Palladium(II) Pincer Complexes of Functionalized Amides with S-Modified Cysteine and Homocysteine Residues: Cytotoxic Activity and Different Aspects of Their Biological Effect on Living Cells

Abstract

In the search for potential new metal-based antitumor agents, two series of nonclassical palladium(II) pincer complexes based on functionalized amides with S-modified cysteine and homocysteine residues have been prepared and fully characterized by 1D and 2D NMR ( 1 H, 13 C, COSY, HMQC or HSQC, 1 H− 13 C, and 1 H− 15 N HMBC) and IR spectroscopy and, in some cases, X-ray diffraction. Most of the resulting complexes exhibit a high level of cytotoxic activity against several human cancer cell lines, including colon (HCT116), breast (MCF7), and prostate (PC3) cancers. Some of the compounds under consideration are also efficient in both native and doxorubicin-resistant transformed breast cells HBL100, suggesting the prospects for the creation of therapeutic agents based on the related compounds that would be able to overcome drug resistance. An analysis of different aspects of their biological effects on living cells has revealed a remarkable ability of the S-modified derivatives to induce cell apoptosis and efficient cellular uptake of their fluorescein-conjugated counterpart, confirming the high anticancer potential of Pd(II) pincer complexes derived from functionalized amides with S-donor amino acid pendant arms.

Stereoselective synthesis of oxime containing Pd(ii) compounds: highly effective, selective and stereo-regulated cytotoxicity against carcinogenic PC-3 cells

“…A variety of palladium "rule-breaker" compounds has shown higher in vitro antitumor activity than their Pt(II) counterparts or cisplatin. 14,15,[97][98][99][100][101][102][103][104][105] The IC 50 values of compound 2a′ are within the range of other highly cytotoxic Pd(II) compounds described so far. For example, our derivative is ca.…”

“…55 times more cytotoxic in prostatic cancer PC-3 cells than the promising [Pd(sac)(terpy)](sac)•4H 2 O (sac = saccharinate, terpy = 2,2′:6′,2″terpyridine), which has shown significant antitumor effects on Balb/c mice in vivo, and inhibit cell growth in vitro with IC 50 values of 9.6 µM in PC-3 and 3.05 µM in MCF-7. 106,107 Other notable examples in the literature are the thiosemicarbazone containing compound [Pd(Ac4Et) 2 ] (Ac4Et = 2-acetyl pyridine 4-N-ethyl thiosemicarbazone, IC 50 = 0.14 µM, in MCF-7 100 ), some monofunctional Pd(II) derivatives with N,N,S pincer ligands (IC 50 within the range 2.6-28 µM in PC-3 and 6.4-70.0 µM in MCF-7 99,108 ) and a variety of cyclopalladated complexes with N-heterocyclic carbenes (IC 50 within the range 0.4-1.8 µM in HeLa and active against HeLa xenograft mice in vivo 100 ).…”

Novel Pd(ii) pincer complexes bearing salicylaldimine-based benzothiazole derivatives: synthesis, structural characterization, DNA/BSA binding, and biological evaluation

“…Recently, Pd(II) pincer complexes containing tridentate ligands (N,C,N-, O,N,N-, and S,N,N-chelating) were synthesized and their anticancer activities were demonstrated. [16][17][18][19] Benzothiazole-imine Schiff bases are considered ''privileged ligands'', among the tridentate chelating ligands bound to Pd(II) ion, because of their facile synthesis, great structural flexibility, and biological applications. [20][21][22] Indeed, benzothiazole-imine Schiff bases constitute a versatile ligand system in coordination chemistry because they enable the formation of stable complexes via 5,5-or 5,6-membered chelate ring with the metal centre in a variety of oxidation states and coordination geometries.…”

“…19,20,23 Over the last few years, Pd(II) complexes bearing pincer ligands have been widely studied in terms of synthesis and applications in medicinal chemistry. 16,19,24,25 Churusova et al reported the cytotoxicity of Pd(II) pincer complexes with N-picolinylamides ligands against various normal and cancer cell lines. The results suggested that most of the complexes with an S-donor atom showed higher toxicity against cancer cells than cisplatin.…”

Half-Sandwich Cyclometalated RhIII Complexes Bearing Thiolate Ligands: Biomolecular Interactions and In Vitro and In Vivo Evaluations

“…Among the existing anticancer remedies with metal atoms, Pt-containing compounds (for instance carboplatin, oxaliplatin, and cisplatin) are the most effective and frequently used drugs with long-lasting therapeutic success in the treatment of cancer patients. − However, chemotherapy with the Pt-based drugs suffers from many limitations, serious side effects, and, in some cases, lack of selectivity . These barriers and drawbacks have engaged the cancer research field to use other transition metals such as gold, ruthenium, iridium, rhodium, and palladium . Some of these metal complexes, auranofin (Au complex), BOLD-100, and TLD1433 (Ru complexes), progressed to clinical trials and provided an appropriate alternatives for Pt antiproliferative agents.…”