_cell_angle_alpha                90
_cell_angle_beta                 90
_cell_angle_gamma                120
_cell_formula_units_Z            9
_cell_length_a                   24.2245(15)
_cell_length_b                   24.2245(15)
_cell_length_c                   12.4413(6)
_cell_measurement_reflns_used    1643
_cell_measurement_temperature    100.00(10)
_cell_measurement_theta_max      71.4670
_cell_measurement_theta_min      5.4930
_cell_volume                     6322.8(6)
_computing_cell_refinement       'CrysAlisPro 1.171.38.43f (Rigaku OD, 2015)'
_computing_data_collection       'CrysAlisPro 1.171.38.43f (Rigaku OD, 2015)'
_computing_data_reduction        'CrysAlisPro 1.171.38.43f (Rigaku OD, 2015)'
_computing_molecular_graphics    'Olex2 (Dolomanov et al., 2009)'
_computing_publication_material  'Olex2 (Dolomanov et al., 2009)'
_computing_structure_refinement  'ShelXL (Sheldrick, 2015)'
_diffrn_ambient_environment      N~2~
_diffrn_ambient_temperature      100.00(10)
_diffrn_detector                 'CCD plate'
_diffrn_detector_area_resol_mean 5.2684
_diffrn_detector_type            AtlasS2
_diffrn_measured_fraction_theta_full 0.996
_diffrn_measured_fraction_theta_max 0.962
_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    -59.00   8.00   1.00    1.00    --  -40.48  37.00 -31.00   67
  2  \w     30.00  96.00   1.00    1.00    --   40.48-125.00-150.00   66
  3  \w     26.00 101.00   1.00   12.00    --  108.20 -94.00-180.00   75
  4  \w     76.00 178.00   1.00   12.00    --  108.20  77.00-180.00  102
  5  \w    104.00 155.00   1.00   12.00    --  108.20 104.00  61.00   51
  6  \w     37.00  80.00   1.00   12.00    --  108.20 -94.00  90.00   43
;
_diffrn_measurement_device       'four-circle diffractometer'
_diffrn_measurement_device_type  'SuperNova, Dual, Cu at zero, AtlasS2'
_diffrn_measurement_method       '\w scans'
_diffrn_orient_matrix_type
'CrysAlisPro convention (1999,Acta A55,543-557)'
_diffrn_orient_matrix_UB_11      0.0169475667
_diffrn_orient_matrix_UB_12      0.0695812333
_diffrn_orient_matrix_UB_13      -0.0191222667
_diffrn_orient_matrix_UB_21      0.0625782000
_diffrn_orient_matrix_UB_22      0.0137117000
_diffrn_orient_matrix_UB_23      -0.0549462000
_diffrn_orient_matrix_UB_31      -0.0344353000
_diffrn_orient_matrix_UB_32      -0.0190355000
_diffrn_orient_matrix_UB_33      -0.1093214000
_diffrn_radiation_monochromator  mirror
_diffrn_radiation_probe          x-ray
_diffrn_radiation_type           CuK\a
_diffrn_radiation_wavelength     1.54184
_diffrn_reflns_av_R_equivalents  0.0338
_diffrn_reflns_av_unetI/netI     0.0632
_diffrn_reflns_Laue_measured_fraction_full 0.996
_diffrn_reflns_Laue_measured_fraction_max 0.962
_diffrn_reflns_limit_h_max       20
_diffrn_reflns_limit_h_min       -30
_diffrn_reflns_limit_k_max       27
_diffrn_reflns_limit_k_min       -29
_diffrn_reflns_limit_l_max       10
_diffrn_reflns_limit_l_min       -15
_diffrn_reflns_number            4714
_diffrn_reflns_point_group_measured_fraction_full 0.566
_diffrn_reflns_point_group_measured_fraction_max 0.546
_diffrn_reflns_theta_full        67.684
_diffrn_reflns_theta_max         73.755
_diffrn_reflns_theta_min         4.131
_diffrn_source                   'micro-focus sealed X-ray tube'
_diffrn_source_type              'SuperNova (Cu) X-ray Source'
_exptl_absorpt_coefficient_mu    0.714
_exptl_absorpt_correction_T_max  1.00000
_exptl_absorpt_correction_T_min  0.55332
_exptl_absorpt_correction_type   multi-scan
_exptl_absorpt_process_details
;
CrysAlisPro 1.171.38.43f (Rigaku Oxford Diffraction, 2015)
Empirical absorption correction using spherical harmonics,
 implemented in SCALE3 ABSPACK scaling algorithm.
;
_exptl_crystal_colour            colourless
_exptl_crystal_colour_primary    colourless
_exptl_crystal_density_diffrn    1.268
_exptl_crystal_description       block
_exptl_crystal_F_000             2538
_exptl_crystal_size_max          0.14
_exptl_crystal_size_mid          0.12
_exptl_crystal_size_min          0.11
_refine_diff_density_max         0.543
_refine_diff_density_min         -0.336
_refine_diff_density_rms         0.088
_refine_ls_abs_structure_details
;
 Classical Flack method preferred over Parsons because s.u. lower.
;
_refine_ls_abs_structure_Flack   0.0(5)
_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     364
_refine_ls_number_reflns         3116
_refine_ls_number_restraints     1
_refine_ls_restrained_S_all      1.069
_refine_ls_R_factor_all          0.0969
_refine_ls_R_factor_gt           0.0793
_refine_ls_shift/su_max          0.014
_refine_ls_shift/su_mean         0.001
_refine_ls_structure_factor_coef Fsqd
_refine_ls_weighting_details
'w=1/[\s^2^(Fo^2^)+(0.1437P)^2^] where P=(Fo^2^+2Fc^2^)/3'
_refine_ls_weighting_scheme      calc
_refine_ls_wR_factor_gt          0.1960
_refine_ls_wR_factor_ref         0.2143
_reflns_Friedel_coverage         0.135
_reflns_Friedel_fraction_full    0.136
_reflns_Friedel_fraction_max     0.130
_reflns_number_gt                2392
_reflns_number_total             3116
_reflns_threshold_expression     'I > 2\s(I)'
_cod_data_source_file            jm0c01271_si_005.cif
_cod_data_source_block           13g-22i
_cod_original_cell_volume        6322.7(9)
_cod_original_sg_symbol_H-M      'R 3'
_cod_database_code               1559412
_shelx_shelxl_version_number     2017/1
_shelx_estimated_absorpt_t_max   0.926
_shelx_estimated_absorpt_t_min   0.907
_reflns_odcompleteness_completeness 99.64
_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, All N(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:
 C21(H21), C18(H18), C19(H19), C23(H23)
2.b Secondary CH2 refined with riding coordinates:
 C20(H20A,H20B), C3(H3A,H3B), C24(H24A,H24B), C25(H25A,H25B)
2.c Aromatic/amide H refined with riding coordinates:
 N2(H2), C28(H28), C31(H31), C12(H12), C29(H29), C30(H30), C13(H13), C14(H14),
 C15(H15)
2.d Idealised Me refined as rotating group:
 C17(H17A,H17B,H17C), C00W(H00A,H00B,H00C)
2.e Idealised tetrahedral OH refined as rotating group:
 O5(H5)
;
_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
- Detector area scaling
;
_oxdiff_exptl_absorpt_empirical_full_max 2.014
_oxdiff_exptl_absorpt_empirical_full_min 0.544