Cycloplatinated(II) Derivatives of Mercaptopurine Capable of Binding Interactions with HSA/DNA

• Published in: Inorganic chemistry 2019-12, Vol.58 (23), p.16154-16170
• Main Authors: Aseman, Marzieh Dadkhah, Aryamanesh, Shiva, Shojaeifard, Zahra, Hemmateenejad, Bahram, Nabavizadeh, S. Masoud
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Binding Sites - drug effects; Cell Proliferation - drug effects; Density Functional Theory; DNA - chemistry; DNA - drug effects; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; K562 Cells; Mercaptopurine - chemistry; Mercaptopurine - pharmacology; Molecular Docking Simulation; Molecular Structure; Organoplatinum Compounds - chemical synthesis; Organoplatinum Compounds - chemistry; Organoplatinum Compounds - pharmacology; Serum Albumin, Human - chemistry; Serum Albumin, Human - drug effects; Structure-Activity Relationship; Thermodynamics
• ISSN: 0020-1669; 1520-510X
• DOI: 10.1021/acs.inorgchem.9b02696

In this study, two new bis-cyclometalated Pt­(II) complexes, [Pt­(C^N)­(S^N)] [S^N = deprotonated 6-mercaptopurine (6-MP) and C^N = deprotonated 2-phenylpyridine (ppy), 2a; C^N = deprotonated benzo­[h]­quinoline (bhq), 2b], are synthesized by the reaction of [PtR­(SMe2)­(C^N)] (R = Me or p-MeC6H4) with 1 equiv of 6-mercaptopurine (6-HMP) at room temperature. The complexes are fully characterized using 1H and 13C NMR spectroscopies, electrospray ionization mass spectrometry, and elemental analysis. Biomolecular interaction of complex 2a with human serum albumin (HSA) is studied by fluorescence, UV–vis, and circular dichroism (CD) spectroscopies. The binding constants (K b) and number of binding sites (n) are evaluated using the Stern–Volmer equation. The intrinsic fluorescence of protein is quenched by a static quenching mechanism, with a binding constant of K b ∼ 105 reflecting a high affinity of complex 2a for HSA. The thermodynamic parameters (ΔH°, ΔG°, and ΔS°) indicate that the interaction is a spontaneous process and hydrophobic forces play a main role in the reaction. The displacement experiments demonstrate that the reactive binding sites of HSA to complex 2a are mainly located within its hydrophobic cavity in subdomain IIA (site I). Synchronous fluorescence spectra reveal that complex 2a affected the microenvironment of tryptophan-214 residues in subdomain IIA of HSA. In the case of interaction of complex 2b and HSA, because of overlapping of the emission spectra of complex 2b with HSA, chemometric approaches are applied. The results indicate significant interaction between the tryptophan residue of HSA and complex 2b. Moreover, the binding of Pt­(II) complexes 2a and 2b causes a reduction of the α-helix content of HSA, as obtained by far-UV CD spectroscopy. The average binding distance (r) between Pt­(II) complexes and HSA is obtained by Förster’s resonance energy-transfer theory. Also, a molecular docking simulation reveals that π–π-stacking and hydrophobic interactions between these complexes and HSA are significant. Furthermore, the interactions of platinum complexes, 2, with calf-thymus DNA (CT-DNA) are investigated. The UV–vis results and ethidium bromide competitive studies support an intercalative interaction of both Pt­(II) complexes with DNA. The new complexes 2 are also screened for anticancer activities. The results show that complexes 2 exhibit significant anticancer activity against the K562 (chronic myelogenous leukemia) cell line.