Evaluation of Antiproliferative Palladium(II) Complexes of Synthetic Bisdemethoxycurcumin towards In Vitro Cytotoxicity and Molecular Docking on DNA Sequence

Abstract

Metallodrugs form a large family of therapeutic agents against cancer, among which is cisplatin, a paradigmatic member. Therapeutic resistance and undesired side effects to Pt(II) related drugs, prompts research on different metal-ligand combinations with potentially enhanced biological activity. We present the synthesis and biological tests of novel palladium(II) complexes containing bisdemethoxycurcumin (BDMC) 1 and 2. Complexes were fully characterized and their structures were determined by X-ray diffraction. Their biological activity was assessed for several selected human tumor cell lines: Jurkat (human leukaemic T-cell lymphoma), HCT-116 (human colorectal carcinoma), HeLa (human cervix epitheloid carcinoma), MCF-7 (human breast adenocarcinoma), MDA-MB-231 (human mammary gland adenocarcinoma), A549 (human alveolar adenocarcinoma), Caco-2 (human colorectal carcinoma), and for non-cancerous 3T3 cells (murine fibroblasts). The cytotoxicity of 1 is comparable to that of cisplatin, and superior to that of 2 in all cell lines. It is a correlation between IC₅₀ values of 1 and 2 in the eight studied cell types, promising a potential use as anti-proliferative drugs. Moreover, for Jurkat cell line, complexes 1 and 2, show an enhanced activity. DFT and docking calculations on the NF-κB protein, Human Serum Albumin (HSA), and DNA were performed for 1 and 2 to correlate with their biological activities.

Keywords: DFT calculations; DNA-binding; HSA binding; cytotoxicity; palladium(II) complexes; synthetic bisdemethoxycurcumin; transcription factor NF-κB.

Scheme 1

Synthetic pathways of palladium(II) complexes 1 and 2.

Figure 1

Arrangement of cations for complex 1, including hydrogen interactions. Multi-disordered acetate anions and solvents molecules are omitted for clarity. Displacement ellipsoids are drawn at the 50% probability level.

Figure 2

Arrangement of cations for complex 2, including hydrogen interactions. Multi-disordered acetate anions and solvents molecules are omitted for clarity. Displacement ellipsoids are drawn at the 50% probability level.

Figure 3

Optimized geometry of compounds 1 (left) and 2 (right) at the ωB97XD/LANL2DZ level of theory.

Figure 4

Binding energies [−kcal/mol] −ΔG_b for the ten highest-ranked binding modes for compounds 1 (yellow) and 2 (green) to HSA.

Figure 5

(a) Intermolecular interactions for compound 1 and HSA (b) Intermolecular interactions for compound 2 and HSA.

Figure 6

Binding energies [-kcal/mol] −ΔG_b for the ten highest ranked binding modes for compounds 1 (yellow) and 2 (green) to the transcription factor NF-κB.

Figure 7

Binding energies −ΔG_b [-kcal/mol] for the ten highest ranked binding modes for compounds 1 (yellow) and 2 (green) to a DNA strand.

Figure 8

(a) DNA-1 complex the inset shows a detail of complex 1 stacking to cytosine 11 with a mean interplanar distance of 2.46 Å (b) DNA-2 complex the inset shows a detail of complex 2 stacking to cytosine 11 with a mean interplanar distance of 2.22 Å.

Figure 9

Sigmoidal dose-response curves for complex 1 (A) and 2 (B) in different cell lines after 72 h of incubation (data are presented as the mean + SD of three independent measurements performed in triplicate).

Figure 10

Cytotoxicity (IC₅₀) of palladium(II) complexes 1, 2 and cisplatin (as standard) in 8 different cell lines.