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_1559410
_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 rmad
_chemical_formula_moiety         'C28 H25 N3 O6, H2 O'
_chemical_formula_sum            'C28 H27 N3 O7'
_chemical_formula_weight         517.52
_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   mixed
_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                90
_cell_angle_beta                 90
_cell_angle_gamma                90
_cell_formula_units_Z            4
_cell_length_a                   7.22366(16)
_cell_length_b                   16.5577(4)
_cell_length_c                   20.6478(5)
_cell_measurement_reflns_used    16141
_cell_measurement_temperature    180.9
_cell_measurement_theta_max      66.9083
_cell_measurement_theta_min      3.4187
_cell_volume                     2469.63(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      180.9
_diffrn_detector_area_resol_mean 10.3592
_diffrn_measured_fraction_theta_full 0.998
_diffrn_measured_fraction_theta_max 0.997
_diffrn_measurement_details
;
  1 omega  -49.00  -23.00   1.0000    1.5000
omega____ theta____ kappa____ phi______ frames
    -      -41.6938  -77.0000   30.0000 26

  2 omega  -97.00  -18.00   1.0000    1.5000
omega____ theta____ kappa____ phi______ frames
    -      -41.6938  125.0000  -30.0000 79

  3 omega -116.00  -90.00   1.0000    1.5000
omega____ theta____ kappa____ phi______ frames
    -      -41.6938  -77.0000   90.0000 26

  4 omega  -34.00   -8.00   1.0000    1.5000
omega____ theta____ kappa____ phi______ frames
    -      -41.6938  -77.0000   90.0000 26

  5 omega  -47.00   -9.00   1.0000    1.5000
omega____ theta____ kappa____ phi______ frames
    -      -41.6938  -77.0000  -60.0000 38

  6 omega   13.00  120.00   1.0000    1.5000
omega____ theta____ kappa____ phi______ frames
    -       41.6938   77.0000 -180.0000 107

  7 omega    9.00  117.00   1.0000    1.5000
omega____ theta____ kappa____ phi______ frames
    -       41.6938   77.0000  -90.0000 108

  8 omega   15.00   84.00   1.0000    1.5000
omega____ theta____ kappa____ phi______ frames
    -       41.6938   38.0000   30.0000 69

  9 omega    8.00  119.00   1.0000    1.5000
omega____ theta____ kappa____ phi______ frames
    -       41.6938   77.0000   90.0000 111

 10 omega    0.00   92.00   1.0000    1.5000
omega____ theta____ kappa____ phi______ frames
    -       41.6938 -125.0000 -150.0000 92

 11 omega  -74.00  -49.00   1.0000    3.0000
omega____ theta____ kappa____ phi______ frames
    -      -83.0000  -77.0000 -120.0000 25

 12 omega  -76.00  -50.00   1.0000    3.0000
omega____ theta____ kappa____ phi______ frames
    -      -83.0000  -76.0000   38.0000 26

 13 omega  -76.00  -50.00   1.0000    3.0000
omega____ theta____ kappa____ phi______ frames
    -      -83.0000  -72.0000    6.0000 26

 14 omega  -75.00  -49.00   1.0000    3.0000
omega____ theta____ kappa____ phi______ frames
    -      -83.0000  -77.0000   90.0000 26

 15 omega  -77.00  -51.00   1.0000    3.0000
omega____ theta____ kappa____ phi______ frames
    -      -83.0000  -69.0000   58.0000 26

 16 omega  -76.00  -50.00   1.0000    3.0000
omega____ theta____ kappa____ phi______ frames
    -      -83.0000  -76.0000 -161.0000 26

 17 omega  -76.00  -50.00   1.0000    3.0000
omega____ theta____ kappa____ phi______ frames
    -      -83.0000  -74.0000  109.0000 26

 18 omega -121.00  -95.00   1.0000    3.0000
omega____ theta____ kappa____ phi______ frames
    -      -83.0000  125.0000 -180.0000 26

 19 omega  -76.00  -50.00   1.0000    3.0000
omega____ theta____ kappa____ phi______ frames
    -      -83.0000  -74.0000  167.0000 26

 20 omega  -75.00  -49.00   1.0000    3.0000
omega____ theta____ kappa____ phi______ frames
    -      -83.0000  -77.0000 -150.0000 26

 21 omega  -74.00  -49.00   1.0000    3.0000
omega____ theta____ kappa____ phi______ frames
    -      -83.0000  -77.0000   60.0000 25

 22 omega  -77.00  -50.00   1.0000    3.0000
omega____ theta____ kappa____ phi______ frames
    -      -83.0000  -73.0000  -87.0000 27

 23 omega  -76.00  -49.00   1.0000    3.0000
omega____ theta____ kappa____ phi______ frames
    -      -83.0000  -77.0000  150.0000 27

 24 omega  -76.00  -50.00   1.0000    3.0000
omega____ theta____ kappa____ phi______ frames
    -      -83.0000  -72.0000  -45.0000 26

