Orthopalladated N,N-dimethyl-1-phenethylamine compounds containing 2,6-lutidine: Synthesis, DNA binding studies and cytotoxicity evaluation

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Zanetti, Renan D. ; da Cunha, Gislaine A. ; Moreira, Mariete B. ; Farias, Renan L. ; de Souza, Ronan F. F. ; de Godoy, Paulo R. D. V. ; Brassesco, Maria Sol ; Rocha, Fillipe V. ; Lima, Mauro A. ; Mauro, Antonio E. ; Netto, Adelino V. G.

• Document type: Journal article
• Source: Polyhedron; v. 229, p. 11-pg., 2023-01-01.

Abstract

Metathetical reactions involving [Pd(C2,N-dmpa)(mu-Cl)]2 (1) and the appropriate halides/pseudohalides salts afforded cyclopalladated dimers of the type [Pd(C2,N-dmpa)(mu-X)]2 (dmpa = S(_ ) enantiomer of N,N-dimethyl-1-phenethylamine; {X = Cl (1) and N3 (2)}. Mononuclear compounds of general formulae [Pd(C2,N-dmpa)(X)(lut)] {X = Cl (1a) and N3 (2a)} were obtained by bridge-splitting reactions involving the corresponding [Pd(C2,N- dmpa)(mu-X)]2 with 2,6-lutidine (lut) in the 1:2 M ratio at room temperature. Both the cyclopalladated compounds were characterized by means of elemental analysis, FT-IR, Raman, 1H and 13C NMR spectroscopy. The anti -proliferative activity of the mononuclear compounds 1a -2a was evaluated towards human glioblastoma (U251 and T98G) and melanoma cell lines (HT144 and LB373) and their IC50 values determined between 1 and 6 mu M. In most cases, the cytotoxic effects of compounds 1a -2a showed to be similar to those of cisplatin (depending on the cell line), what is of utmost importance when considering treatment alternatives for these aggressive tumor types. Binding studies on the representative compound 2a towards ct-DNA, however, showed low or no affinity, suggesting that the observed cytotoxicity against the human cell lines may involve different mechanisms of action compared to that of the platinum-based chemotherapy drug. The ability of 1a to induce the inhibition of topoisomerase II alpha activity has also been investigated. These cyclopalladated compounds can be transported and distributed through the body by human serum albumin (HSA), as observed by competition and computational studies with the protein. These findings are very promising and have motivated further studies for the design of new and bioactive cyclopalladated compounds for future medicinal purposes. (AU)

• FAPESP's process: 09/54011-8 - Acquisition of a single-crystal X-ray diffractometer for the structural analysis of small molecules and proteins
• Grantee: Victor Marcelo Deflon
• Support Opportunities: Multi-user Equipment Program
• FAPESP's process: 12/15486-3 - Pd(II) compounds: synthesis, cytotoxicity, and DNA binding studies
• Grantee: Regina Celia Galvao Frem
• Support Opportunities: Regular Research Grants
• FAPESP's process: 16/17711-5 - INVESTIGATION OF THE ANTITUMOR POTENTIAL OF PALLADIUM(II) COMPOUNDS CONTAINING ORTHOMETALLATED OR N,S-DONOR LIGANDS
• Grantee: Adelino Vieira de Godoy Netto
• Support Opportunities: Regular Research Grants