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_1559413
_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 unk
_chemical_formula_moiety         'C28 H24 N4 O5, C H4 O'
_chemical_formula_sum            'C29 H28 N4 O6'
_chemical_formula_weight         528.55
_space_group_crystal_system      monoclinic
_space_group_IT_number           4
_space_group_name_Hall           'P 2yb'
_space_group_name_H-M_alt        'P 1 21 1'
_atom_sites_solution_hydrogens   geom
_atom_sites_solution_primary     direct
_audit_creation_date             2017-07-11
_audit_creation_method
;
Olex2 1.2
(compiled 2017.03.28 svn.r3405 for OlexSys, GUI svn.r5337)
;
_cell_angle_alpha                90
_cell_angle_beta                 98.481(3)
_cell_angle_gamma                90
_cell_formula_units_Z            4
_cell_length_a                   15.4258(5)
_cell_length_b                   8.2007(2)
_cell_length_c                   20.1539(6)
_cell_measurement_reflns_used    8999
_cell_measurement_temperature    170(2)
_cell_measurement_theta_max      66.8193
_cell_measurement_theta_min      2.8939
_cell_volume                     2521.64(13)
_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      170.0
_diffrn_detector_area_resol_mean 10.3592
_diffrn_measured_fraction_theta_full 0.990
_diffrn_measured_fraction_theta_max 0.990
_diffrn_measurement_details
;
  1 omega  -44.00  -17.00   1.0000    1.5000
omega____ theta____ kappa____ phi______ frames
    -      -41.6938  -77.0000    0.0000 27

  2 omega   -2.00   87.00   1.0000    1.5000
omega____ theta____ kappa____ phi______ frames
    -       41.6938 -125.0000  150.0000 89

  3 omega   15.00   59.00   1.0000    1.5000
omega____ theta____ kappa____ phi______ frames
    -       41.6938  -77.0000 -180.0000 44

  4 omega   11.00  116.00   1.0000    1.5000
omega____ theta____ kappa____ phi______ frames
    -       41.6938   77.0000    0.0000 105

  5 omega   38.00   94.00   1.0000    1.5000
omega____ theta____ kappa____ phi______ frames
    -       41.6938   38.0000  -60.0000 56

  6 omega  -79.00  -53.00   1.0000    3.0000
omega____ theta____ kappa____ phi______ frames
    -      -83.0000  -61.0000  -16.0000 26

  7 omega  -77.00  -50.00   1.0000    3.0000
omega____ theta____ kappa____ phi______ frames
    -      -83.0000  -77.0000  -60.0000 27

  8 omega  -75.00  -49.00   1.0000    3.0000
omega____ theta____ kappa____ phi______ frames
    -      -83.0000  -78.0000  -50.0000 26

  9 omega  -74.00  -49.00   1.0000    3.0000
omega____ theta____ kappa____ phi______ frames
    -      -83.0000  -77.0000   30.0000 25

 10 omega  -76.00  -50.00   1.0000    3.0000
omega____ theta____ kappa____ phi______ frames
    -      -83.0000  -77.0000  -12.0000 26

 11 omega  -75.00  -49.00   1.0000    3.0000
omega____ theta____ kappa____ phi______ frames
    -      -83.0000  -77.0000  -30.0000 26

 12 omega   97.00  149.00   1.0000    3.0000
omega____ theta____ kappa____ phi______ frames
    -       93.5000  125.0000  120.0000 52

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

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

 15 omega   68.00  162.00   1.0000    3.0000
omega____ theta____ kappa____ phi______ frames
    -       93.5000   77.0000  -90.0000 94

 16 omega   61.00  161.00   1.0000    3.0000
omega____ theta____ kappa____ phi______ frames
    -       93.5000   77.0000  -30.0000 100

 17 omega   95.00  145.00   1.0000    3.0000
omega____ theta____ kappa____ phi______ frames
    -       93.5000  125.0000   90.0000 50

 18 omega   33.00   78.00   1.0000    3.0000
omega____ theta____ kappa____ phi______ frames
    -       93.5000  -77.0000 -150.0000 45

 19 omega   16.00  127.00   1.0000    3.0000
omega____ theta____ kappa____ phi______ frames
    -       93.5000  -77.0000  -60.0000 111

 20 omega   62.00  169.00   1.0000    3.0000
omega____ theta____ kappa____ phi______ frames
    -       93.5000   77.0000  -60.0000 107

 21 omega   94.00  165.00   1.0000    3.0000
omega____ theta____ kappa____ phi______ frames
    -       93.5000   45.0000   90.0000 71

