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_1559411
_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_formula_moiety         'C30 H22 N4 O4, C H4 O, C O0.5'
_chemical_formula_sum            'C32 H26 N4 O5.5'
_chemical_formula_weight         554.57
_space_group_crystal_system      triclinic
_space_group_IT_number           2
_space_group_name_Hall           '-P 1'
_space_group_name_H-M_alt        'P -1'
_atom_sites_solution_hydrogens   geom
_atom_sites_solution_primary     direct
_audit_creation_date             2017-09-12
_audit_creation_method
;
Olex2 1.2
(compiled 2017.03.28 svn.r3405 for OlexSys, GUI svn.r5381)
;
_cell_angle_alpha                95.819(3)
_cell_angle_beta                 112.387(3)
_cell_angle_gamma                111.273(3)
_cell_formula_units_Z            2
_cell_length_a                   10.6126(3)
_cell_length_b                   11.4102(4)
_cell_length_c                   13.3071(5)
_cell_measurement_reflns_used    19621
_cell_measurement_temperature    170
_cell_measurement_theta_max      66.8652
_cell_measurement_theta_min      3.7368
_cell_volume                     1333.67(10)
_computing_cell_refinement
;
CrysAlisPro, Agilent Technologies,
Version 1.171.35.11 (release 16-05-2011 CrysAlis171 .NET)
(compiled May 16 2011,17:55:39)
;
_computing_data_collection
;
CrysAlisPro, Agilent Technologies,
Version 1.171.35.11 (release 16-05-2011 CrysAlis171 .NET)
(compiled May 16 2011,17:55:39)
;
_computing_data_reduction
;
CrysAlisPro, Agilent Technologies,
Version 1.171.35.11 (release 16-05-2011 CrysAlis171 .NET)
(compiled May 16 2011,17:55:39)
;
_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    'ShelXS (Sheldrick, 2008)'
_diffrn_ambient_temperature      170
_diffrn_detector_area_resol_mean 10.3592
_diffrn_measured_fraction_theta_full 0.987
_diffrn_measured_fraction_theta_max 0.987
_diffrn_measurement_details
;
  1 omega  -35.00   33.00   1.0000    1.5000
omega____ theta____ kappa____ phi______ frames
    -      -41.6938   38.0000   90.0000 68

  2 omega  -87.00  -58.00   1.0000    1.5000
omega____ theta____ kappa____ phi______ frames
    -      -41.6938  -44.0000  -31.0000 29

  3 omega  -39.00  -14.00   1.0000    1.5000
omega____ theta____ kappa____ phi______ frames
    -      -41.6938  -44.0000  -31.0000 25

  4 omega  -67.00  -38.00   1.0000    1.5000
omega____ theta____ kappa____ phi______ frames
    -      -41.6938   38.0000   90.0000 29

  5 omega  -50.00  -17.00   1.0000    1.5000
omega____ theta____ kappa____ phi______ frames
    -      -41.6938  -47.0000  111.0000 33

  6 omega  -98.00  -26.00   1.0000    1.5000
omega____ theta____ kappa____ phi______ frames
    -      -41.6938  125.0000 -180.0000 72

  7 omega    8.00   57.00   1.0000    1.5000
omega____ theta____ kappa____ phi______ frames
    -       41.6938   77.0000  -60.0000 49

  8 omega   10.00   41.00   1.0000    1.5000
omega____ theta____ kappa____ phi______ frames
    -       41.6938   77.0000  150.0000 31

  9 omega   89.00  118.00   1.0000    1.5000
omega____ theta____ kappa____ phi______ frames
    -       41.6938   77.0000  150.0000 29

 10 omega   60.00  119.00   1.0000    1.5000
omega____ theta____ kappa____ phi______ frames
    -       41.6938   77.0000  -60.0000 59

 11 omega   65.00  114.00   1.0000    1.5000
omega____ theta____ kappa____ phi______ frames
    -       46.0000   76.0000   29.0000 49

