Selective Cu(I) complex with phosphine-peptide (SarGly) conjugate contra breast cancer: Synthesis, spectroscopic characterization and insight into cytotoxic action

• Published in: Journal of inorganic biochemistry Vol. 186; pp. 162 - 175
• Main Authors: Komarnicka, Urszula K., Kozieł, Sandra, Starosta, Radosław, Kyzioł, Agnieszka
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.09.2018
• Subjects: A549 Cells; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Conjugate; Coordination Complexes - chemical synthesis; Coordination Complexes - chemistry; Coordination Complexes - pharmacology; Copper - chemistry; Copper - pharmacology; Copper(I) complex; DNA; Female; Humans; MCF-7 Cells; Peptide carriers; Peptides - chemistry; Peptides - pharmacology; Phosphines - chemistry; Phosphines - pharmacology; ROS; Peptide carriers; Breast cancer; Conjugate; DNA; Copper(I) complex; ROS
• ISSN: 0162-0134; 1873-3344
• DOI: 10.1016/j.jinorgbio.2018.06.009

The main disadvantage of conventional anticancer chemotherapy is the inability to deliver the correct amount of drug directly to cancer. Those molecular delivering systems are very important to destroy cancer cells selectively. Herein we report synthesis of phosphine-peptide conjugate (Ph2PCH2-Sar-Gly-OH, PSG) derived from SarGly (sarcosine-glycine), which can be easily exchanged to other peptide carriers, its oxide (OPh2PCH2-Sar-Gly-OH, OPSG) and the first copper(I) complex ([CuI(dmp)(P(Ph)2CH2-Sar-Gly-OH)], 1-PSG, where dmp stands for 2,9-dimethyl-1,10-phenanthroline). The compounds were characterized by elemental analysis, NMR (1D, 2D), UV–Vis spectroscopy and DFT (Density Functional Theory) methods. PSG and 1-PSG proved to be stable in biological medium in the presence of atmospheric oxygen for several days. The cytotoxicity of the compounds and cisplatin was tested against cancer cell lines: mouse colon carcinoma (CT26; 1-PSGIC50 = 3.12 ± 0.1), human lung adenocarcinoma (A549; 1-PSGIC50 = 2.01 ± 0.2) and human breast adenocarcinoma (MCF7; 1-PSGIC50 = 0.98 ± 0.2) as well as against primary line of human pulmonary fibroblasts (MRC-5; 1-PSGIC50 = 78.56 ± 1.1). Therapeutic index for 1-PSG (MCF7) equals 80. Intracellular accumulation of 1-PSG complex increased with time and was much higher (96%) inside MCF7 cancer cells than in normal MRC5 cells (20%). Attachment of SarGly to cytotoxic copper(I) complex via phosphine motif improved selectivity of copper(I) complex 1-PSG into the cancer cells. Precise mechanistic study revealed that the 1-PSG complex causes apoptotic cells MCF7 death with simultaneous decrease of mitochondrial membrane potential and increase of caspase-9 and -3 activities. Additionally, 1-PSG generated high level of reactive oxygen species that was the reason for oxidative damages to the sugar–phosphate backbone of plasmid DNA. Chemotherapy is still one of the major approaches to treat cancer. However, the main disadvantage of conventional chemotherapy is the inability to deliver the correct amount of drug directly to cancer cells without affecting healthy cells. Cytotoxic copper(I) complexes connected with phosphine-peptide conjugate as a carrier can improve selective transport. [Display omitted] •Phosphine derived from sarcosine-glycine and its Cu(I) complexes were synthesized.•Compounds cytotoxicity was tested in vitro towards: CT26, A549, MCF7 and MRC5 cell lines.•Studied complexes caused single-stranded cleavage of plasmid DNA.•Compounds induce apoptosis via caspase-dependent mitochondrial pathway.•Studied compounds are selective towards cancer cells in opposite to normal one.