Copper(I) complexes with phosphines P(p-OCH3-Ph)2CH2OH and P(p-OCH3-Ph)2CH2SarGly. Synthesis, multimodal DNA interactions, and prooxidative and in vitro antiproliferative activity

doi:10.1016/j.jinorgbio.2019.110926

Journal of Inorganic Biochemistry

Volume 203, February 2020, 110926

https://doi.org/10.1016/j.jinorgbio.2019.110926 Get rights and content

Highlights

•
Cytotoxicity was evaluated in vitro against 5 tumor cell lines and 3 non-tumor cell lines.
•
Methoxy groups in the phenyl rings of phosphine cause cytotoxicity increase of complexes.
•
Studied compounds are selective towards cancer cells in opposite to normal one.
•
Activity of Cu complex is associated with poor interaction with DNA.
•
Compounds generate low level of radicals.

Abstract

Phosphonium salt (p-OCH₃-Ph)₂P(CH₂OH)₂Cl (MPOHC), derived phosphine ligands without and with SarGly (Sarcosine-Glycine) peptide carrier P(p-OCH₃-Ph)₂CH₂OH (MPOH) and P(p-OCH₃-Ph)₂CH₂SarGly (MPSG), respectively, and two copper(I) complexes [Cu(I)(dmp)(MPOH)] (1-MPOH; dmp = (2,9-dimethyl-1,10-phenanthroline)) and [Cu(I)(dmp)(MPSG)] (1-MPSG) were synthesized. The resulting compounds were characterized by elemental analysis, 1D and 2D NMR and UV–Vis absorption spectroscopies, mass spectrometry, cyclic voltammetry and by X-ray diffraction analysis. Cytotoxicity of all compounds was evaluated in vitro against colon, lung, breast, pancreatic, prostate tumor cell lines, as well as towards non-tumor cell lines: lung, kidney and keratinocyte. Stable in biological medium in the presence of atmospheric oxygen, Cu(I) complexes exerted a cytotoxic effect higher than that elicited by cisplatin against tested cancer cell lines. The introduction of methoxy group onto the phenyl rings of the phosphine ligand coordinated to the copper(I) ion resulted in a relevant increase of cytotoxicity in the case of breast, pancreatic and prostate tumor cell lines in vitro. Attachment of a peptide carrier significantly increased the selectivity towards cancer cells. Fluorescence spectroscopic data (calf thymus DNA: CT-DNA) titration), together with analysis of DNA fragmentation (gel electrophoresis) and molecular docking provided evidence for the multimodal interaction of copper compounds with DNA and showed their unusual low genotoxicity. Additionally, copper complexes were able to generate reactive oxygen species as a result of redox processes, proved by fluorescence spectroscopy and cyclic voltamperometry.

Graphical abstract

High cytotoxic activity of [Cu(I)(neocuproine)(P(p-OCH₃-Ph)₂CH₂Sarcosine-Glycine)] is associated with poor interaction with DNA potentially related to negligible genotoxicity, and with low level of reactive oxygen species generation. All these experimental evidences indicate a mechanism of action different from DNA targeting typical of Pt(II) drugs and/or diimine-containing copper(I) complexes.

Introduction

Cancer diseases are one of the mankind biggest problems in recent decades. It is estimated that there will be >16 million new cancer cases every year by 2020 [1,2]. Currently, cisplatin and second-generation Pt(II) derivatives are widely used in cancer chemotherapy. However, intrinsic and/or acquired drug resistance, toxicity and side effects are major disadvantages of Pt(II)-drugs [3,4]. These clinical drawbacks have stimulated an extensive search for other metal-based agents with improved pharmacological properties [5,6].

Copper, as an essential element, is a crucial component of many metallo-proteins and -enzymes and plays a vital role in electron transfer reactions of many cellular processes [7,8]. However, it has been proven that copper is a key factor for angiogenesis [9,10], and elevated levels of this element have been found in many types of human cancers, including prostate, breast, colon, lung, and brain tumors [[11], [12], [13], [14]] suggesting that copper plays a role in the development and progression of cancer. On the other hand, the already demonstrated different response of normal and tumor cells to copper ions could be exploited for the development of novel copper complexes endowed with peculiar antineoplastic characteristics [[15], [16], [17]], for example, to overcome inherited and/or acquired resistance of cancer cells to cisplatin [[18], [19], [20], [21]].

