Chiral Platinum(II) Complexes Featuring Phosphine and Chloroquine Ligands as Cytotoxic and Monofunctional DNA-Binding Agents.

Chiral molecules in nature are involved in many biological events; their selectivity and specificity make them of great interest for understanding the behavior of bioactive molecules, by providing information about the chiral discrimination. Inspired by these conformational properties, we present the design and synthesis of novel chiral platinum(II) complexes featuring phosphine and chloroquine ligands with the general formula [PtCl(P)2(CQ)]PF6 (where (P)2 = triphenylphosphine (PPh3) (5), 1,3-bis(diphenylphosphine)propane (dppp) (6), 1,4-bis(diphenylphosphine)butane (dppb) (7), 1,1'-bis(diphenylphosphine)ferrocene (dppf) (8), and CQ = chloroquine] and their precursors of the type [PtCl2(P)2] are described. The complexes were characterized by elemental analysis, absorption spectroscopy in the infrared and ultraviolet-visible (UV-vis) regions, multinuclear ((1)H, (13)C, (31)P, (15)N, and (195)Pt) NMR spectroscopy, cyclic voltammetry, and mass spectrometry (in the case of chloroquine complexes). The interactions of the new platinum-chloroquine complexes with both albumin (BSA), using fluorescence spectroscopy, and DNA, by four widely reported methods were also evaluated. These experiments showed that these Pt-CQ complexes interact strongly with DNA and have high affinities for BSA, in contrast to CQ and CQDP (chloroquine diphosphate), which interact weakly with these biomolecules. Additional assays were performed in order to investigate the cytotoxicity of the platinum complexes against two healthy cell lines (mouse fibroblasts (L929) and the Chinese hamster lung (V79-4)) and four tumor cell lines (human breast (MDA-MB-231 and MCF-7), human lung (A549), and human prostate (DU-145)). The results suggest that the Pt-CQ complexes are generally more cytotoxic than the free CQ, showing that they are promising as anticancer drugs.

2,4,6-Tri-nitro-phenyl 3-bromo-benzoate.

In the title picryl-substituted ester, C13H6BrN3O8, the mean plane of the central ester C-O-C(=O)-C fragment (r.m.s. deviation= 0.0186 Å) is rotated by 84.73 (7)° and 19.92 (12)° to the picryl and phenyl rings, respectively. In the crystal, the mol-ecules are linked by C-H⋯O inter-actions, forming centrosymmetric dimers enclosing R (2) 2(10) and R (2) 2(22) ring motifs along [001] and further helical chains of dimers enclosing R (2) 2(10) ring motifs along [010].

3-(Di-phenyl-amino)-isobenzo-furan-1(3H)-one.

In the title isobenzo-furan-one derivative, C20H15NO2, the planar fused-ring system (r.m.s. deviation for the 10 fitted atoms = 0.031 Å) forms dihedral angles of 63.58 (6) and 63.17 (8)° with the N-bound phenyl rings; the dihedral angle between the planes of these phenyl rings is 85.92 (7)°. In the crystal, mol-ecules are linked by weak C-H⋯O inter-actions, involving both O atoms, forming helical supra-molecular chains along [001].

2,2'-(1,4-Phenyl-ene)bis-(propane-2,2-di-yl) bis-(benzodi-thio-ate).

The title compound, C26H26S4, shows a dihedral angle of 76.64 (15)° between the central and peripheral benzene rings. An inversion center is located at the centroid of the thio-benzoyl ring. In the crystal, weak C-H⋯S inter-actions form C(5) chains along [001]. There are no classical hydrogen bonds.

4-Formyl-2-nitro-phenyl 2-chloro-benzoate.

In the title compound, C14H8ClNO5, the benzene rings form a dihedral angle of 19.55 (9)°. The mean plane of the central ester group [r.m.s. deviation = 0.024 Å] forms dihedral angles of 53.28 (13) and 36.93 (16)°, respectively, with the nitro- and chloro-substituted rings. The nitro group forms a dihedral angle of 19.24 (19)° with the benzene ring to which it is attached. In the crystal, mol-ecules are linked by weak C-H⋯O hydrogen bonds, forming C(7) chains, which run along [100].

2,2'-(Carbono-thio-yldisulfanedi-yl)bis-(2-methyl-propanoic acid).

The mol-ecular structure of the title compound, C9H14O4S3, exhibits intra-molecular C-H⋯S hydrogen bonds. In the crystal, pairs of O-H⋯O hydrogen bonds lead to the formation of centrosymmetric dimers, which are in turn connected by weak C-H⋯O inter-actions. The combination of these inter-actions generates edge-fused R 2 (2)(8) and R 2 (2)(20) rings running along [211].

4-Formyl-2-nitro-phenyl 4-bromo-benzoate.