 12 omega   14.00   41.00   1.0000    1.5000
omega____ theta____ kappa____ phi______ frames
    -       46.0000   76.0000   29.0000 27

 13 omega   13.00   39.00   1.0000    1.5000
omega____ theta____ kappa____ phi______ frames
    -       46.0000   79.0000  107.0000 26

 14 omega   76.00  126.00   1.0000    1.5000
omega____ theta____ kappa____ phi______ frames
    -       46.0000   79.0000  107.0000 50

 15 omega  -47.00  -15.00   1.0000    1.5000
omega____ theta____ kappa____ phi______ frames
    -      -50.0000  -82.0000  -73.0000 32

 16 omega  -44.00  -18.00   1.0000    1.5000
omega____ theta____ kappa____ phi______ frames
    -      -54.0000  -84.0000  177.0000 26

 17 omega   23.00   49.00   1.0000    1.5000
omega____ theta____ kappa____ phi______ frames
    -       54.0000   78.0000  155.0000 26

 18 omega  -57.00  -24.00   1.0000    1.5000
omega____ theta____ kappa____ phi______ frames
    -      -58.0000  -79.0000    8.0000 33

 19 omega  -50.00  -24.00   1.0000    1.5000
omega____ theta____ kappa____ phi______ frames
    -      -58.0000  -80.0000 -109.0000 26

 20 omega  111.00  136.00   1.0000    1.5000
omega____ theta____ kappa____ phi______ frames
    -       58.0000   76.0000   30.0000 25

 21 omega   25.00   66.00   1.0000    1.5000
omega____ theta____ kappa____ phi______ frames
    -       58.0000   76.0000   30.0000 41

 22 omega  110.00  137.00   1.0000    1.5000
omega____ theta____ kappa____ phi______ frames
    -       62.0000   77.0000  172.0000 27

 23 omega   30.00   56.00   1.0000    1.5000
omega____ theta____ kappa____ phi______ frames
    -       62.0000   78.0000  109.0000 26

 24 omega   28.00   61.00   1.0000    1.5000
omega____ theta____ kappa____ phi______ frames
    -       62.0000   77.0000  172.0000 33

 25 omega   35.00   65.00   1.0000    1.5000
omega____ theta____ kappa____ phi______ frames
    -       66.0000   78.0000  -70.0000 30

 26 omega  -62.00  -37.00   1.0000    2.0000
omega____ theta____ kappa____ phi______ frames
    -      -70.0000  -76.0000  171.0000 25

 27 omega  -73.00  -42.00   1.0000    2.0000
omega____ theta____ kappa____ phi______ frames
    -      -74.0000  -74.0000  -66.0000 31

 28 omega  -65.00  -40.00   1.0000    2.0000
omega____ theta____ kappa____ phi______ frames
    -      -74.0000  -78.0000   70.0000 25

 29 omega  -74.00  -41.00   1.0000    2.0000
omega____ theta____ kappa____ phi______ frames
    -      -74.0000  -73.0000    6.0000 33

 30 omega  -73.00  -46.00   1.0000    2.0000
omega____ theta____ kappa____ phi______ frames
    -      -78.0000  -74.0000 -102.0000 27

 31 omega  -71.00  -45.00   1.0000    2.0000
omega____ theta____ kappa____ phi______ frames
    -      -78.0000  -72.0000  -46.0000 26

 32 omega  -75.00  -50.00   1.0000    2.0000
omega____ theta____ kappa____ phi______ frames
    -      -83.0000  -76.0000  -75.0000 25

 33 omega  -78.00  -52.00   1.0000    2.0000
omega____ theta____ kappa____ phi______ frames
    -      -83.0000  -73.0000   31.0000 26

 34 omega  -76.00  -49.00   1.0000    2.0000
omega____ theta____ kappa____ phi______ frames
    -      -83.0000  -79.0000  170.0000 27