Copper chemistry is dominated by copper(II) compounds, mainly due to the difficulty in stabilizing copper(I) compounds. However, examples of copper(I) complexes that combine phosphines and N,N-diimine ligands are characterized by excellent stability under aerobic conditions and significant cytotoxic activity against tumor cells [[19], [20], [21], [22], [23], [24], [25]]. Stability is promoted by the strong interaction of soft P-donor phosphine with the electron-rich Cu(I)-d¹⁰ metal center [26,27]. Mixed phosphine and N,N-diimine Cu(I) compounds resemble somehow the Cu(II) mixed-ligand arrangement proposed by the family of Casiopeinas® derivatives, that comprise N,N-diimine and O,O-donors (acetylacetonate or aminoacid chelates). To the best of our knowledge, Casiopeina III-ia ((aqua)(4,40-dimethyl-2,20-bipyridine)(acetylacetonato)copper(II)nitrate)] is the unique copper-based antitumor drug that has entered phase I clinical trials in Mexico [28].

Linking peptides via phosphine moiety to copper(I) complexes may decrease the overall lipophilicity and may enable selective delivery to tumor cells. In addition, peptide carriers may allow specific interactions with receptors over-expressed on tumor cells, including, e.g., integrin and somatostatin, folate, epidermal growth factor, or transferrin receptors [29]. It was reported that peptides such as RGD (Arg-Gly-Asp) or NGR (Asn-Gly-Arg) possess high selectivity towards cancer cells. Linking these peptides with anti-cancer drugs such as paclitaxel, fluorouracil or doxorubicin significantly increased cytotoxicity and decreased toxicity against healthy cells comparing to native drugs without peptide motif [[30], [31], [32], [33], [34], [35]].

This paper is a continuation of our on-going projects focused on cytotoxic activity of copper(I) complexes bearing phosphine ligands [[36], [37], [38], [39], [40], [41]]. We have recently reported the synthesis of the phosphine-peptide conjugate (P(Ph)₂CH₂-SarGly-OH, PSG) derived from Sarcosine-Glycine (SarGly), as a short template dipeptide model. The corresponding copper(I) complex ([Cu(I)(dmp)(P(Ph)₂CH₂-SarGly-OH)], 1-PSG, (dmp = 2,9-dimethyl-1,10-phenanthroline) exhibited high cytotoxicity and specificity towards human breast adenocarcinoma (MCF7) cell line [42].

Once verified that the introduction of a peptide arm onto the phosphine framework improved both hydrophilicity and selectivity of Cu(I) compounds, we thought to investigate the biological effects induced by the insertion of a methoxy group into phosphine phenyl rings. It was found that substitution on the 4-position of the phenyl ring is essential to increase cytotoxicity of several therapeutics [43,44]. What is more, it was proven that the insertion of methoxy group on ortho or meta position of the ¹⁸F–labeled benzyl triphenylphosphonium cations increased the liver and lung clearance [45]. The same motif was used by Lange et al. [46] and Hille et al. [47] where they demonstrated a selective action against platinum-resistant ovarian cancer cells and significant increase in activity at the MCF7 and HT-29 cell lines respectively. All these studies strengthened our intention to increase the cytotoxicity of copper(I) complexes with phosphine-peptide conjugate by introduction of a –OCH₃ group into the phosphine phenyl rings. For this purpose, we synthesized the new starting salt (p-OCH₃-Ph)₂P(CH₂OH)₂Cl (MPOHC), the derived phosphine ligands P(p-OCH₃-Ph)₂-CH₂-OH (MPOH) and P(p-OCH₃-Ph)₂-CH₂-SarGly-OH (MPSG), and the corresponding copper(I) complexes [Cu(I)(dmp)MPOH] (1-MPOH) and [Cu(I)(dmp)PSG] (1-MPSG).

Physicochemical properties of these compounds were determined by elemental analysis, 1D and 2D NMR and UV–Vis spectroscopies, and mass spectrometry. Additionally, (p-OCH₃-Ph)₂P(CH₂OH)₂Cl (MPOHC) and the copper(I) complex 1-MPOH were characterized by single crystal X-ray diffraction analysis along with, for comparison purposes, (Ph)₂P(CH₂OH)₂Cl (POHC). In vitro cytotoxic activity of these compounds was tested against five cancer cell lines mouse colon carcinoma (CT26), human lung adenocarcinoma (A549), human breast adenocarcinoma (MCF7), human pancreatic/duct carcinoma (PANC-1); human prostate carcinoma; derived from metastatic site: brain (DU-145), as well as towards one normal cell lines: primary line of human pulmonary fibroblasts (MRC5) and against two immortalized human embryonic kidney (HEK293T) and human keratinocyte (HaCat) cell lines. Moreover, mixed-ligand Cu(I) complexes containing methoxy-derived phosphine ligands (1-MPOH and 1-MPSG) were tested for their ability of interaction with DNA (intercalation, major or minor groove binding) using three different methods: fluorescence spectroscopy, gel electrophoresis and molecular docking. Since generation of free radicals is closely linked to the participation in the redox-active process we also analyzed the ability to produce reactive oxygen species (ROS) using fluorescent probe and by cyclic voltamperometry. The biological behaviour of methoxy-containing complexes was compared with that arising from methoxy-free compounds (1-POH and 1-PSG).

