Phenyl-Guanidine Derivatives as Potential Therapeutic Agents for Glioblastoma Multiforme: Catalytic Syntheses, Cytotoxic Effects and DNA Affinity
Alonso-Moreno, Carlos; BRAVO, IVAN; Posadas, Inmaculada; Albaladejo, José; CARRILLO-HERMOSILLA, FERNANDO; Ceña, Valentín; Garzon, Andres; López-Solera, Isabel; Romero-Castillo, Laura; RSC Adv.  (2016) –; doi:10.1039/C5RA17920C

data_7223856
_publ_section_title
;
 Phenyl-Guanidine Derivatives as Potential Therapeutic Agents for
 Glioblastoma Multiforme: Catalytic Syntheses, Cytotoxic Effects and DNA
 Affinity
;
_journal_name_full               'RSC Adv.'
_journal_paper_doi               10.1039/C5RA17920C
_journal_year                    2016
_chemical_formula_moiety         'C15 H19 F6 N3, 1(C7 H8)'
_chemical_formula_sum            'C22 H27 F6 N3'
_chemical_formula_weight         447.46
_space_group_crystal_system      tetragonal
_space_group_IT_number           88
_space_group_name_Hall           '-I 4ad'
_space_group_name_H-M_alt        'I 41/a'
_symmetry_space_group_name_Hall  '-I 4ad'
_symmetry_space_group_name_H-M   'I 41/a :2'
_atom_sites_solution_hydrogens   geom
_atom_sites_solution_primary     direct
_atom_sites_solution_secondary   difmap
_audit_creation_method           SHELXL-2014/7
_audit_update_record
;
2015-12-22 deposited with the CCDC.
2016-01-07 downloaded from the CCDC.
;
_cell_angle_alpha                90
_cell_angle_beta                 90
_cell_angle_gamma                90
_cell_formula_units_Z            16
_cell_length_a                   23.863(7)
_cell_length_b                   23.863(7)
_cell_length_c                   16.635(5)
_cell_measurement_reflns_used    2523
_cell_measurement_temperature    150(2)
_cell_measurement_theta_max      22.1262
_cell_measurement_theta_min      2.2673
_cell_volume                     9473(5)
_computing_cell_refinement       'Bruker SAINT'
_computing_data_collection       'Bruker APEX'
_computing_data_reduction        'Bruker SAINT'
_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    'SHELXS-97 (Sheldrick, 1990)'
_diffrn_ambient_temperature      150(2)
_diffrn_measured_fraction_theta_full 0.999
_diffrn_measured_fraction_theta_max 0.999
_diffrn_measurement_device_type  'CCD area detector'
_diffrn_measurement_method       'omega scans'
_diffrn_radiation_type           MoK\a
_diffrn_radiation_wavelength     0.71073
_diffrn_reflns_av_R_equivalents  0.1009
_diffrn_reflns_av_unetI/netI     0.0626
_diffrn_reflns_Laue_measured_fraction_full 0.999
_diffrn_reflns_Laue_measured_fraction_max 0.999
_diffrn_reflns_limit_h_max       28
_diffrn_reflns_limit_h_min       -28
_diffrn_reflns_limit_k_max       27
_diffrn_reflns_limit_k_min       -28
_diffrn_reflns_limit_l_max       19
_diffrn_reflns_limit_l_min       -19
_diffrn_reflns_number            29923
_diffrn_reflns_point_group_measured_fraction_full 0.999
_diffrn_reflns_point_group_measured_fraction_max 0.999
_diffrn_reflns_theta_full        25.000
_diffrn_reflns_theta_max         25.010
_diffrn_reflns_theta_min         2.267
_diffrn_source                   'fine-focus sealed tube'
_exptl_absorpt_coefficient_mu    0.108
_exptl_absorpt_correction_T_max  0.7452
_exptl_absorpt_correction_T_min  0.6066
