Structure-Activity Relationship Study Enables the Discovery of a Novel Berberine Analogue as RXRα Activator to Inhibit Colon Cancer.
Xu, Beibei; Jiang, Xunjin; Xiong, Jing; Lan, Jun; Tian, Yuan; Zhong, Linhai; Wang, Xinquan; Xu, Ning; Cao, Hanwei; Zhang, Wenqing; Zhang, Hao; Hong, Xiaoting; Zhan, Yan-Yan; Zhang, Yandong; Hu, Tianhui; Journal of medicinal chemistry  (2020) –; doi:10.1021/acs.jmedchem.0c00088

data_1558132
_publ_section_title
;
 Structure-Activity Relationship Study Enables the Discovery of a Novel
 Berberine Analogue as RXR\a Activator to Inhibit Colon Cancer.
;
_journal_name_full               'Journal of medicinal chemistry'
_journal_paper_doi               10.1021/acs.jmedchem.0c00088
_journal_year                    2020
_chemical_formula_moiety         'Cl, C19 H18 N O2, H2 O, C H4 O'
_chemical_formula_sum            'C20 H24 Cl N O4'
_chemical_formula_weight         377.85
_space_group_crystal_system      monoclinic
_space_group_IT_number           14
_space_group_name_Hall           '-P 2yn'
_space_group_name_H-M_alt        'P 1 21/n 1'
_atom_sites_solution_hydrogens   mixed
_audit_creation_date             2019-06-10
_audit_creation_method
;
Olex2 1.2
(compiled 2018.05.29 svn.r3508 for OlexSys, GUI svn.r5506)
;
_cell_angle_alpha                90
_cell_angle_beta                 113.649(3)
_cell_angle_gamma                90
_cell_formula_units_Z            8
_cell_length_a                   22.7581(6)
_cell_length_b                   7.6989(2)
_cell_length_c                   23.0256(6)
_cell_measurement_reflns_used    15136
_cell_measurement_temperature    100.00(10)
_cell_measurement_theta_max      77.2760
_cell_measurement_theta_min      4.1610
_cell_volume                     3695.56(19)
_computing_cell_refinement       'CrysAlisPro 1.171.39.46 (Rigaku OD, 2018)'
_computing_data_collection       'CrysAlisPro 1.171.39.46 (Rigaku OD, 2018)'
_computing_data_reduction        'CrysAlisPro 1.171.39.46 (Rigaku OD, 2018)'
_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_type            HyPix
_diffrn_measured_fraction_theta_full 0.999
_diffrn_measured_fraction_theta_max 0.999
_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     51.00 122.00   0.50    0.40    --   46.81  29.00-103.00  142
  2  \w     95.00 173.00   0.50    2.00    --  109.48  29.00-103.00  156
  3  \w    120.00 178.00   0.50    2.00    --  109.48  37.00 -90.00  116
  4  \w     98.00 133.00   0.50    2.00    --  109.48 -77.00  90.00   70
  5  \w     82.00 125.00   0.50    2.00    --  109.48 -57.00 -30.00   86
  6  \w     51.00 109.00   0.50    2.00    --  109.48 -99.00-120.00  116
  7  \w     32.00  63.00   0.50    0.40    --   46.81-125.00 -30.00   62
  8  \w     39.00 118.00   0.50    2.00    --  109.48 -29.00  95.00  158
  9  \w     38.00 107.00   0.50    2.00    --  109.48 -99.00 150.00  138
 10  \w     38.00 116.00   0.50    2.00    --  109.48-125.00  90.00  156
 11  \w     39.00  65.00   0.50    2.00    --  109.48 -77.00  90.00   52
 12  \w     39.00  92.00   0.50    2.00    --  109.48 -99.00 120.00  106
 13  \w     -8.00  17.00   0.50    0.40    --   46.81 -29.00  95.00   50
 14  \w    -58.00  28.00   0.50    0.40    --  -46.81  29.00-103.00  172
 15  \w    -83.00 -57.00   0.50    2.00    --  -88.50  29.00-103.00   52
 16  \w   -100.00 -32.00   0.50    0.40    --  -46.81 -19.00 -30.00  136
 17  \w   -104.00 -76.00   0.50    0.40    --  -46.81-125.00  30.00   56
 18  \w   -121.00 -37.00   0.50    0.40    --  -46.81 -29.00  95.00  168
 19  \w   -118.00 -81.00   0.50    2.00    --  -88.50 -29.00  95.00   74
 20  \w    -80.00 -55.00   0.50    2.00    --  -88.50 125.00 -90.00   50
;
_diffrn_measurement_device       'four-circle diffractometer'
_diffrn_measurement_device_type  'XtaLAB Synergy, Dualflex, HyPix'
_diffrn_measurement_method       '\w scans'
_diffrn_orient_matrix_type
'CrysAlisPro convention (1999,Acta A55,543-557)'
_diffrn_orient_matrix_UB_11      -0.0617422000
_diffrn_orient_matrix_UB_12      -0.0762003000
_diffrn_orient_matrix_UB_13      0.0020571000
_diffrn_orient_matrix_UB_21      -0.0323972000
_diffrn_orient_matrix_UB_22      0.0059530000
_diffrn_orient_matrix_UB_23      -0.0729252000
_diffrn_orient_matrix_UB_31      0.0243638000