Section snippets

Materials

All syntheses and operations were carried out under an atmosphere of dry oxygen-free dinitrogen, using standard Schlenk techniques or a glove box. The compounds PSG, 1-PSG were prepared and characterized according to the literature [42] and POH, 1-POH were prepared with following similar procedures according to the literature [37]. SarGly peptide was purchased from Bachem (Switzerland). HP(p-OCH₃-Ph)₂, dmp, CuI, other chemicals and solvents were purchased from Sigma-Aldrich (Germany) and used

Synthesis

All syntheses were carried out under an atmosphere of dry oxygen-free dinitrogen, using standard Schlenk techniques or a glove box. Synthetic routes of compounds MPOHC phosphonium salt (p-OCH₃-Ph)₂P(CH₂OH)₂Cl), the corresponding phosphine ligand MPOH (p-OCH₃-Ph)₂PCH₂OH), and the phosphine-peptide conjugate MPSG (p-OCH₃-Ph)₂P-CH₂-SarGly) are presented in Scheme 1. Likewise, copper(I) complexes [Cu(I)(dmp)(MPOH)] (1-MPOH) and [Cu(I)(dmp)(MPSG)] (1-MPSG) are reported in Scheme 1.

Phosphonium and

Conclusion

Herein, we explored the antitumor potential of a new class of copper(I) complexes comprising a diimine (dmp) and the P(p-OCH₃-Ph)₂CH₂OH and P(p-OCH₃-Ph)₂CH₂SarGly phosphine ligands characterized by the presence of an –OCH₃ group in the phenyl rings and by the SarGly peptide motif. We proved that steric and electronic properties of –OCH₃ and SarGly have a major influence on the cytotoxic activity of copper(I) complexes, especially on their specificity. We proved that linking peptides via

Abbreviations

OCH₃

methoxy group

DNA

deoxyribonucleic acid

NGR

peptide Asn-Gly-Arg

RGD

peptide Arg-Gly-Asp

SarGly

peptide sarcosine-glycine

PET

positron emission tomography

PEPTs

H+/peptide transporters

dmp

2,9-dimethyl-1,10-phenanthroline

NMR

nuclear magnetic resonance spectroscopy

DMEM

Dulbecco's Modified Eagle Medium

DMSO

dimethyl sulfoxide

diimine

H₃PO₄

phosphoric acid

MeOH

methanol

ESI(+)MS

electrospray ionization in the positive ion mode

neocupr

neocuproine

mass spectrometry

CT26

mouse colon carcinoma

A549

human lung adenocarcinoma

Declaration of competing interest

None of the authors of the above manuscript has declared any conflict of interest.

Acknowledgment

The authors gratefully acknowledge financial support from the Polish National Science Centre (Grant 2016/23/D/ST5/00269) and from Ministry of Science and Higher Education (Grants 1233/M/WCH/13 and 1500/M/WCH/15). SK and MKL were supported by Ministry of Science and Higher Education (grant 4478/E-344/M/2018). We would like to thank Prof. Alina Bieńko for motivation and support.

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Citation Excerpt :
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Copper(I) complexes with phosphines P(p-OCH3-Ph)2CH2OH and P(p-OCH3-Ph)2CH2SarGly. Synthesis, multimodal DNA interactions, and prooxidative and in vitro antiproliferative activity

Highlights

Abstract

Graphical abstract

Introduction

Section snippets

Materials

Synthesis

Conclusion

Abbreviations

Declaration of competing interest

Acknowledgment

Cancer Treat. Rev.

Biochem. Pharmacol.

Lung Cancer

Biochim. Biophys. Acta

In Vitro

Eur. J. Med. Chem.

Polyhedron

Polyhedron

Biomed. Pharmacother.

Bioorg. Med. Chem.

Biochem. Pharmacol.

Drug Resist. Updat.

J. Inorg. Biochem.

J. Mol. Struct.

J. Inorg. Biochem.

Bioorg. Med. Chem. Lett.

Nucl. Med. Biol.

Eur. J. Med. Chem.

J. Lumin.

Int. J. Pharm.

J. Less-Common Metals

Polyhedron

CA Cancer J. Clin.

CA Cancer J. Clin.

Chem. Rev.

J Appl Pharm Sci

Clin. Pharmacol. Ther.

Curr. Biol.

Curr. Med. Chem.

Clin. Exp. Pharmacol. Physiol.

Int. J. Mol. Sci.

Oncotarget

Curr. Med. Chem.

Nat. Rev. Cancer

Amino Acids

J. Coord. Chem.

Met Based Drugs

Chem. Rev.

Bioinorg. Chem.

Mol. Cancer Ther.

Copper(I) complexes with phosphines P(p-OCH₃-Ph)₂CH₂OH and P(p-OCH₃-Ph)₂CH₂SarGly. Synthesis, multimodal DNA interactions, and prooxidative and in vitro antiproliferative activity