 35 omega  -75.00  -49.00   1.0000    2.0000
omega____ theta____ kappa____ phi______ frames
    -      -83.0000  -77.0000   60.0000 26

 36 omega  -78.00  -52.00   1.0000    2.0000
omega____ theta____ kappa____ phi______ frames
    -      -83.0000  -69.0000   91.0000 26

 37 omega  -76.00  -50.00   1.0000    2.0000
omega____ theta____ kappa____ phi______ frames
    -      -83.0000  -77.0000 -137.0000 26

 38 omega  -76.00  -50.00   1.0000    2.0000
omega____ theta____ kappa____ phi______ frames
    -      -83.0000  -72.0000  126.0000 26

 39 omega  -75.00  -49.00   1.0000    2.0000
omega____ theta____ kappa____ phi______ frames
    -      -83.0000  -77.0000 -180.0000 26

 40 omega  -75.00  -49.00   1.0000    2.0000
omega____ theta____ kappa____ phi______ frames
    -      -83.0000  -77.0000    0.0000 26

 41 omega  -75.00  -49.00   1.0000    2.0000
omega____ theta____ kappa____ phi______ frames
    -      -83.0000  -77.0000 -120.0000 26

 42 omega   60.00  172.00   1.0000    2.0000
omega____ theta____ kappa____ phi______ frames
    -       93.5000   77.0000   90.0000 112

 43 omega   83.00  109.00   1.0000    2.0000
omega____ theta____ kappa____ phi______ frames
    -       93.5000  -89.0000   31.0000 26

 44 omega   61.00  171.00   1.0000    2.0000
omega____ theta____ kappa____ phi______ frames
    -       93.5000   77.0000 -150.0000 110

 45 omega   97.00  152.00   1.0000    2.0000
omega____ theta____ kappa____ phi______ frames
    -       93.5000   77.0000  150.0000 55

 46 omega   33.00   72.00   1.0000    2.0000
omega____ theta____ kappa____ phi______ frames
    -       93.5000  -89.0000   31.0000 39

 47 omega   83.00  110.00   1.0000    2.0000
omega____ theta____ kappa____ phi______ frames
    -       93.5000  -93.0000  126.0000 27

 48 omega   60.00  157.00   1.0000    2.0000
omega____ theta____ kappa____ phi______ frames
    -       93.5000   77.0000  120.0000 97

 49 omega   48.00  129.00   1.0000    2.0000
omega____ theta____ kappa____ phi______ frames
    -       93.5000  -90.0000 -136.0000 81

 50 omega  108.00  146.00   1.0000    2.0000
omega____ theta____ kappa____ phi______ frames
    -       93.5000   77.0000   60.0000 38

 51 omega   63.00  103.00   1.0000    2.0000
omega____ theta____ kappa____ phi______ frames
    -       93.5000   77.0000   60.0000 40

 52 omega   82.00  117.00   1.0000    2.0000
omega____ theta____ kappa____ phi______ frames
    -       93.5000  -85.0000  -47.0000 35

 53 omega   60.00  171.00   1.0000    2.0000
omega____ theta____ kappa____ phi______ frames
    -       93.5000   77.0000 -180.0000 111

 54 omega   60.00   90.00   1.0000    2.0000
omega____ theta____ kappa____ phi______ frames
    -       93.5000   77.0000  150.0000 30

 55 omega   99.00  168.00   1.0000    2.0000
omega____ theta____ kappa____ phi______ frames
    -       93.5000   77.0000 -120.0000 69

 56 omega   61.00   94.00   1.0000    2.0000
omega____ theta____ kappa____ phi______ frames
    -       93.5000   77.0000 -120.0000 33

 57 omega   62.00  170.00   1.0000    2.0000
omega____ theta____ kappa____ phi______ frames
    -       93.5000   77.0000    0.0000 108

