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

Natalia Miklášová,Peter Herich,Juan Carlos Dávila-Becerril,Jindra Valentová,Peter Takáč,Janka Leskovská,Joaquín Barroso-Flores,Jozef Kožíšek,Ján Mojžiš,Eva Fischer-Fodor

doi:10.3390/molecules26144369

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.

Highlights

Cancer is still one of the main causes of death in the world, for which one of the most common treatment for oncological diseases is based on combined therapies which use platinum metallodrugs such as cisplatin [1,2,3], oxaliplatin [4,5], carboplatin [4], nedaplatin [6], and lobaplatin [7,8]
Palladium(II) complexes exhibited great cytotoxicity on human prostate cancer cells (DU145, LnCaP, PC3) which confirmed the potential of such organometallic derivatives to inhibit the tumor cell growth and to initiate the apoptosis [28]
Our previous research was focused on the synthesis of palladium(II) complexes containing curcuminoids, which display a significant antiproliferative activity against several different human cancer cell lines [29,30,31,32,33]

Summary

Introduction

Cancer is still one of the main causes of death in the world, for which one of the most common treatment for oncological diseases is based on combined therapies which use platinum metallodrugs such as cisplatin [1,2,3], oxaliplatin [4,5], carboplatin [4], nedaplatin [6], and lobaplatin [7,8]. Metal-based complexes with more enhanced anti-cancer activity than conventional platinum drugs include metals such as ruthenium [13,14,15,16] and gold(III) [17,18], which have even been effective on cisplatin-resistant cell lines [19], as well as silver(I) complexes, which have proven increased cytotoxicity and selectivity as compared to cisplatin [20]. Several studies already confirmed the fact that palladium complexes show promising in vivo and in vitro antitumor activity They are able to internalize in the cells, to modify the secondary structure of the DNA, and to inhibit the cell growth selectively towards the cancer cell lines, comparable to platinum-based anticancer drugs [26]. Our research on palladium complexes containing the β-diketo moiety suggested that such compounds will not exert severe side effects as anticancer drugs, since they displayed a limited toxicity against normal, healthy cell populations such as colon epithelial cells [30], lymphocytes [31], and hepatocytes [33] in vitro

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Conclusion