Discovery, Synthesis, and Evaluation of Oxynitidine Derivatives as Dual Inhibitors of DNA Topoisomerase IB (TOP1) and Tyrosyl-DNA Phosphodiesterase 1 (TDP1), and Potential Antitumor Agents.
Zhang, Xiao-Ru; Wang, Hao-Wen; Tang, Wen-Lin; Zhang, Yu; Yang, Hui; Hu, De-Xuan; Ravji, Azhar; Marchand, Christophe; Kiselev, Evgeny; Ofori-Atta, Kwabena; Agama, Keli; Pommier, Yves; An, Lin-Kun; Journal of medicinal chemistry 61 (2018) 9908–9930; doi:10.1021/acs.jmedchem.8b00639

data_1553261
_publ_section_title
;
 Discovery, Synthesis, and Evaluation of Oxynitidine Derivatives as Dual
 Inhibitors of DNA Topoisomerase IB (TOP1) and Tyrosyl-DNA
 Phosphodiesterase 1 (TDP1), and Potential Antitumor Agents.
;
_journal_issue                   22
_journal_name_full               'Journal of medicinal chemistry'
_journal_page_first              9908
_journal_page_last               9930
_journal_paper_doi               10.1021/acs.jmedchem.8b00639
_journal_volume                  61
_journal_year                    2018
_chemical_formula_moiety         'C27 H32 N2 O4'
_chemical_formula_sum            'C27 H32 N2 O4'
_chemical_formula_weight         448.54
_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   geom
_atom_sites_solution_primary     iterative
_audit_creation_date             2017-10-17
_audit_creation_method
;
Olex2 1.2
(compiled 2017.08.10 svn.r3458 for OlexSys, GUI svn.r5381)
;
_cell_angle_alpha                90
_cell_angle_beta                 91.6653(13)
_cell_angle_gamma                90
_cell_formula_units_Z            4
_cell_length_a                   9.41991(12)
_cell_length_b                   10.11440(12)
_cell_length_c                   23.7285(4)
_cell_measurement_reflns_used    5610
_cell_measurement_temperature    100
_cell_measurement_theta_max      71.6480
_cell_measurement_theta_min      4.6910
_cell_volume                     2259.82(5)
_computing_cell_refinement
;
CrysAlisPro, Agilent Technologies,
Version 1.171.37.34 (release 22-05-2014 CrysAlis171 .NET)
(compiled May 22 2014,16:03:01)
;
_computing_data_collection
;
CrysAlisPro, Agilent Technologies,
Version 1.171.37.34 (release 22-05-2014 CrysAlis171 .NET)
(compiled May 22 2014,16:03:01)
;
_computing_data_reduction
;
CrysAlisPro, Agilent Technologies,
Version 1.171.37.34 (release 22-05-2014 CrysAlis171 .NET)
(compiled May 22 2014,16:03:01)
;
_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    'olex2.solve (Bourhis et al., 2015)'
_diffrn_ambient_temperature      100
_diffrn_detector                 'CCD plate'
_diffrn_detector_area_resol_mean 8.2417
_diffrn_detector_type            Onyx
_diffrn_measured_fraction_theta_full 0.999
_diffrn_measured_fraction_theta_max 0.999
_diffrn_measurement_details
;
  1 omega   26.00   64.00   1.0000    1.0000
omega____ theta____ kappa____ phi______ frames
    -       42.2034   77.0000  120.0000 38

  2 omega   67.00  166.00   1.0000    2.5000
omega____ theta____ kappa____ phi______ frames
    -      100.0000   77.0000  150.0000 99

  3 omega   74.00  145.00   1.0000    2.5000
omega____ theta____ kappa____ phi______ frames
    -      100.0000   77.0000   60.0000 71

  4 omega   66.00  177.00   1.0000    2.5000
omega____ theta____ kappa____ phi______ frames
    -      100.0000   77.0000  120.0000 111

  5 omega   78.00  104.00   1.0000    2.5000
omega____ theta____ kappa____ phi______ frames
    -      100.0000   77.0000 -120.0000 26

  6 omega  139.00  164.00   1.0000    2.5000
omega____ theta____ kappa____ phi______ frames
    -      100.0000   77.0000 -120.0000 25

  7 omega   80.00  162.00   1.0000    2.5000
omega____ theta____ kappa____ phi______ frames
    -      100.0000   77.0000 -180.0000 82

  8 omega   22.00  121.00   1.0000    1.0000
omega____ theta____ kappa____ phi______ frames
    -       42.2034   77.0000  -60.0000 99

  9 omega  -76.00  -10.00   1.0000    1.0000
omega____ theta____ kappa____ phi______ frames
    -      -42.2034   77.0000  -60.0000 66

