Publications by authors named "Marta Jakubaszek"

11 Publications

  • Page 1 of 1

Ruthenium(II) Complex Containing a Redox-Active Semiquinonate Ligand as a Potential Chemotherapeutic Agent: From Synthesis to Studies.

J Med Chem 2020 05 7;63(10):5568-5584. Epub 2020 May 7.

Chimie ParisTech, PSL University, CNRS, Institute of Chemistry for Life and Health Sciences, Laboratory for Inorganic Chemical Biology, F-75005 Paris, France.

Chemotherapy remains one of the dominant treatments to cure cancer. However, due to the many inherent drawbacks, there is a search for new chemotherapeutic drugs. Many classes of compounds have been investigated over the years to discover new targets and synergistic mechanisms of action including multicellular targets. In this work, we designed a new chemotherapeutic drug candidate against cancer, namely, () (DIP = 4,7-diphenyl-1,10-phenanthroline; sq = semiquinonate ligand). The aim was to combine the great potential expressed by Ru(II) polypyridyl complexes and the singular redox and biological properties associated with the catecholate moiety. Experimental evidence (., X-ray crystallography, electron paramagnetic resonance, electrochemistry) demonstrates that the semiquinonate is the preferred oxidation state of the dioxo ligand in this complex. The biological activity of was then scrutinized and , and the results highlight the promising potential of this complex as a chemotherapeutic agent against cancer.
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http://dx.doi.org/10.1021/acs.jmedchem.0c00431DOI Listing
May 2020

Synthesis, Characterization, Cytotoxic Activity, and Metabolic Studies of Ruthenium(II) Polypyridyl Complexes Containing Flavonoid Ligands.

Inorg Chem 2020 Apr 19;59(7):4424-4434. Epub 2020 Mar 19.

Chimie ParisTech, PSL University, CNRS, Institute of Chemistry for Life and Health Sciences, Laboratory for Inorganic Chemical Biology, F-75005 Paris, France.

Four novel monocationic Ru(II) polypyridyl complexes were synthesized with the general formula [Ru(DIP)flv]X, where DIP is 4,7-diphenyl-1,10-phenanthroline, flv stands for the flavonoid ligand (5-hydroxyflavone in [Ru(DIP)(5-OHF)](PF), genistein in [Ru(DIP)(gen)](PF), chrysin in [Ru(DIP)(chr)](OTf), and morin in [Ru(DIP)(mor)](OTf)), and X is the counterion, PF, and OTf ̅ (triflate, CFSO̅), respectively. Following the chemical characterization of the complexes by H and C NMR, mass spectrometry, and elemental analysis, their cytotoxicity was tested against several cancer cell lines. The most promising complex, [Ru(DIP)(gen)](PF), was further investigated for its biological activity. Metabolic studies revealed that this complex severely impaired mitochondrial respiration and glycolysis processes, contrary to its precursor, Ru(DIP)Cl, which showed a prominent effect only on the mitochondrial respiration. In addition, its preferential accumulation in MDA-MB-435S cells (a human melanoma cell line previously described as mammary gland/breast; derived from metastatic site: pleural effusion), which are used for the study of metastasis, explained the better activity in this cell line compared to MCF-7 (human, ductal carcinoma).
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http://dx.doi.org/10.1021/acs.inorgchem.9b03562DOI Listing
April 2020

Rationally Designed Long-Wavelength Absorbing Ru(II) Polypyridyl Complexes as Photosensitizers for Photodynamic Therapy.

J Am Chem Soc 2020 04 25;142(14):6578-6587. Epub 2020 Mar 25.

Chimie ParisTech, PSL University, CNRS, Institute of Chemistry for Life and Health Sciences, Laboratory for Inorganic Chemical Biology, 75005 Paris, France.

The utilization of photodynamic therapy (PDT) for the treatment of various types of cancer has gained increasing attention over the last decades. Despite the clinical success of approved photosensitizers (PSs), their application is sometimes limited due to poor water solubility, aggregation, photodegradation, and slow clearance from the body. To overcome these drawbacks, research efforts are devoted toward the development of metal complexes and especially Ru(II) polypyridine complexes based on their attractive photophysical and biological properties. Despite the recent research developments, the vast majority of complexes utilize blue or UV-A light to obtain a PDT effect, limiting the penetration depth inside tissues and, therefore, the possibility to treat deep-seated or large tumors. To circumvent these drawbacks, we present the first example of a DFT guided search for efficient PDT PSs with a substantial spectral red shift toward the biological spectral window. Thanks to this design, we have unveiled a Ru(II) polypyridine complex that causes phototoxicity in the very low micromolar to nanomolar range at clinically relevant 595 nm, in monolayer cells as well as in 3D multicellular tumor spheroids.
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http://dx.doi.org/10.1021/jacs.9b13620DOI Listing
April 2020

Increasing the Cytotoxicity of Ru(II) Polypyridyl Complexes by Tuning the Electronic Structure of Dioxo Ligands.

