Identification of Betulinic Acid Derivatives as Potent TGR5 Agonists with Antidiabetic Effects via Humanized TGR5<sup>H88Y</sup> Mutant Mice.
Yun, Ying; Zhang, Chenlu; Guo, Shimeng; Liang, Xiaoying; Lan, Yuan; Wang, Min; Zhuo, Ning; Yin, Jianpeng; Liu, Huanan; Gu, Min; Li, Jing; Xie, Xin; Nan, Fajun; Journal of medicinal chemistry 64 (2021) 12181–12199; doi:10.1021/acs.jmedchem.1c00851

data_1564530
_publ_section_title
;
 Identification of Betulinic Acid Derivatives as Potent TGR5 Agonists with
 Antidiabetic Effects via Humanized TGR5<sup>H88Y</sup> Mutant Mice.
;
_journal_issue                   16
_journal_name_full               'Journal of medicinal chemistry'
_journal_page_first              12181
_journal_page_last               12199
_journal_paper_doi               10.1021/acs.jmedchem.1c00851
_journal_volume                  64
_journal_year                    2021
_chemical_absolute_configuration rmad
_chemical_formula_moiety         'C40 H59 N O5'
_chemical_formula_sum            'C40 H59 N O5'
_chemical_formula_weight         633.88
_space_group_crystal_system      tetragonal
_space_group_IT_number           96
_space_group_name_Hall           'P 4nw 2abw'
_space_group_name_H-M_alt        'P 43 21 2'
_atom_sites_solution_hydrogens   geom
_atom_sites_solution_primary     dual
_audit_creation_date             2019-07-10
_audit_creation_method
;
Olex2 1.2
(compiled 2018.05.29 svn.r3508 for OlexSys, GUI svn.r5506)
;
_cell_angle_alpha                90
_cell_angle_beta                 90
_cell_angle_gamma                90
_cell_formula_units_Z            8
_cell_length_a                   23.7717(8)
_cell_length_b                   23.7717(8)
_cell_length_c                   14.8492(6)
_cell_measurement_reflns_used    9672
_cell_measurement_temperature    298
_cell_measurement_theta_max      72.239
_cell_measurement_theta_min      3.510
_cell_volume                     8391.2(5)
_computing_cell_refinement       'SAINT V8.38A (?, 2016)'
_computing_data_reduction        'SAINT V8.38A (?, 2016)'
_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_temperature      298.0
_diffrn_measured_fraction_theta_full 0.996
_diffrn_measured_fraction_theta_max 0.991
_diffrn_measurement_device_type  'Bruker APEX-II CCD'
_diffrn_measurement_method       '\f and \w scans'
_diffrn_radiation_type           CuK\a
_diffrn_radiation_wavelength     1.54178
_diffrn_reflns_av_R_equivalents  0.0500
_diffrn_reflns_av_unetI/netI     0.0330
_diffrn_reflns_Laue_measured_fraction_full 0.996
_diffrn_reflns_Laue_measured_fraction_max 0.991
_diffrn_reflns_limit_h_max       23
_diffrn_reflns_limit_h_min       -28
_diffrn_reflns_limit_k_max       29
_diffrn_reflns_limit_k_min       -27
_diffrn_reflns_limit_l_max       18
_diffrn_reflns_limit_l_min       -18
_diffrn_reflns_number            46355
_diffrn_reflns_point_group_measured_fraction_full 0.997
_diffrn_reflns_point_group_measured_fraction_max 0.992
_diffrn_reflns_theta_full        67.679
_diffrn_reflns_theta_max         72.780
_diffrn_reflns_theta_min         3.509
_diffrn_standards_number         0
_exptl_absorpt_coefficient_mu    0.508
_exptl_absorpt_correction_T_max  0.7536
_exptl_absorpt_correction_T_min  0.6660
_exptl_absorpt_correction_type   multi-scan
_exptl_absorpt_process_details
'SADABS-2016/2 (Bruker,2016/2) was used for absorption correction. wR2(int) was 0.1292 before and 0.0876 after correction. The Ratio of minimum to maximum transmission is 0.8838. The \l/2 correction factor is Not present.'
