Discovery of Highly Potent, Selective, and Orally Efficacious p300/CBP Histone Acetyltransferases Inhibitors.
Yang, Yaxi; Zhang, Rukang; Li, Zhaojun; Mei, Lianghe; Wan, Shili; Ding, Hong; Chen, Zhifeng; Xing, Jing; Feng, Huijin; Han, Jie; Jiang, Hualiang; Zheng, Mingyue; Luo, Cheng; Zhou, Bing; Journal of medicinal chemistry  (2020) –; doi:10.1021/acs.jmedchem.9b01721

data_1557184
_publ_section_title
;
 Discovery of Highly Potent, Selective, and Orally Efficacious p300/CBP
 Histone Acetyltransferases Inhibitors.
;
_journal_name_full               'Journal of medicinal chemistry'
_journal_paper_doi               10.1021/acs.jmedchem.9b01721
_journal_year                    2020
_chemical_absolute_configuration rmad
_chemical_formula_moiety         'C13 H13 N3 O4, H2 O'
_chemical_formula_sum            'C13 H15 N3 O5'
_chemical_formula_weight         293.28
_space_group_crystal_system      orthorhombic
_space_group_IT_number           19
_space_group_name_Hall           'P 2ac 2ab'
_space_group_name_H-M_alt        'P 21 21 21'
_atom_sites_solution_hydrogens   mixed
_atom_sites_solution_primary     dual
_audit_creation_date             2019-05-23
_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            4
_cell_length_a                   8.4194(2)
_cell_length_b                   8.5433(2)
_cell_length_c                   19.1641(5)
_cell_measurement_reflns_used    9955
_cell_measurement_temperature    100
_cell_measurement_theta_max      72.293
_cell_measurement_theta_min      2.305
_cell_volume                     1378.46(6)
_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      100.0
_diffrn_measured_fraction_theta_full 0.979
_diffrn_measured_fraction_theta_max 0.981
_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  0.0342
_diffrn_reflns_av_unetI/netI     0.0288
_diffrn_reflns_Laue_measured_fraction_full 0.979
_diffrn_reflns_Laue_measured_fraction_max 0.981
_diffrn_reflns_limit_h_max       8
_diffrn_reflns_limit_h_min       -10
_diffrn_reflns_limit_k_max       10
_diffrn_reflns_limit_k_min       -10
_diffrn_reflns_limit_l_max       23
_diffrn_reflns_limit_l_min       -23
_diffrn_reflns_number            11510
_diffrn_reflns_point_group_measured_fraction_full 0.983
_diffrn_reflns_point_group_measured_fraction_max 0.984
_diffrn_reflns_theta_full        67.679
_diffrn_reflns_theta_max         72.286
_diffrn_reflns_theta_min         4.615
_diffrn_standards_number         0
_exptl_absorpt_coefficient_mu    0.934
_exptl_absorpt_correction_T_max  0.7536
_exptl_absorpt_correction_T_min  0.5694
_exptl_absorpt_correction_type   multi-scan
_exptl_absorpt_process_details
'SADABS-2016/2 (Bruker,2016/2) was used for absorption correction. wR2(int) was 0.1079 before and 0.0551 after correction. The Ratio of minimum to maximum transmission is 0.7556. The \l/2 correction factor is Not present.'
_exptl_crystal_colour            colourless
_exptl_crystal_colour_primary    colourless
_exptl_crystal_density_diffrn    1.413
_exptl_crystal_description       block
_exptl_crystal_F_000             616
_exptl_crystal_size_max          0.28
_exptl_crystal_size_mid          0.15
_exptl_crystal_size_min          0.12
_refine_diff_density_max         0.215
_refine_diff_density_min         -0.121
_refine_diff_density_rms         0.030
_refine_ls_abs_structure_details
;
 Flack x determined using 1102 quotients [(I+)-(I-)]/[(I+)+(I-)]
 (Parsons, Flack and Wagner, Acta Cryst. B69 (2013) 249-259).
;
_refine_ls_abs_structure_Flack   0.03(5)
_refine_ls_extinction_method     none
_refine_ls_goodness_of_fit_ref   1.073
_refine_ls_hydrogen_treatment    mixed
_refine_ls_matrix_type           full
_refine_ls_number_parameters     203
_refine_ls_number_reflns         2683
_refine_ls_number_restraints     0
_refine_ls_restrained_S_all      1.073
_refine_ls_R_factor_all          0.0256
_refine_ls_R_factor_gt           0.0255
_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^)+(0.0217P)^2^+0.3067P] where P=(Fo^2^+2Fc^2^)/3'
_refine_ls_weighting_scheme      calc
_refine_ls_wR_factor_gt          0.0625
_refine_ls_wR_factor_ref         0.0626
_reflns_Friedel_coverage         0.720
_reflns_Friedel_fraction_full    0.988
_reflns_Friedel_fraction_max     0.988
_reflns_number_gt                2665
_reflns_number_total             2683
_reflns_threshold_expression     'I > 2\s(I)'
_cod_data_source_file            jm9b01721_si_005.cif
_cod_data_source_block           22019583_0m
_cod_database_code               1557184
_shelx_shelxl_version_number     2018/3
_shelx_estimated_absorpt_t_max   0.896
_shelx_estimated_absorpt_t_min   0.780
_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
2.a Secondary CH2 refined with riding coordinates:
 C4(H4A,H4B), C5(H5A,H5B)
2.b Aromatic/amide H refined with riding coordinates:
 N3(H3), N2(H2), C8(H8), C9(H9), C11(H11)
2.c Idealised Me refined as rotating group:
 C13(H13A,H13B,H13C)
;
_olex2_submission_special_instructions 'No special instructions were received'