_exptl_absorpt_correction_type   multi-scan
_exptl_absorpt_process_details   SADABS
_exptl_crystal_colour            Colorless
_exptl_crystal_density_diffrn    1.255
_exptl_crystal_density_method    'not measured'
_exptl_crystal_description       Prismatic
_exptl_crystal_F_000             3744
_exptl_crystal_size_max          0.53
_exptl_crystal_size_mid          0.45
_exptl_crystal_size_min          0.34
_refine_diff_density_max         0.363
_refine_diff_density_min         -0.300
_refine_diff_density_rms         0.046
_refine_ls_extinction_method     none
_refine_ls_goodness_of_fit_ref   1.031
_refine_ls_hydrogen_treatment    constr
_refine_ls_matrix_type           full
_refine_ls_number_parameters     386
_refine_ls_number_reflns         4177
_refine_ls_number_restraints     436
_refine_ls_restrained_S_all      1.094
_refine_ls_R_factor_all          0.1337
_refine_ls_R_factor_gt           0.0743
_refine_ls_shift/su_max          0.004
_refine_ls_shift/su_mean         0.000
_refine_ls_structure_factor_coef Fsqd
_refine_ls_weighting_details
'w=1/[\s^2^(Fo^2^)+(0.0784P)^2^+14.0664P] where P=(Fo^2^+2Fc^2^)/3'
_refine_ls_weighting_scheme      calc
_refine_ls_wR_factor_gt          0.1653
_refine_ls_wR_factor_ref         0.1946
_reflns_Friedel_coverage         0.000
_reflns_number_gt                2430
_reflns_number_total             4177
_reflns_threshold_expression     'I > 2\s(I)'
_cod_data_source_file            c5ra17920c2.cif
_cod_data_source_block           13
_cod_original_cell_volume        9473(6)
_cod_database_code               7223856
_shelx_shelxl_version_number     2014/7
_olex2_refinement_description
;
1. Fixed Uiso
 At 1.2 times of:
  All C(H) groups, All N(H) groups
 At 1.5 times of:
  All C(H,H,H) groups
2. Restrained distances
 C15-C17 \\sim C17A-C15
 with sigma of 0.02
 F1-F2 \\sim F1-F3 \\sim F2-F3
 with sigma of 0.04
 C17-C15 \\sim C17-F1 \\sim C17-F2 \\sim C17-F3
 with sigma of 0.02
 F1A-F2A \\sim F1A-F3A \\sim F2A-F3A
 with sigma of 0.04
 C17A-C15 \\sim C17A-F1A \\sim C17A-F2A \\sim C17A-F3A
 with sigma of 0.02
 C21_1-C22_1 \\sim C22_1-C23_1 \\sim C23_1-C24_1 \\sim C24_1-C25_1 
\\sim C25_1-C26_1 \\sim C26_1-C21_1
 C21_2-C22_2 \\sim C22_2-C23_2 \\sim C23_2-C24_2 \\sim C24_2-C25_2 
\\sim C25_2-C26_2 \\sim C26_2-C21_2
 with sigma of 0.02
 C21_1-C25_1 \\sim C21_1-C23_1 \\sim C26_1-C24_1 \\sim C22_1-C26_1 
\\sim C23_1-C25_1 \\sim C22_1-C24_1
 C21_2-C25_2 \\sim C21_2-C23_2 \\sim C26_2-C24_2 \\sim C22_2-C26_2 
\\sim C23_2-C25_2 \\sim C22_2-C24_2
 with sigma of 0.04
 C20_1-C26_1 \\sim C20_1-C22_1
 C20_2-C26_2 \\sim C20_2-C22_2
 with sigma of 0.04
 C21_1-C22_1 \\sim C22_1-C23_1 \\sim C23_1-C24_1 \\sim C24_1-C25_1 
\\sim C25_1-C26_1 \\sim C26_1-C21_1
 C21_2-C22_2 \\sim C22_2-C23_2 \\sim C23_2-C24_2 \\sim C24_2-C25_2 
\\sim C25_2-C26_2 \\sim C26_2-C21_2
 with sigma of 0.02
 C21_1-C25_1 \\sim C21_1-C23_1 \\sim C26_1-C24_1 \\sim C22_1-C26_1 
\\sim C23_1-C25_1 \\sim C22_1-C24_1
 C21_2-C25_2 \\sim C21_2-C23_2 \\sim C26_2-C24_2 \\sim C22_2-C26_2 
\\sim C23_2-C25_2 \\sim C22_2-C24_2
 with sigma of 0.04
 C20_1-C26_1 \\sim C20_1-C22_1
 C20_2-C26_2 \\sim C20_2-C23_2
 with sigma of 0.04
 C21_1-C22_1 \\sim C22_1-C23_1 \\sim C23_1-C24_1 \\sim C24_1-C25_1 
\\sim C25_1-C26_1 \\sim C26_1-C21_1
