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_1559414
_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 ad
_chemical_formula_moiety         'C37 H29 N5 O5'
_chemical_formula_sum            'C37 H29 N5 O5'
_chemical_formula_weight         623.65
_space_group_crystal_system      orthorhombic
_space_group_IT_number           19
_space_group_name_Hall           'P 2ac 2ab'
_space_group_name_H-M_alt        'P 21 21 21'
_atom_sites_solution_hydrogens   geom
_atom_sites_solution_primary     direct
_audit_creation_date             2017-11-07
_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                90
_cell_formula_units_Z            4
_cell_length_a                   9.05425(19)
_cell_length_b                   14.2458(3)
_cell_length_c                   22.2227(4)
_cell_measurement_reflns_used    11795
_cell_measurement_temperature    100.00(10)
_cell_measurement_theta_max      73.3400
_cell_measurement_theta_min      5.2120
_cell_volume                     2866.40(10)
_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)'
_computing_structure_solution    'ShelXT (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 1.000
_diffrn_measured_fraction_theta_max 1.000
_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   -115.00 -17.00   1.00    1.00    --  -40.98 -37.00-120.00   98
  2  \w   -117.00  -8.00   1.00    1.00    --  -40.98 -77.00   0.00  109
  3  \w    -96.00  -2.00   1.00    1.00    --  -40.98 125.00-180.00   94
  4  \w     34.00 121.00   1.00    3.78    --  106.95-125.00 -90.00   87
  5  \w     94.00 178.00   1.00    3.78    --  106.95 125.00-150.00   84
  6  \w     34.00 121.00   1.00    3.78    --  106.95-125.00  90.00   87
  7  \w     31.00 135.00   1.00    3.78    --  106.95 -30.00  60.00  104
  8  \w     31.00 140.00   1.00    3.78    --  106.95 -77.00  90.00  109
  9  \w     34.00 133.00   1.00    3.78    --  106.95 -45.00  30.00   99
 10  \w   -113.00 -13.00   1.00    1.00    --  -40.98 -57.00  60.00  100
 11  \w   -113.00 -13.00   1.00    1.00    --  -40.98 -57.00 120.00  100
 12  \w    -69.00  32.00   1.00    1.00    --  -40.98  57.00  30.00  101
 13  \w     54.00 147.00   1.00    3.78    --  106.95  15.00 -90.00   93
;
_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      0.0455261000
_diffrn_orient_matrix_UB_12      -0.1015507000
_diffrn_orient_matrix_UB_13      0.0150350000
_diffrn_orient_matrix_UB_21      -0.0095463000
_diffrn_orient_matrix_UB_22      -0.0259708000
_diffrn_orient_matrix_UB_23      -0.0672130000
_diffrn_orient_matrix_UB_31      0.1635925000
_diffrn_orient_matrix_UB_32      0.0266109000
_diffrn_orient_matrix_UB_33      -0.0081483000
_diffrn_radiation_monochromator  mirror
_diffrn_radiation_probe          x-ray
_diffrn_radiation_type           CuK\a
_diffrn_radiation_wavelength     1.54184
_diffrn_reflns_av_R_equivalents  0.0729
_diffrn_reflns_av_unetI/netI     0.0508
_diffrn_reflns_Laue_measured_fraction_full 1.000
_diffrn_reflns_Laue_measured_fraction_max 1.000
_diffrn_reflns_limit_h_max       10
_diffrn_reflns_limit_h_min       -7
_diffrn_reflns_limit_k_max       16
_diffrn_reflns_limit_k_min       -16
_diffrn_reflns_limit_l_max       19
_diffrn_reflns_limit_l_min       -26
_diffrn_reflns_number            18939
_diffrn_reflns_point_group_measured_fraction_full 1.000
_diffrn_reflns_point_group_measured_fraction_max 1.000
_diffrn_reflns_theta_full        64.999
_diffrn_reflns_theta_max         64.999
_diffrn_reflns_theta_min         3.686
_diffrn_source                   'micro-focus sealed X-ray tube'
_diffrn_source_type              'SuperNova (Cu) X-ray Source'
_exptl_absorpt_coefficient_mu    0.800
_exptl_absorpt_correction_T_max  1.00000
_exptl_absorpt_correction_T_min  0.74731
_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    1.445
_exptl_crystal_description       block
_exptl_crystal_F_000             1304
_exptl_crystal_size_max          0.14
_exptl_crystal_size_mid          0.13
_exptl_crystal_size_min          0.11
_refine_diff_density_max         0.367
_refine_diff_density_min         -0.324
_refine_diff_density_rms         0.080
_refine_ls_abs_structure_details
;
 Flack x determined using 1905 quotients [(I+)-(I-)]/[(I+)+(I-)]
 (Parsons, Flack and Wagner, Acta Cryst. B69 (2013) 249-259).
;
_refine_ls_abs_structure_Flack   -0.18(17)
_refine_ls_extinction_method     none
_refine_ls_goodness_of_fit_ref   1.042
_refine_ls_hydrogen_treatment    constr
_refine_ls_matrix_type           full
_refine_ls_number_parameters     426
_refine_ls_number_reflns         4880
_refine_ls_number_restraints     0
_refine_ls_restrained_S_all      1.042
_refine_ls_R_factor_all          0.0583
_refine_ls_R_factor_gt           0.0525
_refine_ls_shift/su_max          0.000
_refine_ls_shift/su_mean         0.000
_refine_ls_structure_factor_coef Fsqd
_refine_ls_weighting_details
'w=1/[\s^2^(Fo^2^)+(0.0960P)^2^+0.9242P] where P=(Fo^2^+2Fc^2^)/3'
_refine_ls_weighting_scheme      calc
_refine_ls_wR_factor_gt          0.1375
_refine_ls_wR_factor_ref         0.1403
_reflns_Friedel_coverage         0.757
_reflns_Friedel_fraction_full    1.000
_reflns_Friedel_fraction_max     1.000
_reflns_number_gt                4671
_reflns_number_total             4880
_reflns_threshold_expression     'I > 2\s(I)'
_cod_data_source_file            jm0c01271_si_006.cif
_cod_data_source_block           13g-29i
_cod_database_code               1559414
_shelx_shelxl_version_number     2017/1
_shelx_estimated_absorpt_t_max   0.917
_shelx_estimated_absorpt_t_min   0.896
_reflns_odcompleteness_completeness 99.93
_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
2.a Ternary CH refined with riding coordinates:
 C20(H20), C00T(H00T), C21(H21)
2.b Secondary CH2 refined with riding coordinates:
 C22(H22A,H22B), C19(H19A,H19B)
2.c Aromatic/amide H refined with riding coordinates:
 N2(H2), N3(H3), N4(H4), C28(H28), C29(H29), C30(H30), C26(H26), C17(H17),
 C15(H15), C16(H16), C18(H18), C4(H4A), C1(H1), C31(H31), C3(H3A), C2(H2A)
2.d Idealised Me refined as rotating group:
 C00Y(H00A,H00B,H00C), C016(H01A,H01B,H01C)
;
_olex2_date_sample_data_collection 2017-11-06
_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 2.341
_oxdiff_exptl_absorpt_empirical_full_min 0.451