J Am Chem Soc 2020 04 17;142(13):6066-6084. Epub 2020 Mar 17.

Department of Chemistry, University of Konstanz, Universitätsstrasse 10, D-78457 Konstanz, Germany.

Due to the great potential expressed by an anticancer drug candidate previously reported by our group, namely, Ru-sq ([Ru(DIP)(sq)](PF) (DIP, 4,7-diphenyl-1,10-phenanthroline; sq, semiquinonate ligand), we describe in this work a structure-activity relationship (SAR) study that involves a broader range of derivatives resulting from the coordination of different catecholate-type dioxo ligands to the same Ru(DIP) core. In more detail, we chose catechols carrying either an electron-donating group (EDG) or an electron-withdrawing group (EWG) and investigated the physicochemical and biological properties of their complexes. Several pieces of experimental evidences demonstrated that the coordination of catechols bearing EDGs led to deep-red positively charged complexes - in which the preferred oxidation state of the dioxo ligand is the uninegatively charged semiquinonate. Complexes and , on the other hand, are blue/violet neutral complexes, which carry an EWG-substituted dinegatively charged catecholate ligand. The biological investigation of complexes - led to the conclusion that the difference in their physicochemical properties has a strong impact on their biological activity. Thus, complexes - expressed much higher cytotoxicities than complexes and . Complex constitutes the most promising compound in the series and was selected for a more in depth biological investigation. Apart from its remarkably high cytotoxicity (IC = 0.07-0.7 μM in different cancerous cell lines), complex was taken up by HeLa cells very efficiently by a passive transportation mechanism. Moreover, its moderate accumulation in several cellular compartments (i.e., nucleus, lysosomes, mitochondria, and cytoplasm) is extremely advantageous in the search for a potential drug with multiple modes of action. Further DNA metalation and metabolic studies pointed to the direct interaction of complex with DNA and to the severe impairment of the mitochondrial function. Multiple targets, together with its outstanding cytotoxicity, make complex a valuable candidate in the field of chemotherapy research. It is noteworthy that a preliminary biodistribution study on healthy mice demonstrated the suitability of complex for further in vivo studies.
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http://dx.doi.org/10.1021/jacs.9b12464DOI Listing
April 2020

A Maltol-Containing Ruthenium Polypyridyl Complex as a Potential Anticancer Agent.

Chemistry 2020 Apr 26;26(22):4997-5009. Epub 2020 Mar 26.

Chimie ParisTech, PSL University, CNRS, Institute of Chemistry for Life and Health Sciences, Laboratory for Inorganic Chemical Biology, 75005, Paris, France.

Cancer is one of the main causes of death worldwide. Chemotherapy, despite its severe side effects, is to date one of the leading strategies against cancer. Metal-based drugs present several potential advantages when compared to organic compounds and they have gained trust from the scientific community after the approval on the market of the drug cisplatin. Recently, we reported the ruthenium complex ([Ru(DIP) (sq)](PF ) (where DIP is 4,7-diphenyl-1,10-phenantroline and sq is semiquinonate) with a remarkable potential as chemotherapeutic agent against cancer, both in vitro and in vivo. In this work, we analyse a structurally similar compound, namely [Ru(DIP) (mal)](PF ), carrying the flavour-enhancing agent approved by the FDA, maltol (mal). To possess an FDA approved ligand is crucial for a complex, whose mechanism of action might include ligand exchange. Herein, we describe the synthesis and characterisation of [Ru(DIP) (mal)](PF ), its stability in solutions and under conditions that resemble the physiological ones, and its in-depth biological investigation. Cytotoxicity tests on different cell lines in 2D model and on HeLa MultiCellular Tumour Spheroids (MCTS) demonstrated that our compound has higher activity than cisplatin, inspiring further tests. [Ru(DIP) (mal)](PF ) was efficiently internalised by HeLa cells through a passive transport mechanism and severely affected the mitochondrial metabolism.
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http://dx.doi.org/10.1002/chem.201904877DOI Listing
April 2020

Fe -Salen-Based Probes for the Selective and Sensitive Detection of E450 in Foodstuff.

Chemistry 2020 May 15;26(25):5717-5723. Epub 2020 Apr 15.

Department of Chemistry, University of Zurich, Winterthurerstrasse 190, 8057, Zurich, Switzerland.