In the title compound, C14H8BrNO5, the benzene rings form a dihedral angle of 62.90 (7)°. The central ester group is twisted away from the nitro-substituted and bromo-substituted rings by 71.67 (7) and 8.78 (15)°, respectively. The nitro group forms a dihedral angle of 7.77 (16)° with the benzene ring to which it is attached. In the crystal, mol-ecules are linked by weak C-H⋯O inter-actions, forming C(12) chains which run along [001]. Halogen-halogen inter-actions [Br⋯Br = 3.523 (3) Å] within the chains stabilized by C-H⋯O inter-actions are observed.

2,4,6-Tri-nitro-phenyl 3-chloro-benzoate.

In the title benzoate derivative, C13H6ClN3O8, the planes of the benzene rings form a dihedral angle of 73.59 (7)°. The central ester unit forms an angle of 20.38 (12)° with the chloro-substituted benzene ring. In the crystal, mol-ecules are linked by weak C-H⋯O inter-actions, forming helical chains along [101] and [100].

5-Chloro-quinolin-8-yl furan-2-carboxyl-ate.

In the title compound, C14H8ClNO3, the central ester CO2 group is twisted away from the quinoline and furoyl rings by 57.46 (5) and 2.0 (1)°, respectively. In the crystal, mol-ecules are linked by weak C-H⋯O inter-actions, forming chains in [001].

2,4,6-Trinitro-phenyl 4-chloro-benzoate.

In the title benzoate derivative, C13H6ClN3O8, the planes of the benzene rings form a dihedral angle of 63.46 (5)°. The dihedral angles between the benzene ring and its nitro groups are 12.78 (16)° for the first ortho, 28.4 (4) and 17.4 (4)° for the second (disordered) ortho and 3.58 (16)° for the para nitro group. The central ester moiety, -C-(C=O)-O-, is essentially planar (r.m.s. deviation for all non-H atoms = 0.0229 Å) and forms dihedral angles of 7.37 (14)° with the chloro-substituted benzene ring and 69.85 (6)° with the trinitro-substituted benzene ring. One of the nitro groups was refined as disordered over two sets of sites with fixed site occupancies of 0.61 and 0.39. In the crystal, mol-ecules are linked by weak C-H⋯O hydrogen bonds, forming a three-dimensional network.

2-[1'-(Benz-yloxy)spiro-[indane-1,2'-pyrrolidine]-5'-yl]aceto-nitrile.

In the title compound, C21H22N2O, the planes of the two six-membered rings make a dihedral angle of 89.51 (7)°. The pyrrolidine ring has a puckering amplitude q 2 = 0.418 (3) and a pseudo-rotation phase angle ϕ2 = -166.8 (5), adopting a twist conformation (T). The other five-membered ring has a puckering amplitude q 2 = 0.247 (2) and a pseudo-rotation phase angle ϕ2 = -173.7 (5), adopting an envelope conformation with the CH2 atom adjacent to the C atom common with the pyrrolidine ring as the flap. In the crystal, mol-ecules are linked via C-H⋯N, enclosing R (2) 2(20) rings, forming chains propagating along [100]. The aceto-nitrile group is disordered over two positions and was refined with a fixed occupancy ratio of 0.56:0.44.

(±)-3-(5-Amino-3-methyl-1-phenyl-1H-pyrazol-4-yl)-2-benzo-furan-1(3H)-one.

In the title compound, C18H15N3O2, the benzo-furan ring system is essentially planar, the rings making a dihedral angle of 0.57 (9)°. The phenyl, furan and benzene rings subtend dihedral angles of 47.07 (10), 85.76 (7) and 86.04 (7)°, respectively, with the pyrazole ring. In the crystal, mol-ecules are linked by weak N-H⋯N, N-H⋯O and C-H⋯O inter-actions, generating edge-fused R 4 (4)(20), and R 1 (2)(7) rings linked into sheets which are parallel to (010).

2,4,6-Trinitro-phenyl 3-methyl-benzoate.

In the title benzoate derivative, C(14)H(9)N(3)O(8), the benzene rings form a dihedral angle of 87.48 (5)°. The central ester unit forms an angle of 19.42 (7)° with the methyl-benzene ring, indicating a significant twist. In the crystal, the mol-ecules are linked by weak C-H⋯O inter-actions forming a helical chain along [010].

2,4,6-Trinitro-phenyl 4-methyl-benzoate.

In the title compound, C(14)H(9)N(3)O(8), the benzene rings form a dihedral angle of 69.02 (5)°. The central ester group is rotated by 25.86 (9)° relative to the p-tolyl group. In the crystal, the mol-ecules are linked by C-H⋯O inter-actions into helical chains along [010].

3,5-Bis(benz-yloxy)benzoic acid.

In the title compound, C(21)H(18)O(4), the outer benzyl rings are disordered over two resolved positions in a 0.50 ratio. The O-CH(2) groups form dihedral angles of 4.1 (2) and 10.9 (4)° with the central benzene ring, adopting a syn-anti conformation with respect to this ring. In the crystal, the mol-ecules are linked by O-H⋯O hydrogen bonds and weak C-H⋯O inter-actions, forming chains along [010].

9-(4-Bromo-but-yl)-9H-carbazole.