 C21_2-C22_2 \\sim C22_2-C23_2 \\sim C23_2-C24_2 \\sim C24_2-C25_2 
\\sim C25_2-C26_2 \\sim C26_2-C21_2
 with sigma of 0.02
 C21_1-C25_1 \\sim C21_1-C23_1 \\sim C26_1-C24_1 \\sim C22_1-C26_1 
\\sim C23_1-C25_1 \\sim C22_1-C24_1
 C21_2-C25_2 \\sim C21_2-C23_2 \\sim C26_2-C24_2 \\sim C22_2-C26_2 
\\sim C23_2-C25_2 \\sim C22_2-C24_2
 with sigma of 0.04
 C20_1-C26_1 \\sim C20_1-C22_1
 C20_2-C26_2 \\sim C20_2-C22_2
 with sigma of 0.04
3. Restrained planarity
 C20_1, C21_1, C22_1, C23_1, C24_1, C25_1, C26_1
 C20_2, C21_2, C22_2, C23_2, C24_2, C25_2, C26_2
 with sigma of 0.1
 C20_1, C21_1, C22_1, C23_1, C24_1, C25_1, C26_1
 C20_2, C21_2, C22_2, C23_2, C24_2, C25_2, C26_2
 with sigma of 0.1
 C20_1, C21_1, C22_1, C23_1, C24_1, C25_1, C26_1
 C20_2, C21_2, C22_2, C23_2, C24_2, C25_2, C26_2
 with sigma of 0.1
4. Uiso/Uaniso restraints and constraints
C0 \\sim C1: within 2A with sigma of 0.04 and sigma for terminal atoms of 0.08
C20_1 \\sim C21_1 \\sim C22_1 \\sim C23_1 \\sim C24_1 \\sim C25_1 \\sim C26_1 
\\sim C20_2 \\sim C21_2 \\sim C22_2 \\sim C23_2 \\sim C24_2 \\sim C25_2 
\\sim C26_2: within 2A with sigma of 0.04 and sigma for terminal atoms of 0.08
C20_1 \\sim C21_1 \\sim C22_1 \\sim C23_1 \\sim C24_1 \\sim C25_1 \\sim C26_1 
\\sim C20_2 \\sim C21_2 \\sim C22_2 \\sim C23_2 \\sim C24_2 \\sim C25_2 
\\sim C26_2: within 2A with sigma of 0.04 and sigma for terminal atoms of 0.08
C20_1 \\sim C21_1 \\sim C22_1 \\sim C23_1 \\sim C24_1 \\sim C25_1 \\sim C26_1 
\\sim C20_2 \\sim C21_2 \\sim C22_2 \\sim C23_2 \\sim C24_2 \\sim C25_2 
\\sim C26_2: within 2A with sigma of 0.04 and sigma for terminal atoms of 0.08
5. Rigid body (RIGU) restrains
 C15, C17, F2, F3, F1
 with sigma for 1-2 distances of 0.004 and sigma for 1-3 distances of 0.004
 C17A, F1A, F2A, F3A, C15
 with sigma for 1-2 distances of 0.004 and sigma for 1-3 distances of 0.004
 C20_1, C21_1, C22_1, C23_1, C24_1, C25_1, C26_1
 C20_2, C21_2, C22_2, C23_2, C24_2, C25_2, C26_2
 with sigma for 1-2 distances of 0.004 and sigma for 1-3 distances of 0.004
 C20_1, C21_1, C22_1, C23_1, C24_1, C25_1, C26_1
 C20_2, C21_2, C22_2, C23_2, C24_2, C25_2, C26_2
 with sigma for 1-2 distances of 0.004 and sigma for 1-3 distances of 0.004
 C20_1, C21_1, C22_1, C23_1, C24_1, C25_1, C26_1
 C20_2, C21_2, C22_2, C23_2, C24_2, C25_2, C26_2
 with sigma for 1-2 distances of 0.004 and sigma for 1-3 distances of 0.004
6. Others
 Sof(F1A)=Sof(F2A)=Sof(F3A)=Sof(C20)=Sof(C20)=Sof(H20A)=Sof(H20B)=Sof(H20C)=
 Sof(C21)=Sof(C22)=Sof(H22)=Sof(C23)=Sof(H23)=Sof(C24)=Sof(H24)=Sof(C25)=
 Sof(H25)=Sof(C26)=Sof(H26)=1-FVAR(1)
 Sof(C17)=Sof(F1)=Sof(F2)=Sof(F3)=Sof(C20)=Sof(H20A)=Sof(H20B)=Sof(H20C)=
 Sof(C21)=Sof(C22)=Sof(H22)=Sof(C23)=Sof(H23)=Sof(C24)=Sof(H24)=Sof(C25)=
 Sof(H25)=Sof(C26)=Sof(H26)=FVAR(1)
7.a Ternary CH refined with riding coordinates:
 C5(H5), C2(H2)
7.b Aromatic/amide H refined with riding coordinates:
 N3(H3), N2(H2), C16(H16), C12(H12), C14(H14),
 C22(H22), C23(H23), C24(H24), C25(H25), C26(H26), C22(H22), C23(H23), 
 C24(H24), C25(H25), C26(H26)
7.c Idealised Me refined as rotating group:
 C6(H6A,H6B,H6C), C7(H7A,H7B,H7C), C3(H3A,H3B,H3C), C4(H4A,
 H4B,H4C), C20(H20A,H20B,H20C), C20(H20A,H20B,H20C)
;
_shelx_res_checksum              71057