Synthesis and Pharmacological Evaluation of Tetrahydro-γ-carboline Derivatives as Potent Anti-inflammatory Agents Targeting Cyclic GMP–AMP Synthase
Tan, Jing; Wu, Bing; Chen, Tingting; Fan, Chen; Zhao, Jiannan; Xiong, Chaodong; Feng, Chunlan; Xiao, Ruoxuan; Ding, Chunyong; Tang, Wei; Zhang, Ao; Journal of Medicinal Chemistry  (2021) –; doi:10.1021/acs.jmedchem.1c00398

data_1562965
_publ_section_title
;
 Synthesis and Pharmacological Evaluation of Tetrahydro-\g-carboline
 Derivatives as Potent Anti-inflammatory Agents Targeting Cyclic GMP--AMP
 Synthase
;
_journal_name_full               'Journal of Medicinal Chemistry'
_journal_paper_doi               10.1021/acs.jmedchem.1c00398
_journal_year                    2021
_chemical_formula_moiety         'C20 H16 Cl2 F3 N3 O2, 1/3(C H Cl3)'
_chemical_formula_sum            'C20.33333 H16.33333 Cl3 F3 N3 O2'
_chemical_formula_weight         398.05
_space_group_crystal_system      monoclinic
_space_group_IT_number           14
_space_group_name_Hall           '-P 2ybc'
_space_group_name_H-M_alt        'P 1 21/c 1'
_atom_sites_solution_hydrogens   mixed
_atom_sites_solution_primary     dual
_audit_creation_date             2020-05-13
_audit_creation_method
;
Olex2 1.2
(compiled 2018.05.29 svn.r3508 for OlexSys, GUI svn.r5506)
;
_cell_angle_alpha                90
_cell_angle_beta                 94.217(2)
_cell_angle_gamma                90
_cell_formula_units_Z            12
_cell_length_a                   21.8663(14)
_cell_length_b                   13.1340(9)
_cell_length_c                   23.2675(16)
_cell_measurement_reflns_used    3930
_cell_measurement_temperature    170
_cell_measurement_theta_max      24.950
_cell_measurement_theta_min      2.468
_cell_volume                     6664.1(8)
_computing_cell_refinement       'SAINT V8.40A (?, 2016)'
_computing_data_reduction        'SAINT V8.40A (?, 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      170.0
_diffrn_measured_fraction_theta_full 0.980
_diffrn_measured_fraction_theta_max 0.980
_diffrn_measurement_device_type  'D8 VENTURE'
_diffrn_measurement_method       '\f and \w scans'
_diffrn_radiation_type           MoK\a
_diffrn_radiation_wavelength     0.71073
_diffrn_reflns_av_R_equivalents  0.1161
_diffrn_reflns_av_unetI/netI     0.1168
_diffrn_reflns_Laue_measured_fraction_full 0.980
_diffrn_reflns_Laue_measured_fraction_max 0.980
_diffrn_reflns_limit_h_max       26
_diffrn_reflns_limit_h_min       -26
_diffrn_reflns_limit_k_max       15
_diffrn_reflns_limit_k_min       -13
_diffrn_reflns_limit_l_max       27
_diffrn_reflns_limit_l_min       -27
_diffrn_reflns_number            44527
_diffrn_reflns_point_group_measured_fraction_full 0.980
_diffrn_reflns_point_group_measured_fraction_max 0.980
_diffrn_reflns_theta_full        25.045
_diffrn_reflns_theta_max         25.045
_diffrn_reflns_theta_min         1.927
_diffrn_standards_number         0
_exptl_absorpt_coefficient_mu    0.460
_exptl_absorpt_correction_T_max  0.7452
_exptl_absorpt_correction_T_min  0.6225
_exptl_absorpt_correction_type   multi-scan
_exptl_absorpt_process_details
'SADABS-2016/2 (Bruker,2016/2) was used for absorption correction. wR2(int) was 0.1438 before and 0.0664 after correction. The Ratio of minimum to maximum transmission is 0.8353. The \l/2 correction factor is Not present.'