_exptl_crystal_colour            colourless
_exptl_crystal_colour_primary    colourless
_exptl_crystal_density_diffrn    1.004
_exptl_crystal_description       plate
_exptl_crystal_F_000             2768
_exptl_crystal_size_max          0.19
_exptl_crystal_size_mid          0.15
_exptl_crystal_size_min          0.12
_platon_squeeze_details
;
TITL zz_a.res in P4(3)2(1)2
CELL   23.7717   23.7717   14.8492     90.00     90.00     90.00
SPGR P43212
C101 0.047 0.897 0.608 !       0.97 eA-3
C102 0.017 0.913 0.609 !       0.92 eA-3
C103 0.432 0.423 0.507 !       0.87 eA-3
C104 0.043 0.916 0.196 !       0.74 eA-3
C105 0.571 0.495 0.296 !       0.63 eA-3
C106 0.942 0.052 0.673 !       0.55 eA-3
;
_refine_diff_density_max         0.156
_refine_diff_density_min         -0.142
_refine_diff_density_rms         0.028
_refine_ls_abs_structure_details
;
 Flack x determined using 2782 quotients [(I+)-(I-)]/[(I+)+(I-)]
 (Parsons, Flack and Wagner, Acta Cryst. B69 (2013) 249-259).
;
_refine_ls_abs_structure_Flack   0.03(8)
_refine_ls_extinction_method     none
_refine_ls_goodness_of_fit_ref   1.068
_refine_ls_hydrogen_treatment    constr
_refine_ls_matrix_type           full
_refine_ls_number_parameters     422
_refine_ls_number_reflns         8310
_refine_ls_number_restraints     30
_refine_ls_restrained_S_all      1.130
_refine_ls_R_factor_all          0.0487
_refine_ls_R_factor_gt           0.0435
_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^)+(0.0948P)^2^] where P=(Fo^2^+2Fc^2^)/3'
_refine_ls_weighting_scheme      calc
_refine_ls_wR_factor_gt          0.1332
_refine_ls_wR_factor_ref         0.1384
_reflns_Friedel_coverage         0.780
_reflns_Friedel_fraction_full    0.998
_reflns_Friedel_fraction_max     0.992
_reflns_number_gt                7117
_reflns_number_total             8310
_reflns_threshold_expression     'I > 2\s(I)'
_cod_data_source_file            jm1c00851_si_003.cif
_cod_data_source_block           zz_sq
_cod_original_cell_volume        8391.2(7)
_cod_database_code               1564530
_shelx_shelxl_version_number     2018/3
_shelx_estimated_absorpt_t_max   0.942
_shelx_estimated_absorpt_t_min   0.910
_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. Uiso/Uaniso restraints and constraints
Uanis(C39) \\sim Ueq, Uanis(C38) \\sim Ueq, Uanis(C40) \\sim Ueq, Uanis(C35)
\\sim Ueq, Uanis(C37) \\sim Ueq: with sigma of 0.005 and sigma for terminal
atoms of 0.01
3.a Ternary CH refined with riding coordinates:
 C3(H3), C5(H5A), C9(H9), C13(H13), C18(H18), C19(H19), C20(H20), C31(H31)
3.b Secondary CH2 refined with riding coordinates:
 C1(H1A,H1B), C2(H2A,H2B), C6(H6A,H6B), C7(H7A,H7B), C11(H11A,H11B), C12(H12A,
 H12B), C15(H15A,H15B), C16(H16A,H16B), C21(H21A,H21B), C22(H22A,H22B),
 C32(H32A,H32B), C33(H33A,H33B), C34(H34A,H34B)
3.c Aromatic/amide H refined with riding coordinates:
 N1(H1), C36(H36), C37(H37), C38(H38), C39(H39), C40(H40)
3.d Idealised Me refined as rotating group:
 C23(H23A,H23B,H23C), C24(H24A,H24B,H24C), C25(H25A,H25B,H25C), C26(H26A,H26B,
 H26C), C27(H27A,H27B,H27C), C29(H29A,H29B,H29C)
3.e Idealised tetrahedral OH refined as rotating group:
 O5(H5)
;
_platon_squeeze_void_probe_radius 1.20
_olex2_submission_special_instructions 'No special instructions were received'