Inorganic pyrophosphate (PPi) is considered as a diagnostic marker for various diseases such as cancer and vascular calcification. PPi also plays an important preservative role as an additive E450 in foodstuff. In this work, a selective Fe -salen-based probe for PPi is described; this probe disassembles in the presence of the target analyte into its molecular blocks, 1,2-propanediamine and 3-chloro-5-formyl-4-hydroxybenzenesulfonic acid. The latter signaling unit leads to a fluorometric response. Compared with a related prototype, the new complex shows a 2.3-times stronger emission at 500 nm and a 155-times better selectivity of PPi over adenosine triphosphate (ATP). Importantly, the new probe was successfully applied for detecting E450 in foodstuff.
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http://dx.doi.org/10.1002/chem.201905686DOI Listing
May 2020

Synthesis, characterization, kinetic investigation and biological evaluation of Re(i) di- and tricarbonyl complexes with tertiary phosphine ligands.

Dalton Trans 2020 Jan 19;49(1):35-46. Epub 2019 Nov 19.

University of the Free State, Department of Chemistry, Nelson Mandela Drive, Bloemfontein, South Africa.

Rhenium(i) di- and tri-carbonyl complexes of the form fac-[Re(CO)(L,L'-Bid)X] and [Re(CO)(L,L'-Bid)X], where X = aqua (HO), methanol (CHOH), triphenylphosphine (PPh), 1,3,5-triaza-7-phosphaadamantane (PTA), tricyclohexylphosphine (PCy) and L,L'-Bid = O,O' bidentate ligands (tropolone = TropH and 3-hydroxyflavone = FlavH) and N,O bidentate ligands (8-hydroxyquinoline = QuinH, 5,7-chloro-8-hydroxyquinoline = diCl-QuinH and quinoline-2,4-dicarboxylic acid = QuinH), were synthesized and unambiguously characterized by H-, C-and P-NMR, IR, UV/Vis and micro-analysis. The crystal structures of four complexes, namely fac-[Re(CO)(QuinH)(HO)]·HO (5), fac-[Re(CO)(Quin)(PPh)] (11), fac-[Re(CO)(diCl-Quin)(PPh)] (12) and [Re(CO)(Trop)(PPh)]·2CHCH (20) were obtained. Re-P bonding distances for 11 and 12 are 2.4948(8) and 2.4908(8) Å, respectively, indicating the effect of the electron-withdrawing substituents of the diCl-Quin ligand. The second-order rate constants for the substitutions of methanol at 25.1 °C in fac-[Re(CO)(L,L'-Bid)(CHOH)] (L,L'-Bid = Trop, Flav and QuinH) type complexes by different entering phosphine ligands (PPh, PCy, and PTA) varied between 7.23(7) × 10 and 1.32(3) × 10 M s and were found to depend on the coordinated bidentate ligand (in general k (QuinH) < k (Trop) < k (Flav)). The toxicity of fac-[Re(CO)(QuinH)(PTA)], fac-[Re(CO)(Trop)(PTA)], fac-[Re(CO)(Trop)(PPh)] and fac-[Re(CO)(Flav)(PPh)] on the cervical cancer HeLa and epithelial RPE-1 cell lines was then evaluated. Complex fac-[Re(CO)(Flav)(PPh)] (16) and fac-[Re(CO)(Trop)(PPh)] (13) displayed the highest cytotoxicity with IC values of 12.21 ± 0.17 μM and 13.35 ± 0.94 μM, respectively in HeLa cells. Interestingly, a small selectivity towards cancer over non-cancerous cells was observed for these compounds (IC = 18.41 ± 3.16 μM and >25 μM in RPE-1 cells).
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http://dx.doi.org/10.1039/c9dt04025kDOI Listing
January 2020

Synthesis and Characterization of an Epidermal Growth Factor Receptor-Selective Ru Polypyridyl-Nanobody Conjugate as a Photosensitizer for Photodynamic Therapy.

Chembiochem 2020 02 22;21(4):531-542. Epub 2019 Oct 22.

Chimie ParisTech, PSL University, CNRS, Institute of Chemistry for Life and Health Sciences, Laboratory for Inorganic Chemical Biology, 75005, Paris, France.