_exptl_crystal_colour            colourless
_exptl_crystal_colour_primary    colourless
_exptl_crystal_density_diffrn    1.489
_exptl_crystal_description       needle
_exptl_crystal_F_000             3040
_exptl_crystal_size_max          0.12
_exptl_crystal_size_mid          0.05
_exptl_crystal_size_min          0.02
_platon_squeeze_details
;
TITL mo_22020196_0m_a.res in P2(1)/c
CELL   21.8663   13.1340   23.2675     90.00     94.22     90.00
SPGR P21/c
C101 0.998 0.857 0.024 !       8.51 eA-3
C102 0.916 0.520 0.456 !       8.06 eA-3
C103 0.029 0.438 0.484 !       4.03 eA-3
C104 0.037 0.493 0.500 !       2.62 eA-3
C105 0.907 0.490 0.503 !       2.37 eA-3
C106 0.962 0.485 0.452 !       1.80 eA-3
Q107 0.977 0.362 0.509 !       1.20 eA-3
Q108 0.961 0.568 0.459 !       1.20 eA-3
Q109 0.958 0.689 0.545 !       1.17 eA-3
Q110 0.008 0.583 0.474 !       1.13 eA-3
Q111 0.846 0.635 0.539 !       1.07 eA-3
Q112 0.471 0.891 0.751 !       1.00 eA-3
Q113 0.875 0.588 0.420 !       0.99 eA-3
C114 0.961 0.034 0.915 !       0.98 eA-3
Q115 0.983 0.192 0.126 !       0.93 eA-3
Q116 0.172 0.936 0.002 !       0.93 eA-3
Q117 0.415 0.460 0.245 !       0.85 eA-3
Q118 0.882 0.314 0.403 !       0.85 eA-3
Q119 0.701 0.711 0.671 !       0.83 eA-3
Q120 0.030 0.857 0.069 !       0.83 eA-3
Q121 0.197 0.354 0.405 !       0.82 eA-3
Q122 0.302 0.223 0.276 !       0.82 eA-3
C123 0.946 0.127 0.978 !       0.81 eA-3
Q124 0.681 0.761 0.677 !       0.79 eA-3
Q125 0.268 0.215 0.799 !       0.77 eA-3
Q126 0.329 0.615 0.840 !       0.76 eA-3
Q127 0.436 0.545 0.062 !       0.76 eA-3
Q128 0.787 0.315 0.225 !       0.76 eA-3
Q129 0.716 0.920 0.906 !       0.76 eA-3
Q130 0.468 0.283 0.007 !       0.74 eA-3
Q131 0.928 0.738 0.516 !       0.74 eA-3
Q132 0.116 0.996 0.969 !       0.74 eA-3
Q133 0.865 0.784 0.885 !       0.73 eA-3
Q134 0.606 0.781 0.279 !       0.73 eA-3
Q135 0.134 0.591 0.520 !       0.73 eA-3
Q136 0.134 0.724 0.109 !       0.71 eA-3
Q137 0.806 0.293 0.113 !       0.71 eA-3
Q138 0.318 0.151 0.296 !       0.70 eA-3
Q139 0.502 0.751 0.272 !       0.70 eA-3
Q140 0.795 1.006 0.328 !       0.70 eA-3
Q141 0.999 0.276 0.018 !       0.70 eA-3
Q142 0.790 0.317 0.293 !       0.70 eA-3
Q143 0.031 0.435 0.049 !       0.70 eA-3
Q144 0.639 0.685 0.182 !       0.70 eA-3
Q145 0.461 0.264 0.249 !       0.69 eA-3
Q146 0.267 0.575 0.635 !       0.69 eA-3
Q147 0.447 0.301 0.071 !       0.69 eA-3
Q148 0.251 0.644 0.297 !       0.69 eA-3
Q149 0.977 0.020 0.765 !       0.69 eA-3
Q150 0.849 0.764 0.623 !       0.69 eA-3
Q151 0.104 0.461 0.593 !       0.69 eA-3
Q152 0.328 0.169 0.246 !       0.68 eA-3
Q153 0.384 0.903 0.154 !       0.68 eA-3
Q154 0.372 0.221 0.827 !       0.68 eA-3
Q155 0.885 0.991 0.073 !       0.68 eA-3
Q156 0.039 0.986 0.137 !       0.68 eA-3
Q157 0.814 0.643 0.499 !       0.68 eA-3
Q158 0.608 0.162 0.396 !       0.68 eA-3
Q159 0.376 0.448 0.457 !       0.68 eA-3
Q160 0.338 0.158 0.339 !       0.67 eA-3
Q161 0.709 0.703 0.616 !       0.67 eA-3
Q162 0.085 0.252 0.538 !       0.67 eA-3
Q163 0.586 0.376 0.957 !       0.67 eA-3
Q164 0.313 0.966 0.059 !       0.67 eA-3
Q165 0.078 0.094 0.531 !       0.66 eA-3
Q166 0.962 0.653 0.382 !       0.66 eA-3
Q167 0.070 0.130 0.933 !       0.66 eA-3
Q168 0.125 0.739 0.254 !       0.66 eA-3
Q169 0.422 0.424 0.785 !       0.66 eA-3
Q170 0.442 0.055 0.204 !       0.66 eA-3
Q171 0.726 0.348 0.396 !       0.65 eA-3
Q172 0.681 0.406 0.524 !       0.65 eA-3
Q173 0.431 0.407 0.909 !       0.65 eA-3