 22 omega   92.00  172.00   1.0000    3.0000
omega____ theta____ kappa____ phi______ frames
    -       93.5000   77.0000    0.0000 80
;
_diffrn_measurement_device_type  'Xcalibur, Atlas, Gemini ultra'
_diffrn_measurement_method       '\w scans'
_diffrn_orient_matrix_UB_11      0.0560460000
_diffrn_orient_matrix_UB_12      0.0555622000
_diffrn_orient_matrix_UB_13      0.0657472000
_diffrn_orient_matrix_UB_21      0.0837318000
_diffrn_orient_matrix_UB_22      -0.0230102000
_diffrn_orient_matrix_UB_23      -0.0322345000
_diffrn_orient_matrix_UB_31      -0.0067281000
_diffrn_orient_matrix_UB_32      0.1780107000
_diffrn_orient_matrix_UB_33      -0.0246585000
_diffrn_radiation_monochromator  mirror
_diffrn_radiation_type           CuK\a
_diffrn_radiation_wavelength     1.54184
_diffrn_reflns_av_R_equivalents  0.0653
_diffrn_reflns_av_unetI/netI     0.0518
_diffrn_reflns_Laue_measured_fraction_full 0.990
_diffrn_reflns_Laue_measured_fraction_max 0.990
_diffrn_reflns_limit_h_max       16
_diffrn_reflns_limit_h_min       -18
_diffrn_reflns_limit_k_max       9
_diffrn_reflns_limit_k_min       -9
_diffrn_reflns_limit_l_max       23
_diffrn_reflns_limit_l_min       -23
_diffrn_reflns_number            21408
_diffrn_reflns_point_group_measured_fraction_full 0.970
_diffrn_reflns_point_group_measured_fraction_max 0.970
_diffrn_reflns_theta_full        66.931
_diffrn_reflns_theta_max         66.931
_diffrn_reflns_theta_min         2.896
_diffrn_source                   'Enhance Ultra (Cu) X-ray Source'
_exptl_absorpt_coefficient_mu    0.816
_exptl_absorpt_correction_T_max  1.00000
_exptl_absorpt_correction_T_min  0.46191
_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    1.392
_exptl_crystal_description       plate
_exptl_crystal_F_000             1112
_exptl_crystal_size_max          0.48
_exptl_crystal_size_mid          0.36
_exptl_crystal_size_min          0.3
_refine_diff_density_max         0.306
_refine_diff_density_min         -0.279
_refine_diff_density_rms         0.050
_refine_ls_abs_structure_details
;
 Flack x determined using 2946 quotients [(I+)-(I-)]/[(I+)+(I-)]
 (Parsons, Flack and Wagner, Acta Cryst. B69 (2013) 249-259).
;
_refine_ls_abs_structure_Flack   0.22(17)
_refine_ls_extinction_method     none
_refine_ls_goodness_of_fit_ref   1.046
_refine_ls_hydrogen_treatment    constr
_refine_ls_matrix_type           full
_refine_ls_number_parameters     713
_refine_ls_number_reflns         8694
_refine_ls_number_restraints     1
_refine_ls_restrained_S_all      1.046
_refine_ls_R_factor_all          0.0591
_refine_ls_R_factor_gt           0.0502
_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^)+(0.0732P)^2^+0.2512P] where P=(Fo^2^+2Fc^2^)/3'
_refine_ls_weighting_scheme      calc
_refine_ls_wR_factor_gt          0.1234
_refine_ls_wR_factor_ref         0.1335
_reflns_Friedel_coverage         0.820
_reflns_Friedel_fraction_full    0.947
_reflns_Friedel_fraction_max     0.947
_reflns_number_gt                7560
_reflns_number_total             8694
_reflns_threshold_expression     'I > 2\s(I)'
_cod_data_source_file            jm0c01271_si_008.cif
_cod_data_source_block           170710_wjh_22d_cu
_cod_original_cell_volume        2521.63(12)
_cod_database_code               1559413
_shelx_shelxl_version_number     2016/6
_chemical_oxdiff_formula         'c h n o'
_shelx_estimated_absorpt_t_max   0.792
_shelx_estimated_absorpt_t_min   0.696
_reflns_odcompleteness_completeness 99.98
_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
 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), C49(H49)
2.b Secondary CH2 refined with riding coordinates:
 C2(H2A,H2B), C23(H23A,H23B), C30(H30A,H30B), C51(H51A,H51B)
2.c Aromatic/amide H refined with riding coordinates:
 N1(H1), N4(H4), C11(H11), C12(H12), C13(H13), C14(H14), C17(H17), C18(H18),
 C19(H19), C20(H20), N5(H5), N8(H8), C39(H39), C40(H40), C41(H41), C42(H42),
 C45(H45), C46(H46), C47(H47), C48(H48)
2.d Idealised Me refined as rotating group:
 C25(H25A,H25B,H25C), C26(H26A,H26B,H26C), C28(H28A,H28B,H28C), C53(H53A,H53B,
 H53C), C54(H54A,H54B,H54C), C56(H56A,H56B,H56C), C57(H57A,H57B,H57C), C58(H58A,
 H58B,H58C)
2.e Idealised tetrahedral OH refined as rotating group:
 O11(H11A), O12(H12A)
;
_shelx_res_checksum              31059
_shelx_hkl_checksum              39697
_olex2_submission_special_instructions 'No special instructions were received'