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_1562966
_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_absolute_configuration rm
_chemical_formula_moiety         'C21 H21 Cl2 N3 O4'
_chemical_formula_sum            'C21 H21 Cl2 N3 O4'
_chemical_formula_weight         450.31
_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     dual
_audit_creation_date             2020-05-14
_audit_creation_method
;
Olex2 1.2
(compiled 2018.05.29 svn.r3508 for OlexSys, GUI svn.r5506)
;
_cell_angle_alpha                90
_cell_angle_beta                 103.842(4)
_cell_angle_gamma                90
_cell_formula_units_Z            6
_cell_length_a                   12.9023(17)
_cell_length_b                   12.7420(14)
_cell_length_c                   18.9596(19)
_cell_measurement_reflns_used    3359
_cell_measurement_temperature    170
_cell_measurement_theta_max      26.139
_cell_measurement_theta_min      2.699
_cell_volume                     3026.5(6)
_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 0.991
_diffrn_measured_fraction_theta_max 0.991
_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  0.0629
_diffrn_reflns_av_unetI/netI     0.0975
_diffrn_reflns_Laue_measured_fraction_full 0.991
_diffrn_reflns_Laue_measured_fraction_max 0.991
_diffrn_reflns_limit_h_max       15
_diffrn_reflns_limit_h_min       -13
_diffrn_reflns_limit_k_max       15
_diffrn_reflns_limit_k_min       -13
_diffrn_reflns_limit_l_max       22
_diffrn_reflns_limit_l_min       -22
_diffrn_reflns_number            22726
_diffrn_reflns_point_group_measured_fraction_full 0.930
_diffrn_reflns_point_group_measured_fraction_max 0.930
_diffrn_reflns_theta_full        25.027
_diffrn_reflns_theta_max         25.027
_diffrn_reflns_theta_min         1.944
_diffrn_standards_number         0
_exptl_absorpt_coefficient_mu    0.357
_exptl_absorpt_correction_T_max  0.7454
_exptl_absorpt_correction_T_min  0.6658
_exptl_absorpt_correction_type   multi-scan
_exptl_absorpt_process_details
'SADABS-2016/2 (Bruker,2016/2) was used for absorption correction. wR2(int) was 0.1131 before and 0.0614 after correction. The Ratio of minimum to maximum transmission is 0.8932. The \l/2 correction factor is Not present.'
_exptl_crystal_colour            colourless
_exptl_crystal_colour_primary    colourless
_exptl_crystal_density_diffrn    1.482
_exptl_crystal_description       needle
_exptl_crystal_F_000             1404
_exptl_crystal_size_max          0.08
_exptl_crystal_size_mid          0.05
_exptl_crystal_size_min          0.02
_refine_diff_density_max         1.008
_refine_diff_density_min         -0.803
_refine_diff_density_rms         0.101
_refine_ls_abs_structure_details
;
 Flack x determined using 1239 quotients [(I+)-(I-)]/[(I+)+(I-)]
 (Parsons, Flack and Wagner, Acta Cryst. B69 (2013) 249-259).
;
_refine_ls_abs_structure_Flack   0.00(5)
_refine_ls_extinction_method     none
_refine_ls_goodness_of_fit_ref   1.075
_refine_ls_hydrogen_treatment    constr
_refine_ls_matrix_type           full
_refine_ls_number_parameters     829
_refine_ls_number_reflns         9954
_refine_ls_number_restraints     834
_refine_ls_restrained_S_all      1.050
_refine_ls_R_factor_all          0.1713
_refine_ls_R_factor_gt           0.0998
_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^)+(0.0641P)^2^+15.1438P] where P=(Fo^2^+2Fc^2^)/3'
_refine_ls_weighting_scheme      calc
_refine_ls_wR_factor_gt          0.2061
_refine_ls_wR_factor_ref         0.2543
_reflns_Friedel_coverage         0.788
_reflns_Friedel_fraction_full    0.862
_reflns_Friedel_fraction_max     0.862
_reflns_number_gt                5239
_reflns_number_total             9954
_reflns_threshold_expression     'I > 2\s(I)'
_cod_data_source_file            jm1c00398_si_005.cif
_cod_data_source_block           mo_22020197_0m
_cod_database_code               1562966
_shelx_shelxl_version_number     2018/3
_shelx_estimated_absorpt_t_max   0.993
_shelx_estimated_absorpt_t_min   0.972
_olex2_refinement_description
;
1. Fixed Uiso
 At 1.2 times of:
  All C(H) groups, All C(H,H) groups, All C(H,H,H,H) groups, All N(H) groups
 At 1.5 times of:
  All C(H,H,H) groups, All O(H) groups
2. Restrained distances
 O7-H8
 2.1 with sigma of 0.02
 O12-H11
 2.1 with sigma of 0.02
 C41-C39 \\sim C40-C39 \\sim N4-C41 \\sim N4-C40
 with sigma of 0.02
3. Uiso/Uaniso restraints and constraints
Uanis(C59) \\sim Ueq: with sigma of 0.005 and sigma for terminal atoms of 0.01
Uanis(C40) \\sim Ueq, Uanis(C39) \\sim Ueq: with sigma of 0.005 and sigma for
terminal atoms of 0.01
Uanis(N4) \\sim Ueq: with sigma of 0.005 and sigma for terminal atoms of 0.01
Uanis(C40) \\sim Ueq: with sigma of 0.001 and sigma for terminal atoms of 0.002
Uanis(C54) \\sim Ueq: with sigma of 0.005 and sigma for terminal atoms of 0.01
Uanis(C56) \\sim Ueq: with sigma of 0.005 and sigma for terminal atoms of 0.01
4. Rigid body (RIGU) restrains
 All non-hydrogen atoms
 with sigma for 1-2 distances of 0.004 and sigma for 1-3 distances of 0.004
5. Others
 Fixed Sof: H39A(0.5) H39B(0.5) H39C(0.5) H39D(0.5) C40(0.5) H40A(0.5)
 H40B(0.5) C41(0.5) H41A(0.5) H41B(0.5)
6.a Secondary CH2 refined with riding coordinates:
 C54(H54A,H54B), C17(H17A,H17B), C56(H56A,H56B), C19(H19A,H19B), C58(H58A,
 H58B), C21(H21A,H21B), C39(H39A,H39B), C39(H39C,H39D), C43(H43A,H43B),
 C38(H38A,H38B), C55(H55A,H55B), C18(H18A,H18B), C40(H40A,H40B), C41(H41A,H41B)
6.b Aromatic/amide H refined with riding coordinates:
 N3(H3), N6(H6), N9(H9), N1(H1), N7(H7), C63(H63), N5(H5), C16(H16), C37(H37),
 C15(H15), C01I(H01I), C36(H36), C4(H4), C3(H3A), C24(H24), C50(H50), C25(H25),
 C45(H45)
6.c Idealised Me refined as rotating group:
 C8(H8A,H8B,H8C), C1(H1A,H1B,H1C), C51(H51A,H51B,H51C), C27(H27A,H27B,H27C),
 C22(H22A,H22B,H22C), C44(H44A,H44B,H44C)
6.d Idealised tetrahedral OH refined as rotating group:
 O8(H8), O11(H11), O2(H2)
;
_olex2_submission_special_instructions 'No special instructions were received'