Cationic Pd(II)/Pt(II) 5,5-diethylbarbiturate complexes with bis(2-pyridylmethyl)amine and terpyridine: Synthesis, structures,DNA/BSA interactions, intracellular distribution, cytotoxic activity and induction of apoptosis.
Four new cationic Pd(II) and Pt(II) 5,5-diethylbarbiturate (barb) complexes, [M(barb)(bpma)]X·H2O [M = Pd(II), X = Cl (1); M = Pt(II), X = NO3(-) (2)] and [M(barb)(terpy)]NO3·0.5H2O [M = Pd(II) (3); M = Pt(II) (4)], where bpma = bis(2-pyridylmethyl)amine and terpy = terpyridine, were synthesized and characterized by elemental analysis, IR, UV–vis, NMR, ESI-MS and X-ray crystallography. The DNA binding properties of the cationic complexes were investigated by spectroscopic titrations, displacement experiments, viscosity, DNA melting and electrophoresis measurements. The results revealed that the complexes effectively bind to FS-DNA (fish sperm DNA) via intercalative/minor groove binding modes with intrinsic binding constants (Kb) in the range of 0.50 × 10(4)–1.67 × 10(5) M(-1). Absorption, emission and synchronous fluorescence measurements showed strong association of the complexes with protein (BSA) through a static mechanism. The mode of interaction of complexes towards DNA and protein was also supported by molecular docking. Complexes 1 and 3 showed significant nuclear uptake in HT-29 cells. In addition, 1 and 3 showed higher inhibition than cisplatin on the growth of MCF-7 and HT-29 cells and induced apoptosis on these cells much more effectively than the rest of the complexes as evidenced by pyknotic nuclear morphology. The levels of caspase-cleaved cytokeratin 18 (M30 antigen) in HT-29 cells treated with 1 and 3 increased in a dose-dependent manner, suggesting apoptosis. Moreover, qRT-PCR experiments showed that 1 and 3 caused significant increases in the expression of TNFRSF10B in HT-29 cells, indicating the initiation of apoptosis via cell surface death receptors.
Department of Chemistry, Faculty of Arts and Sciences, Uludag University, 16059 Bursa, Turkey.
Ceyda
C
Icsel
Department of Chemistry, Faculty of Arts and Sciences, Uludag University, 16059 Bursa, Turkey. Electronic address: vtyilmaz@uludag.edu.tr.
Veysel T
VT
Yilmaz
Department of Chemistry, Faculty of Arts and Sciences, Uludag University, 16059 Bursa, Turkey.
Yunus
Y
Kaya
Department of Medical Biochemistry, Medical School, Uludag University, 16059 Bursa, Turkey.
Selvi
S
Durmus
Department of Biology, Faculty of Arts and Sciences, Uludag University, 16059 Bursa, Turkey.
Mehmet
M
Sarimahmut
Department of Physics, Faculty of Arts and Sciences, Ondokuz Mayis University, 55159 Samsun, Turkey.
Orhan
O
Buyukgungor
Department of Medical Biochemistry, Medical School, Uludag University, 16059 Bursa, Turkey.
Engin
E
Ulukaya
D000595:Amino Acid Sequence; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects*; D001463:Barbiturates / Q000737:chemistry*; D001483:Base Sequence; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D019073:HT29 Cells; D006801:Humans; D061986:MCF-7 Cells; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D009944:Organoplatinum Compounds / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D010165:Palladium / Q000737:chemistry*; D011485:Protein Binding; D011725:Pyridines / Q000737:chemistry; D012710:Serum Albumin, Bovine / Q000737:chemistry / Q000378:metabolism*
D000970:Antineoplastic Agents; D001463:Barbiturates; C000599032:N,N-bis(2-pyridylmethyl)amine; D009944:Organoplatinum Compounds; D011725:Pyridines; D012710:Serum Albumin, Bovine; D010165:Palladium; D004247:DNA
Anticancer activity; DNA/BSA binding; Electrophoresis; Nuclear uptake; Pd(II)/Pt(II) 5,5-Diethylbarbiturate complexes