There is a current surge of interest in the development of novel photosensitizers (PSs) for photodynamic therapy (PDT), as those currently approved are not completely ideal. Among the tested compounds, we have previously investigated the use of Ru polypyridyl complexes with a [Ru(bipy) (dppz)] and [Ru(phen) (dppz)] scaffold (bipy=2,2'-bipyridine; dppz=dipyrido[3,2-a:2',3'-c]phenazine; phen=1,10-phenanthroline). These complexes selectively target DNA. However, because DNA is ubiquitous, it would be of great interest to increase the selectivity of our PDT PSs by linking them to a targeting vector in view of targeted PDT. Herein, we present the synthesis, characterization, and in-depth photophysical evaluation of a nanobody-containing Ru polypyridyl conjugate selective for the epidermal growth factor receptor (EGFR) in view of targeted PDT. Using ICP-MS and confocal microscopy, we could demonstrate that our conjugate has high selectivity for the EGFR receptor, which is a crucial oncological target because it is overexpressed and/or deregulated in a variety of solid tumors. However, in contrast to expectations, this conjugate was found to not produce reactive oxygen species (ROS) in cancer cells and is therefore not phototoxic.
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http://dx.doi.org/10.1002/cbic.201900419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7065149PMC
February 2020

Systematic investigation of the antiproliferative activity of a series of ruthenium terpyridine complexes.

J Inorg Biochem 2019 09 17;198:110752. Epub 2019 Jun 17.

Chimie ParisTech, PSL University, CNRS, Institute of Chemistry for Life and Health Sciences, Laboratory for Inorganic Chemical Biology, 75005 Paris, France. Electronic address:

Due to acquired resistance or limitations of the currently approved drugs against cancer, there is an urgent need for the development of new classes of compounds. Among others, there is an increasing attention towards the use of Ru(II) polypyridyl complexes. Most studies in the literature were made on complexes based on the coordination of N-donating bidentate ligands to the ruthenium core whereas studies on 2,2':6', 2″-terpyridine (terpy) coordinating ligands are relatively scare. However, several studies have shown that [Ru(terpy)2] derivatives are able bind to DNA through various binding modes making these compounds potentially suitable as chemotherapeutic agents. Additionally, light irradiation of these compounds was shown to enable DNA cleavage, highlighting their potential use as photosensitizers (PSs) for photodynamic therapy (PDT). In this work, we present the systematic investigation of the potential of 7 complexes of the type [Ru(terpy)(terpy-X)]2+ (X = H (1), Cl (2), Br (3), OMe (4), COOH (5), COOMe (6), NMe2 (7)) as potential chemotherapeutic agents and PDT PSs. Importantly, six of the seven complexes were found to be stable in human plasma as well as photostable in acetonitrile upon continuous light irradiation (480 nm). The determination of the distribution coefficient logP values for the 7 complexes revealed their good water solubility. Complex 7 was found to be cytotoxic in the micromolar range in the dark as well as to have some phototoxicity upon light exposure at 480 nm in non-cancerous retinal pigment epithelium (RPE-1) and cancerous human cervical carcinoma (HeLa) cells. SYNOPSIS: The systematic investigation of the potential of 7 complexes of the type [Ru(terpy)(terpy-X)] (terpy: 2,2':6', 2″-terpyridine; X = H (1), Cl (2), Br (3), OMe (4), COOH (5), COOMe (6), NMe2 (7)) as potential chemotherapeutic agents and photosensitizers for photodynamic therapy is presented.
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http://dx.doi.org/10.1016/j.jinorgbio.2019.110752DOI Listing
September 2019

Synthesis, characterization and biological activity of organometallic derivatives of the antimalarial drug mefloquine as new antischistosomal drug candidates.

Medchemcomm 2018 Nov 10;9(11):1905-1909. Epub 2018 Oct 10.

Laboratory for Inorganic Chemical Biology , Chimie ParisTech , PSL University , F-75005 Paris , France . Email:

We present the design, synthesis, characterization and biological evaluation of new ferrocenyl and ruthenocenyl derivatives of the organic antimalarial mefloquine, a drug also known for its antischistosomal activity. The two metallocenyl derivatives prepared ( and ) demonstrated comparable activity to mefloquine against adult-stage . Importantly, both compounds were found to have lower toxicity in all cell lines than mefloquine itself. Administration of a 200 mg kg oral dose of and to -infected mice did not significantly reduce worm burden, contrary to mefloquine.
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http://dx.doi.org/10.1039/c8md00396cDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6256353PMC
November 2018

Mechanisms of action of Ru(ii) polypyridyl complexes in living cells upon light irradiation.

Chem Commun (Camb) 2018 Nov;54(93):13040-13059

Chimie ParisTech, PSL University, Laboratory for Inorganic Chemical Biology, Paris, France.

The unique photophysical properties of Ru(ii) polypyridyl complexes make them very attractive candidates as photosensitisers in Photodynamic Therapy (PDT). However, to date, there are not many studies exploring in detail the mechanism(s) of action of such compounds in living systems upon light irradiation. This feature article provides an overview of the most in-depth biological studies on such compounds.
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http://dx.doi.org/10.1039/c8cc05928dDOI Listing
November 2018