 25 omega  -77.00  -51.00   1.0000    3.0000
omega____ theta____ kappa____ phi______ frames
    -      -83.0000  -72.0000  -21.0000 26

 26 omega -139.00 -112.00   1.0000    3.0000
omega____ theta____ kappa____ phi______ frames
    -      -83.0000  -69.0000   58.0000 27

 27 omega  -75.00  -49.00   1.0000    3.0000
omega____ theta____ kappa____ phi______ frames
    -      -83.0000  -77.0000  -60.0000 26

 28 omega  -76.00  -50.00   1.0000    3.0000
omega____ theta____ kappa____ phi______ frames
    -      -83.0000  -73.0000 -103.0000 26

 29 omega   65.00  168.00   1.0000    3.0000
omega____ theta____ kappa____ phi______ frames
    -       93.5000   77.0000   30.0000 103

 30 omega   91.00  162.00   1.0000    3.0000
omega____ theta____ kappa____ phi______ frames
    -       93.5000   77.0000  -90.0000 71

 31 omega   44.00  119.00   1.0000    3.0000
omega____ theta____ kappa____ phi______ frames
    -       93.5000  -93.0000  -76.0000 75

 32 omega   62.00   88.00   1.0000    3.0000
omega____ theta____ kappa____ phi______ frames
    -       93.5000   77.0000  -90.0000 26

 33 omega   82.00  108.00   1.0000    3.0000
omega____ theta____ kappa____ phi______ frames
    -       93.5000  -86.0000  -28.0000 26

 34 omega   93.00  172.00   1.0000    3.0000
omega____ theta____ kappa____ phi______ frames
    -       93.5000   77.0000 -180.0000 79

 35 omega   62.00   90.00   1.0000    3.0000
omega____ theta____ kappa____ phi______ frames
    -       93.5000   77.0000 -180.0000 28

 36 omega   20.00   66.00   1.0000    3.0000
omega____ theta____ kappa____ phi______ frames
    -       93.5000  -86.0000  -28.0000 46

 37 omega   64.00  126.00   1.0000    3.0000
omega____ theta____ kappa____ phi______ frames
    -       93.5000  -77.0000  150.0000 62

 38 omega   90.00  172.00   1.0000    3.0000
omega____ theta____ kappa____ phi______ frames
    -       93.5000   77.0000  120.0000 82

 39 omega   22.00  116.00   1.0000    3.0000
omega____ theta____ kappa____ phi______ frames
    -       93.5000  -89.0000  144.0000 94

 40 omega   60.00   87.00   1.0000    3.0000
omega____ theta____ kappa____ phi______ frames
    -       93.5000   77.0000  120.0000 27

 41 omega   61.00  171.00   1.0000    3.0000
omega____ theta____ kappa____ phi______ frames
    -       93.5000   77.0000 -120.0000 110

 42 omega   61.00  171.00   1.0000    3.0000
omega____ theta____ kappa____ phi______ frames
    -       93.5000   77.0000  150.0000 110

 43 omega   46.00  122.00   1.0000    3.0000
omega____ theta____ kappa____ phi______ frames
    -       93.5000  -77.0000    0.0000 76

 44 omega   60.00  172.00   1.0000    3.0000
omega____ theta____ kappa____ phi______ frames
    -       93.5000   77.0000  -60.0000 112

 45 omega  121.00  169.00   1.0000    3.0000
omega____ theta____ kappa____ phi______ frames
    -       93.5000   77.0000 -150.0000 48

 46 omega   93.00  170.00   1.0000    3.0000
omega____ theta____ kappa____ phi______ frames
    -       93.5000   77.0000    0.0000 77

 47 omega   91.00  118.00   1.0000    3.0000
omega____ theta____ kappa____ phi______ frames
    -       93.5000   77.0000 -150.0000 27

 48 omega   61.00   87.00   1.0000    3.0000
omega____ theta____ kappa____ phi______ frames
    -       93.5000   77.0000    0.0000 26

 49 omega   67.00  169.00   1.0000    3.0000
omega____ theta____ kappa____ phi______ frames
    -       93.5000   77.0000   60.0000 102

 50 omega   62.00   87.00   1.0000    3.0000
omega____ theta____ kappa____ phi______ frames
    -       93.5000   77.0000 -150.0000 25

 51 omega   61.00  172.00   1.0000    3.0000
omega____ theta____ kappa____ phi______ frames
    -       93.5000   77.0000  -30.0000 111