_diffrn_orient_matrix_UB_32      -0.1849831000
_diffrn_orient_matrix_UB_33      -0.0031934000
_diffrn_radiation_monochromator  mirror
_diffrn_radiation_probe          x-ray
_diffrn_radiation_type           CuK\a
_diffrn_radiation_wavelength     1.54184
_diffrn_reflns_av_R_equivalents  0.0413
_diffrn_reflns_av_unetI/netI     0.0352
_diffrn_reflns_Laue_measured_fraction_full 0.999
_diffrn_reflns_Laue_measured_fraction_max 0.999
_diffrn_reflns_limit_h_max       26
_diffrn_reflns_limit_h_min       -22
_diffrn_reflns_limit_k_max       5
_diffrn_reflns_limit_k_min       -9
_diffrn_reflns_limit_l_max       27
_diffrn_reflns_limit_l_min       -27
_diffrn_reflns_number            24024
_diffrn_reflns_point_group_measured_fraction_full 0.999
_diffrn_reflns_point_group_measured_fraction_max 0.999
_diffrn_reflns_theta_full        64.983
_diffrn_reflns_theta_max         64.983
_diffrn_reflns_theta_min         2.306
_diffrn_source                   'micro-focus sealed X-ray tube'
_diffrn_source_type              'PhotonJet (Cu) X-ray Source'
_exptl_absorpt_coefficient_mu    2.044
_exptl_absorpt_correction_T_max  1.00000
_exptl_absorpt_correction_T_min  0.73949
_exptl_absorpt_correction_type   multi-scan
_exptl_absorpt_process_details
;
CrysAlisPro 1.171.39.46 (Rigaku Oxford Diffraction, 2018)
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    1.358
_exptl_crystal_description       block
_exptl_crystal_F_000             1600
_exptl_crystal_size_max          0.05
_exptl_crystal_size_mid          0.05
_exptl_crystal_size_min          0.05
_refine_diff_density_max         2.035
_refine_diff_density_min         -1.139
_refine_diff_density_rms         0.153
_refine_ls_extinction_method     none
_refine_ls_goodness_of_fit_ref   1.098
_refine_ls_hydrogen_treatment    constr
_refine_ls_matrix_type           full
_refine_ls_number_parameters     483
_refine_ls_number_reflns         6266
_refine_ls_number_restraints     48
_refine_ls_restrained_S_all      1.102
_refine_ls_R_factor_all          0.1345
_refine_ls_R_factor_gt           0.1301
_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^)+(0.1054P)^2^+57.9538P] where P=(Fo^2^+2Fc^2^)/3'
_refine_ls_weighting_scheme      calc
_refine_ls_wR_factor_gt          0.3442
_refine_ls_wR_factor_ref         0.3462
_reflns_Friedel_coverage         0.000
_reflns_number_gt                5750
_reflns_number_total             6266
_reflns_threshold_expression     'I > 2\s(I)'
_cod_data_source_file            jm0c00088_si_003.cif
_cod_data_source_block           exp_4880
_cod_original_cell_volume        3695.56(18)
_cod_database_code               1558132
_shelx_shelxl_version_number     2014/7
_shelx_estimated_absorpt_t_max   0.905
_shelx_estimated_absorpt_t_min   0.905
_reflns_odcompleteness_completeness 99.96
_reflns_odcompleteness_iscentric 1
_reflns_odcompleteness_theta     66.49
_olex2_refinement_description
;
1. Fixed Uiso
 At 1.2 times of:
  All C(H) groups, All C(H,H) groups
 At 1.5 times of:
  All C(H,H,H) groups, All O(H) groups, All O(H,H) groups
2. Uiso/Uaniso restraints and constraints
C01F \\sim C01G \\sim C00V \\sim C00D \\sim C00H \\sim N00A: within 2A with
sigma of 0.005 and sigma for terminal atoms of 0.01
Uanis(C01F) \\sim Ueq, Uanis(C01G) \\sim Ueq: with sigma of 0.05 and sigma for
terminal atoms of 0.1
3.a Free rotating group:
 O1(H1D,H1E), O4(H4A,H4B)
3.b Secondary CH2 refined with riding coordinates:
 C01D(H01Q,H01R), C01E(H01S,H01T), C01F(H01G,H01H), C01G(H01I,H01J)
3.c Aromatic/amide H refined with riding coordinates:
 C00O(H00O), C00Q(H00Q), C00R(H00R), C00S(H00S), C00U(H00U), C00W(H00W),
 C00X(H00X), C00Y(H00Y), C00Z(H00Z), C010(H010), C011(H011), C012(H012),
 C014(H014), C015(H015), C016(H016), C018(H018)
3.d Idealised Me refined as rotating group:
 C013(H01A,H01B,H01C), C017(H01K,H01L,H01M), C019(H01N,H01O,H01P), C01C(H01D,
 H01E,H01F), C1(H1A,H1B,H1C), C0AA(H0AA,H0AB,H0AC)
3.e Idealised tetrahedral OH refined as rotating group:
 O2(H2), O3(H3)
;
_shelx_res_checksum              60256
_shelx_hkl_checksum              33726
_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
;
_oxdiff_exptl_absorpt_empirical_full_max 1.275
_oxdiff_exptl_absorpt_empirical_full_min 0.738