 10 omega -123.00  -28.00   1.0000    2.5000
omega____ theta____ kappa____ phi______ frames
    -      -95.0000   77.0000  -90.0000 95
;
_diffrn_measurement_device       'four-circle diffractometer'
_diffrn_measurement_device_type  'Xcalibur, Onyx, Nova'
_diffrn_measurement_method       '\w scans'
_diffrn_orient_matrix_UB_11      0.0168274000
_diffrn_orient_matrix_UB_12      0.1222090000
_diffrn_orient_matrix_UB_13      0.0383633000
_diffrn_orient_matrix_UB_21      0.1618283000
_diffrn_orient_matrix_UB_22      -0.0029480000
_diffrn_orient_matrix_UB_23      -0.0076702000
_diffrn_orient_matrix_UB_31      -0.0172640000
_diffrn_orient_matrix_UB_32      0.0909136000
_diffrn_orient_matrix_UB_33      -0.0518279000
_diffrn_radiation_monochromator  mirror
_diffrn_radiation_probe          x-ray
_diffrn_radiation_type           CuK\a
_diffrn_radiation_wavelength     1.54184
_diffrn_reflns_av_R_equivalents  0.0458
_diffrn_reflns_av_unetI/netI     0.0437
_diffrn_reflns_Laue_measured_fraction_full 0.999
_diffrn_reflns_Laue_measured_fraction_max 0.999
_diffrn_reflns_limit_h_max       10
_diffrn_reflns_limit_h_min       -11
_diffrn_reflns_limit_k_max       12
_diffrn_reflns_limit_k_min       -10
_diffrn_reflns_limit_l_max       28
_diffrn_reflns_limit_l_min       -28
_diffrn_reflns_number            9926
_diffrn_reflns_point_group_measured_fraction_full 0.999
_diffrn_reflns_point_group_measured_fraction_max 0.999
_diffrn_reflns_theta_full        67.079
_diffrn_reflns_theta_max         67.079
_diffrn_reflns_theta_min         3.727
_diffrn_source                   'sealed X-ray tube'
_diffrn_source_type              'Nova (Cu) X-ray Source'
_exptl_absorpt_coefficient_mu    0.710
_exptl_absorpt_correction_T_max  1.00000
_exptl_absorpt_correction_T_min  0.32455
_exptl_absorpt_correction_type   multi-scan
_exptl_absorpt_process_details
;
CrysAlisPro, Agilent Technologies,
Version 1.171.37.34 (release 22-05-2014 CrysAlis171 .NET)
(compiled May 22 2014,16:03:01)
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    1.318
_exptl_crystal_description       block
_exptl_crystal_F_000             960
_exptl_crystal_size_max          0.4
_exptl_crystal_size_mid          0.2
_exptl_crystal_size_min          0.1
_refine_diff_density_max         0.244
_refine_diff_density_min         -0.293
_refine_diff_density_rms         0.051
_refine_ls_extinction_method     none
_refine_ls_goodness_of_fit_ref   1.044
_refine_ls_hydrogen_treatment    constr
_refine_ls_matrix_type           full
_refine_ls_number_parameters     302
_refine_ls_number_reflns         4039
_refine_ls_number_restraints     0
_refine_ls_restrained_S_all      1.044
_refine_ls_R_factor_all          0.0561
_refine_ls_R_factor_gt           0.0460
_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^)+(0.0753P)^2^+0.3343P] where P=(Fo^2^+2Fc^2^)/3'
_refine_ls_weighting_scheme      calc
_refine_ls_wR_factor_gt          0.1225
_refine_ls_wR_factor_ref         0.1325
_reflns_Friedel_coverage         0.000
_reflns_number_gt                3327
_reflns_number_total             4039
_reflns_threshold_expression     'I > 2\s(I)'
_cod_data_source_file            jm8b00639_si_002.cif
_cod_data_source_block           zxr_ntd97_150421
_cod_database_code               1553261
_shelx_shelxl_version_number     2016/6
_shelx_estimated_absorpt_t_max   0.932
_shelx_estimated_absorpt_t_min   0.764
_reflns_odcompleteness_completeness 99.91
_reflns_odcompleteness_iscentric 1
_reflns_odcompleteness_theta     66.97
_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
2.a Secondary CH2 refined with riding coordinates:
 C23(H23A,H23B), C8(H8A,H8B), C3(H3A,H3B), C24(H24A,H24B), C26(H26A,H26B),
 C21(H21A,H21B), C22(H22A,H22B)
2.b Aromatic/amide H refined with riding coordinates:
 C1(H1), C13(H13), C16(H16), C10(H10), C17(H17), C5(H5)
2.c Idealised Me refined as rotating group:
 C19(H19A,H19B,H19C), C20(H20A,H20B,H20C), C27(H27A,H27B,H27C), C25(H25A,H25B,
 H25C)
;
_shelx_res_checksum              71723
_shelx_hkl_checksum              60549
_olex2_submission_special_instructions 'No special instructions were received'