 58 omega   32.00   70.00   1.0000    2.0000
omega____ theta____ kappa____ phi______ frames
    -       93.5000  -94.0000  -66.0000 38

 59 omega   36.00   76.00   1.0000    2.0000
omega____ theta____ kappa____ phi______ frames
    -       93.5000  -45.0000  -60.0000 40

 60 omega  135.00  172.00   1.0000    2.0000
omega____ theta____ kappa____ phi______ frames
    -       93.5000   77.0000  -30.0000 37

 61 omega   99.00  132.00   1.0000    2.0000
omega____ theta____ kappa____ phi______ frames
    -       93.5000   77.0000  -30.0000 33

 62 omega   61.00   96.00   1.0000    2.0000
omega____ theta____ kappa____ phi______ frames
    -       93.5000   77.0000  -30.0000 35

 63 omega   60.00  172.00   1.0000    2.0000
omega____ theta____ kappa____ phi______ frames
    -       93.5000   77.0000  -90.0000 112

 64 omega   95.00  170.00   1.0000    2.0000
omega____ theta____ kappa____ phi______ frames
    -       93.5000   77.0000   30.0000 75

 65 omega   63.00   92.00   1.0000    2.0000
omega____ theta____ kappa____ phi______ frames
    -       93.5000   77.0000   30.0000 29

 66 omega   90.00  172.00   1.0000    2.0000
omega____ theta____ kappa____ phi______ frames
    -       93.5000   77.0000  -60.0000 82

 67 omega   42.00  127.00   1.0000    2.0000
omega____ theta____ kappa____ phi______ frames
    -       93.5000  -77.0000   60.0000 85

 68 omega   60.00   86.00   1.0000    2.0000
omega____ theta____ kappa____ phi______ frames
    -       93.5000   77.0000  -60.0000 26

 69 omega  -99.00  -18.00   1.0000    1.5000
omega____ theta____ kappa____ phi______ frames
    -      -41.6938  125.0000 -120.0000 81

 70 omega  -82.00    9.00   1.0000    1.5000
omega____ theta____ kappa____ phi______ frames
    -      -41.6938   94.0000   66.0000 91

 71 omega  -99.00  -18.00   1.0000    1.5000
omega____ theta____ kappa____ phi______ frames
    -      -41.6938  125.0000   90.0000 81

 72 omega -120.00   -8.00   1.0000    1.5000
omega____ theta____ kappa____ phi______ frames
    -      -41.6938  -77.0000  -60.0000 112

 73 omega   15.00  118.00   1.0000    1.5000
omega____ theta____ kappa____ phi______ frames
    -       41.6938   38.0000   90.0000 103

 74 omega  -47.00  -15.00   1.0000    1.5000
omega____ theta____ kappa____ phi______ frames
    -      -50.0000  -82.0000  -73.0000 32

 75 omega  -48.00  -15.00   1.0000    1.5000
omega____ theta____ kappa____ phi______ frames
    -      -50.0000  -81.0000  152.0000 33

 76 omega  -50.00  -24.00   1.0000    1.5000
omega____ theta____ kappa____ phi______ frames
    -      -58.0000  -80.0000 -109.0000 26

 77 omega   24.00  138.00   1.0000    1.5000
omega____ theta____ kappa____ phi______ frames
    -       58.0000   79.0000  144.0000 114

 78 omega   24.00  138.00   1.0000    1.5000
omega____ theta____ kappa____ phi______ frames
    -       58.0000   79.0000 -170.0000 114

 79 omega   24.00  137.00   1.0000    1.5000
omega____ theta____ kappa____ phi______ frames
    -       58.0000   78.0000   -9.0000 113

 80 omega   28.00  141.00   1.0000    1.5000
omega____ theta____ kappa____ phi______ frames
    -       62.0000   78.0000 -111.0000 113

 81 omega   29.00  140.00   1.0000    1.5000
omega____ theta____ kappa____ phi______ frames
    -       62.0000   76.0000   51.0000 111