 52 omega   60.00  145.00   1.0000    3.0000
omega____ theta____ kappa____ phi______ frames
    -       93.5000   77.0000   90.0000 85
;
_diffrn_measurement_device_type  'Xcalibur, Atlas, Gemini ultra'
_diffrn_measurement_method       '\w scans'
_diffrn_orient_matrix_UB_11      0.0478648000
_diffrn_orient_matrix_UB_12      0.0431635000
_diffrn_orient_matrix_UB_13      -0.0638682000
_diffrn_orient_matrix_UB_21      0.1544777000
_diffrn_orient_matrix_UB_22      0.0473871000
_diffrn_orient_matrix_UB_23      0.0348996000
_diffrn_orient_matrix_UB_31      0.1390898000
_diffrn_orient_matrix_UB_32      -0.0674180000
_diffrn_orient_matrix_UB_33      -0.0164186000
_diffrn_radiation_monochromator  mirror
_diffrn_radiation_type           CuK\a
_diffrn_radiation_wavelength     1.54184
_diffrn_reflns_av_R_equivalents  0.0803
_diffrn_reflns_av_unetI/netI     0.0275
_diffrn_reflns_Laue_measured_fraction_full 0.998
_diffrn_reflns_Laue_measured_fraction_max 0.997
_diffrn_reflns_limit_h_max       8
_diffrn_reflns_limit_h_min       -8
_diffrn_reflns_limit_k_max       19
_diffrn_reflns_limit_k_min       -19
_diffrn_reflns_limit_l_max       24
_diffrn_reflns_limit_l_min       -24
_diffrn_reflns_number            44471
_diffrn_reflns_point_group_measured_fraction_full 0.996
_diffrn_reflns_point_group_measured_fraction_max 0.995
_diffrn_reflns_theta_full        67.020
_diffrn_reflns_theta_max         67.020
_diffrn_reflns_theta_min         3.422
_diffrn_source                   'Enhance Ultra (Cu) X-ray Source'
_exptl_absorpt_coefficient_mu    0.839
_exptl_absorpt_correction_T_max  1.00000
_exptl_absorpt_correction_T_min  0.64558
_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            'dark green'
_exptl_crystal_colour_modifier   dark
_exptl_crystal_colour_primary    green
_exptl_crystal_density_diffrn    1.392
_exptl_crystal_description       block
_exptl_crystal_F_000             1088
_exptl_crystal_size_max          0.48
_exptl_crystal_size_mid          0.4
_exptl_crystal_size_min          0.36
_refine_diff_density_max         0.177
_refine_diff_density_min         -0.174
_refine_diff_density_rms         0.042
_refine_ls_abs_structure_details
;
 Flack x determined using 1631 quotients [(I+)-(I-)]/[(I+)+(I-)]
 (Parsons, Flack and Wagner, Acta Cryst. B69 (2013) 249-259).
;
_refine_ls_abs_structure_Flack   -0.07(11)
_refine_ls_extinction_method     none
_refine_ls_goodness_of_fit_ref   1.070
_refine_ls_hydrogen_treatment    constr
_refine_ls_matrix_type           full
_refine_ls_number_parameters     351
_refine_ls_number_reflns         4396
_refine_ls_number_restraints     0
_refine_ls_restrained_S_all      1.070
_refine_ls_R_factor_all          0.0402
_refine_ls_R_factor_gt           0.0356
_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^)+(0.0565P)^2^+0.3716P] where P=(Fo^2^+2Fc^2^)/3'
_refine_ls_weighting_scheme      calc
_refine_ls_wR_factor_gt          0.0914
_refine_ls_wR_factor_ref         0.0967
_reflns_Friedel_coverage         0.738
_reflns_Friedel_fraction_full    0.994
_reflns_Friedel_fraction_max     0.993
_reflns_number_gt                4062
_reflns_number_total             4396
_reflns_threshold_expression     'I > 2\s(I)'
_cod_data_source_file            jm0c01271_si_007.cif
_cod_data_source_block           170908_13g_20e
_cod_original_cell_volume        2469.62(10)
_cod_database_code               1559410
_shelx_shelxl_version_number     2016/6
_chemical_oxdiff_formula         'c h n o'
_shelx_estimated_absorpt_t_max   0.752
_shelx_estimated_absorpt_t_min   0.689
_reflns_odcompleteness_completeness 99.92
_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 N(H) groups
 At 1.5 times of:
  All C(H,H,H) groups, All O(H) groups, All O(H,H) groups
2.a Free rotating group:
 O7(H7A,H7B)
2.b Ternary CH refined with riding coordinates:
 C2(H2), C22(H22), C23(H23), C24(H24), C25(H25)
2.c Aromatic/amide H refined with riding coordinates:
 N1(H1), C11(H11), C12(H12), C13(H13), C14(H14), C17(H17), C18(H18), C19(H19),
 C20(H20)
2.d Idealised Me refined as rotating group:
 C26(H26A,H26B,H26C), C27(H27A,H27B,H27C), C28(H28A,H28B,H28C)
2.e Idealised tetrahedral OH refined as rotating group:
 O4(H4), O5(H5)
;
_shelx_res_checksum              81580
_shelx_hkl_checksum              20923
_olex2_submission_special_instructions 'No special instructions were received'