Role of Seroalbumin in the Cytotoxicity of cis-Dichloro Pt(II) Complexes with (N^N)-Donor Ligands Bearing Functionalized Tails

Abstract

Given the potent anticancer properties of cis-diamminedichloroplatinum(II) and knowing its mode of action, we synthesized four new cis-[PtCl(N^N)] organoplatinum complexes, two with N-substituted pbi ligands (pbiR = 1-R-2-(2-pyridyl)benzimidazole) (namely, 1 and 2) and two more with 4,4'-disubstituted bpy ligands (bpy = 2,2'-bipyridine) (namely, 3 and 4). We explored their cytotoxicity and ability to bind to deoxyguanosine monophosphate (dGMP), DNA, and albumin models. By H NMR and UV-vis spectroscopies, circular dichroism, agarose gel electrophoresis, differential scanning calorimetry measurements, and density functional theory calculations, we verified that only 3 can form aquacomplex species after dimethyl sulfoxide solvation; surprisingly, 1, 2, and 3 can bind covalently to DNA, whereas 4 can form a noncovalent complex. Interestingly, only complexes 1 and 4 exhibit good cytotoxicity against human ovarian carcinoma (HeLa) cell line, whereas 2 and 3 are inactive. Although lung carcinoma (A549) cells are more resistant to the four platinum complexes than HeLa cells, when the protein concentration in the extracellular media is lower, the cytotoxicity becomes substantially enhanced. By native electrophoresis of bovine seroalbumin (BSA) and inductively coupled plasma mass spectrometry uptake studies we bear out, on one hand, that 2 and 3 can interact strongly with BSA and its cellular uptake is negligible and, on the other hand, that 1 and 4 can interact with BSA only weakly, its cellular uptake being higher by several orders. These results point up the important role of the protein binding features on their biological activity and cellular uptake of cis-"PtCl" derivatives. Our results are valuable in the future rational design of new platinum complexes with improved biological properties, as they expose the importance not only of their DNA binding abilities but also of additional factors such as protein binding.

Pyridylbenzimidazole‐Based Gold(III) Complexes: Lysozyme Metalation, DNA Binding Studies, and Biological Activity

“…This compares well with the published data of [PtCl 2 L SO3H ] . The low cytotoxic activity of isoelectronic and isostructural [PtCl 2 L SO3H ] was attributed to sequestration by human serum albumin . Complex 1 (6.1 nM) exhibited higher cytotoxic activity than 3 (19.40 nM).…”

DNA/bovine serum albumin binding and cytotoxicity of transition metal ternary complexes based on sulfamethazine and bromazepam drugs

“…The low cytotoxicity of complex 1 may be attributed to its sequestration by human serum albumin. [ 44 ]…”

Interacción de ARN con doxorrubicina: Influencia del ligando y del metal en la actividad biológica de complejos organometálicos

“…In a previous work we demonstrated that cytotoxicity of platinum complexes depended on their sequestration by seroalbumin [156]: at higher interaction with BSA, lower amount of complex reach the cell. Native acrylamide gel electrophoresis (Figure 19) exhibit the interaction of the complexes with BSA, interacts with BSA but also with DNA.…”

“…Since albumin is the most abundant plasma protein, the interaction of the studied compounds with this biomolecule can easily affect their bioavailability [156]. Therefore, to verify if the differences reported above between cellular uptake of [Ir(ppy)2(HNAIP)] + and [Rh(ppy)2(HNAIP)] + could be attributed to the interaction with albumin and, consequently, to a reduction in the final drug concentration that reaches the cell, the interaction with BSA was tested for the two complexes and also for the ligand.…”

“…Anticancer activity of some new metal complexes is conditioned by protein binding which improves accumulation in the tumour [213]. However serum protein interaction, can negatively affect in the cellular uptake due to protein sequestration of the drug [156]. Considering this fact, in an attempt to explain the observed lack of correlation between cytotoxicity and cellular uptake, the interaction of these complexes with bovine serum albumin (BSA) was studied due to its similarity with human serum albumin (HSA), present in blood plasma.…”