Spectroscopic determination of binding between human serum albumin and a platinum(II) dimethylsulfoxide complex

Abstract

We have used electronic absorption and fluorescence spectroscopy to study binding between a platinum(II) dimethylsulfoxide complex (cis-[Pt(DMSO) 2 Cl 2 ]) and human serum albumin (HSA), and the effect of complexation on the structure of the protein. We have calculated the binding parameters for binding between cis-[Pt(DMSO) 2 Cl 2 ] and HSA. We have determined the binding constant K B = (1.2 ± 0.1)⋅10 3 M -1 and the Hill coefficient h = 1.03 ± 0.1. We have determined that binding between cis-[Pt(DMSO) 2 Cl 2 ] and the protein leads to a change in the internal packing of the macromolecule. Introduction. As we know [1, 2], cisplatin (cis-[Pt(NH 3 ) 2 Cl 2 ]) is used as an effective drug for treatment of cancers: ovarian tumors, sarcomas, breast cancer, and prostate cancer. However, the therapeutic action of the drug is accompanied by various side effects (vomiting, nephrotoxicity, neurotoxicity, alopecia, ototoxicity, etc.) which are due to inactivation of proteins. Biotransformation of cisplatin in the body occurs by binding platinum to serum albumin [3]. This protein can reversibly bind to drugs and biologically active substances and is distinguished by rather low ligand-protein binding selectivity. It has been established that binding with the active centers of albumin occurs as a result of different types of interactions: hydrophobic, dipole, electrostatic, via van der Waals forces, hydrogen bonds. Complexes formed in this case are unstable and readily dissociated; the binding energy is no greater than 8-10 kcal/mol, which allows the ligands to easily interact with other substances [4]. The problem is complex because the structural diversity of drugs requires an individual approach to experimental assessment of these interactions, taking into account the spectral, physicochemical, and structural characteristics of the studied drug.In order to reduce the toxicity of cancer drugs based on Pt(II), sulfur-containing ligands (thiols, thiocarbamates) are used in third-generation drugs [5,6]. In this work, as the sulfur-containing compound we selected dimethylsulfoxide (DMSO), which has unique biomedical and pharmacological properties: it penetrates through biological membranes, improves transport properties of drugs, stimulates the immune system, and reduces the effects of chemotherapy and radiation therapy [7,8].Experimental Section. We used human serum albumin (HSA) from Sigma Chemical (USA), a solution of 0.9% sodium chloride (physiological saline) from the pharmaceutical company Likvor (Armenia). Cis-[Pt(DMSO) 2 Cl 2 ] was synthesized as in [9]. In all the experiments, we used a 0.9% sodium chloride solution to prepare the protein solutions. The protein concentration (0.4 mg/mL) in solution was determined using electronic absorption spectra in the UV region (UV spectroscopy), where we used the molar absorption coefficient ε = 36.500 M -1 ⋅cm -1 for λ = 280 nm [10]. The concentration of cis-[Pt(DMSO) 2 Cl 2 ] was varied within the range (0-5)⋅10 -5 M. The electronic absorption spectra of the solutions were mea...

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