 82 omega   29.00  140.00   1.0000    1.5000
omega____ theta____ kappa____ phi______ frames
    -       62.0000   76.0000  -51.0000 111

 83 omega   28.00  141.00   1.0000    1.5000
omega____ theta____ kappa____ phi______ frames
    -       62.0000   77.0000  172.0000 113

 84 omega   28.00  141.00   1.0000    1.5000
omega____ theta____ kappa____ phi______ frames
    -       62.0000   78.0000  109.0000 113

 85 omega   33.00  144.00   1.0000    1.5000
omega____ theta____ kappa____ phi______ frames
    -       66.0000   76.0000    1.0000 111

 86 omega   32.00  145.00   1.0000    1.5000
omega____ theta____ kappa____ phi______ frames
    -       66.0000   78.0000  -70.0000 113

 87 omega   66.00  164.00   1.0000    2.0000
omega____ theta____ kappa____ phi______ frames
    -       93.5000   45.0000   90.0000 98

 88 omega   32.00  177.00   1.0000    2.0000
omega____ theta____ kappa____ phi______ frames
    -       93.5000   15.0000 -120.0000 145

 89 omega   73.00  168.00   1.0000    2.0000
omega____ theta____ kappa____ phi______ frames
    -       93.5000  125.0000    0.0000 95

 90 omega   66.00  168.00   1.0000    2.0000
omega____ theta____ kappa____ phi______ frames
    -       93.5000   45.0000  -60.0000 102

 91 omega   19.00   77.00   1.0000    2.0000
omega____ theta____ kappa____ phi______ frames
    -       93.5000  -45.0000  150.0000 58

 92 omega   73.00  168.00   1.0000    2.0000
omega____ theta____ kappa____ phi______ frames
    -       93.5000  125.0000  120.0000 95

 93 omega   15.00  127.00   1.0000    2.0000
omega____ theta____ kappa____ phi______ frames
    -       93.5000  -77.0000   30.0000 112