Q174 0.118 0.203 0.020 !       0.65 eA-3
Q175 0.138 0.144 0.029 !       0.65 eA-3
Q176 0.492 0.187 0.169 !       0.65 eA-3
Q177 0.070 0.480 0.397 !       0.65 eA-3
Q178 0.265 0.043 0.871 !       0.65 eA-3
Q179 0.029 0.701 0.816 !       0.65 eA-3
Q180 0.179 0.562 0.683 !       0.65 eA-3
Q181 0.389 0.081 0.274 !       0.65 eA-3
Q182 0.025 0.157 0.353 !       0.64 eA-3
Q183 0.361 0.434 0.847 !       0.64 eA-3
Q184 0.477 0.323 0.171 !       0.64 eA-3
Q185 0.876 0.056 0.937 !       0.64 eA-3
Q186 0.991 0.520 0.388 !       0.64 eA-3
Q187 0.306 0.298 0.279 !       0.64 eA-3
Q188 0.367 0.761 0.596 !       0.64 eA-3
Q189 0.312 0.614 0.149 !       0.64 eA-3
Q190 0.041 0.885 0.944 !       0.63 eA-3
Q191 0.369 0.795 0.756 !       0.63 eA-3
Q192 0.734 0.138 0.164 !       0.63 eA-3
Q193 0.095 0.883 0.100 !       0.63 eA-3
Q194 0.882 0.875 0.004 !       0.63 eA-3
Q195 0.261 0.173 0.086 !       0.63 eA-3
Q196 0.180 0.433 0.220 !       0.62 eA-3
Q197 0.720 0.323 0.411 !       0.62 eA-3
Q198 0.531 0.396 0.277 !       0.62 eA-3
Q199 0.060 0.906 0.063 !       0.62 eA-3
;
_refine_diff_density_max         0.573
_refine_diff_density_min         -0.562
_refine_diff_density_rms         0.080
_refine_ls_extinction_method     none
_refine_ls_goodness_of_fit_ref   1.016
_refine_ls_hydrogen_treatment    mixed
_refine_ls_matrix_type           full
_refine_ls_number_parameters     851
_refine_ls_number_reflns         11571
_refine_ls_number_restraints     1
_refine_ls_restrained_S_all      1.016
_refine_ls_R_factor_all          0.1822
_refine_ls_R_factor_gt           0.0762
_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^)+(0.0885P)^2^+5.7287P] where P=(Fo^2^+2Fc^2^)/3'
_refine_ls_weighting_scheme      calc
_refine_ls_wR_factor_gt          0.1687
_refine_ls_wR_factor_ref         0.2289
_reflns_Friedel_coverage         0.000
_reflns_number_gt                5296
_reflns_number_total             11571
_reflns_threshold_expression     'I > 2\s(I)'
_cod_data_source_file            jm1c00398_si_003.cif
_cod_data_source_block           mo_22020196_0m_sq
_cod_depositor_comments
;

2022-05-15
Z value and formula fixed to values more according to usual
chemical conventions.                 miguel
;
_cod_original_formula_sum            'C61 H49 Cl9 F9 N9 O6'
_cod_original_formula_weight         1494.14
_cod_original_formula_moiety         '3(C20 H16 Cl2 F3 N3 O2), C H Cl3'
_cod_original_formula_units_Z            4
_cod_database_code               1562965
_shelx_shelxl_version_number     2018/3
_shelx_estimated_absorpt_t_max   0.991
_shelx_estimated_absorpt_t_min   0.947
_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 O(H) groups
2. Restrained distances
 O4-H4
 0.84 with sigma of 0.02
3.a Ternary CH refined with riding coordinates:
 C02O(H02O)
3.b Secondary CH2 refined with riding coordinates:
 C36(H36A,H36B), C18(H18A,H18B), C49(H49A,H49B), C50(H50A,H50B), C38(H38A,
 H38B), C17(H17A,H17B), C53(H53A,H53B), C51(H51A,H51B), C16(H16A,H16B),
 C37(H37A,H37B), C40(H40A,H40B), C20(H20A,H20B)
3.c Aromatic/amide H refined with riding coordinates:
 N5(H5), N1(H1), N7(H7), C6(H6), C44(H44), C7(H7A), C24(H24), C56(H56),
 C26(H26), C55(H55), C9(H9), C30(H30), C60(H60), C59(H59), C4(H4A), C43(H43),
 C31(H31), C3(H3), C27(H27), C10(H10), C23(H23)
3.d Tetrahedral OH refined with riding coordinates:
 O2(H2), O5(H5A)
;
_platon_squeeze_void_probe_radius 1.20
_olex2_submission_special_instructions 'No special instructions were received'