In the title compound, C(16)H(16)BrN, the tricyclic carbazole system is essentially planar (r.m.s. deviation of all non-H atoms = 0.010 Å). The dihedral angle between the two outer carbazole rings is 1.1 (3)°. There are no directional inter-molecular contacts in the crystal packing.

4-(2,5-Dioxo-2,5-dihydro-1H-pyrrol-1-yl)benzoic acid: X-ray and DFT-calculated structure.

In the title compound, C(11)H(7)NO(4), there is a dihedral angle of 45.80 (7)° between the planes of the benzene and maleimide rings. The presence of O-H···O hydrogen bonding and weak C-H···O interactions allows the formation of R(3)(3)(19) edge-connected rings parallel to the (010) plane. Structural, spectroscopic and theoretical studies were carried out. Density functional theory (DFT) optimized structures at the B3LYP/6-311 G(d,p) and 6-31++G(d,p) levels are compared with the experimentally determined molecular structure in the solid state. Additional IR and UV theoretical studies allowed the presence of functional groups and the transition bands of the system to be identified.

Synthesis, spectroscopic (FT-IR and UV-Vis), crystallographic and theoretical studies, and a molecular docking simulation of an imatinib-like template.

The aim of the present study was to report the crystal structure and spectroscopic, electronic, supramolecular and electrostatic properties of a new polymorph of 4-(pyridin-2-yl)pyrimidin-2-amine (C9H8N4). The compound was synthesized under microwave irradiation. The single-crystal X-ray structure analysis revealed an angle of 13.36 (8)° between the planes of the rings, as well as molecules linked by Nsp2-H...N hydrogen bonds forming dimers along the crystal. The material was analyzed by FT-IR vibrational spectroscopy, while a computational approach was used to elucidate the vibrational frequency couplings. The existence of Nsp2-H...N hydrogen bonds in the crystal was confirmed spectroscopically by the IR peaks from the N-H stretching vibration shifting to lower wavenumbers in the solid state relative to those in the gas phase. The supramolecular studies confirmed the formation of centrosymmetric R22(8) rings, which correspond to the formation of dimers that stack parallel to the b direction. Other weak C-H...π interactions, essential for crystal growth, were found. The UV-Vis spectroscopic analysis showed a donor-acceptor process, where the amino group acts as a donor and the pyridine and pyrimidine rings act as acceptors. The reactive sites of the molecule were identified and their quantitative values were defined using the electrostatic potential model proposed in the multifunctional wave function analyzer multiwfn. The calculated interaction energies between pairs of molecules were used to visualize the electrostatic terms as the leading factors against the dispersion factors in the crystal-growth process. The docking results showed that the amino group of the pyrimidine moiety was simultaneously anchored by hydrogen-bonding interactions with the Asp427 and His407 protein residues. This compound could be key for the realization of a series of syntheses of molecules that could be used as possible inhibitors of chronic myelogenous leukemia.

Analysis of solvent-accessible voids and proton-coupled electron transfer of 2,6-bis(1H-imidazol-2-yl)pyridine and its hydrochloride.

The crystal structures of the solid form of solvated 2,6-bis(1H-imidazol-2-yl)pyridine (H2dimpy) trihydrate, C11H9N5·3H2O·[+solvent], I, and its hydrate hydrochloride salt 2-[6-(1H-imidazol-2-yl)pyridin-2-yl]-1H-imidazol-3-ium chloride trihydrate, C11H10N5+·Cl-·3H2O, II, are reported and analysed in detail, along with potentiometric and spectrophotometric titrations for evaluation of the acid-base equilibria and proton-coupled electron-transfer reactions. Compound I crystallizes in the high-symmetry trigonal space group P3221 with an atypical formation of solvent-accessible voids, as a consequence of the 32 screw axis in the crystallographic c-axis direction, which are probably occupied by uncharacterized disordered solvent molecules. Additionally, the trihydrated chloride salt crystallizes in the conventional monoclinic space group P21/c without the formation of solvent-accessible voids. The acid-base equilibria of H2dimpy were studied by potentiometric and spectrophotometric titrations, and the results suggest the formation of H3dimpy+ (pKa1 = 5.40) and H4dimpy2+ (pKa2 = 3.98), with the electrochemical behaviour of these species showing two consecutive irreversible proton-coupled electron-transfer reactions. Density functional theory (DFT) calculations corroborate the interpretation of the experimental results and support the assignment of the electrochemical behaviour.

Crystal structure of 4-formyl-2-nitro-phenyl 4-chloro-2-nitro-benzoate.

In the title compound, C14H7ClN2O7, the central ester moiety is essentially planar, with an r.m.s. deviation of 0.0113 Å. The ester group is twisted away from the chloro- and formyl-substituted rings by 84.60 (9) and 88.55 (9)°, respectively. The crystal packing shows inter-molecular C-H⋯O inter-actions. These inter-actions generate R 2 (2)(20) and R 4 (4)(22) edge-fused rings parallel to (20-2).