 94 omega    9.00   83.00   1.0000    2.0000
omega____ theta____ kappa____ phi______ frames
    -       93.5000  -94.0000  -66.0000 74
;
_diffrn_measurement_device_type  'Xcalibur, Atlas, Gemini ultra'
_diffrn_measurement_method       '\w scans'
_diffrn_orient_matrix_UB_11      -0.0107948000
_diffrn_orient_matrix_UB_12      -0.0045026000
_diffrn_orient_matrix_UB_13      -0.1192181000
_diffrn_orient_matrix_UB_21      0.0351596000
_diffrn_orient_matrix_UB_22      0.1461781000
_diffrn_orient_matrix_UB_23      0.0215802000
_diffrn_orient_matrix_UB_31      0.1705667000
_diffrn_orient_matrix_UB_32      0.0369184000
_diffrn_orient_matrix_UB_33      0.0480764000
_diffrn_radiation_monochromator  mirror
_diffrn_radiation_type           CuK\a
_diffrn_radiation_wavelength     1.54184
_diffrn_reflns_av_R_equivalents  0.0618
_diffrn_reflns_av_unetI/netI     0.0222
_diffrn_reflns_Laue_measured_fraction_full 0.987
_diffrn_reflns_Laue_measured_fraction_max 0.987
_diffrn_reflns_limit_h_max       12
_diffrn_reflns_limit_h_min       -12
_diffrn_reflns_limit_k_max       13
_diffrn_reflns_limit_k_min       -13
_diffrn_reflns_limit_l_max       15
_diffrn_reflns_limit_l_min       -15
_diffrn_reflns_number            45204
_diffrn_reflns_point_group_measured_fraction_full 0.987
_diffrn_reflns_point_group_measured_fraction_max 0.987
_diffrn_reflns_theta_full        66.977
_diffrn_reflns_theta_max         66.977
_diffrn_reflns_theta_min         3.740
_diffrn_source                   'Enhance Ultra (Cu) X-ray Source'
_exptl_absorpt_coefficient_mu    0.788
_exptl_absorpt_correction_T_max  1.00000
_exptl_absorpt_correction_T_min  0.61355
_exptl_absorpt_correction_type   multi-scan
_exptl_absorpt_process_details
;
CrysAlisPro, Agilent Technologies,
Version 1.171.35.11 (release 16-05-2011 CrysAlis171 .NET)
(compiled May 16 2011,17:55:39)
Empirical absorption correction using spherical harmonics,
 implemented in SCALE3 ABSPACK scaling algorithm.
;
_exptl_crystal_colour            yellow
_exptl_crystal_colour_primary    yellow
_exptl_crystal_density_diffrn    1.381
_exptl_crystal_description       block
_exptl_crystal_F_000             580
_exptl_crystal_size_max          0.48
_exptl_crystal_size_mid          0.46
_exptl_crystal_size_min          0.4
_refine_diff_density_max         0.278
_refine_diff_density_min         -0.438
_refine_diff_density_rms         0.059
_refine_ls_extinction_method     none
_refine_ls_goodness_of_fit_ref   1.034
_refine_ls_hydrogen_treatment    constr
_refine_ls_matrix_type           full
_refine_ls_number_parameters     380
_refine_ls_number_reflns         4692
_refine_ls_number_restraints     0
_refine_ls_restrained_S_all      1.034
_refine_ls_R_factor_all          0.0550
_refine_ls_R_factor_gt           0.0493
_refine_ls_shift/su_max          0.001
_refine_ls_shift/su_mean         0.000
_refine_ls_structure_factor_coef Fsqd
_refine_ls_weighting_details
'w=1/[\s^2^(Fo^2^)+(0.0765P)^2^+0.7536P] where P=(Fo^2^+2Fc^2^)/3'
_refine_ls_weighting_scheme      calc
_refine_ls_wR_factor_gt          0.1312
_refine_ls_wR_factor_ref         0.1381
_reflns_Friedel_coverage         0.000
_reflns_number_gt                4151
_reflns_number_total             4692
_reflns_threshold_expression     'I > 2\s(I)'
_cod_data_source_file            jm0c01271_si_004.cif
_cod_data_source_block           170907_a61_34g
_cod_original_cell_volume        1333.67(8)
_cod_original_formula_sum        'C32 H26 N4 O5.50'
_cod_database_code               1559411
_shelx_shelxl_version_number     2016/6
_chemical_oxdiff_formula         'c h n o'
_shelx_estimated_absorpt_t_max   0.743
_shelx_estimated_absorpt_t_min   0.703
_reflns_odcompleteness_completeness 99.80
_reflns_odcompleteness_iscentric 1
_reflns_odcompleteness_theta     64.99
_olex2_refinement_description
;
1. Fixed Uiso
 At 1.2 times of:
  All C(H) groups, All C(H,H) groups, All N(H) groups, All N(H,H) groups
 At 1.5 times of:
  All C(H,H,H) groups, All O(H) groups
2.a Secondary CH2 refined with riding coordinates:
 C1(H1A,H1B)
2.b Aromatic/amide H refined with riding coordinates:
 N1(H1), N3(H3), C11(H11), C12(H12), C13(H13), C14(H14), C17(H17), C18(H18),
 C19(H19), C20(H20), C23(H23), C25(H25), C28(H28), C29(H29)
2.c X=CH2 refined with riding coordinates:
 N4(H4A,H4B)
2.d Idealised Me refined as rotating group:
 C30(H30A,H30B,H30C), C31(H31A,H31B,H31C)
2.e Idealised tetrahedral OH refined as rotating group:
 O4(H4), O5(H5)
;
_shelx_res_checksum              5195
_shelx_hkl_checksum              74675
_olex2_submission_special_instructions 'No special instructions were received'