Publications by authors named "Gilles Gasser"

144 Publications

cis-Locked Ru(II)-DMSO Precursors for the Microwave-Assisted Synthesis of Bis-Heteroleptic Polypyridyl Compounds.

Inorg Chem 2021 Apr 28. Epub 2021 Apr 28.

Department of Chemical and Pharmaceutical Sciences, University of Trieste, Via L. Giorgieri 1, 34127 Trieste, Italy.

We describe a synthetic strategy for the preparation of bis-heteroleptic polypyridyl Ru(II) complexes of the type [Ru(L1)(L2)] (L1 and L2 = diimine ligands) from well-defined Ru(II) precursors. For this purpose, a series of six neutral, anionic, and cationic -locked Ru(II)-DMSO complexes (-) of the general formula [Y] -[RuX(DMSO-S)(O-O)] (where O-O is a symmetrical chelating anion: oxalate (ox), malonate (mal), acetylacetonate (acac); X = DMSO-O or Cl; = -1/0/+1 depending on the nature and charge of X and O-O; when present, Y = K or PF) were efficiently prepared from the well-known -[RuCl(DMSO)] (). When treated with diimine chelating ligands (L1 = bpy, phen, dpphen), the compounds - afforded the target [Ru(L1)(O-O)] complex together with the undesired (and unexpected) [Ru(L1)] species. Nevertheless, we found that the formation of [Ru(L1)]can be minimized by carefully adjusting the reaction conditions: in particular, high selectivity toward [Ru(L1)(O-O)] and almost complete conversion of the precursor was obtained within minutes, also on a 100-200 mg scale, when the reactions were performed in absolute ethanol at 150 °C in a microwave reactor. Depending on the nature of L1 and concentration, with the oxalate and malonate precursors, the neutral product [Ru(L1)(O-O)] can precipitate spontaneously from the final mixture, in pure form and acceptable-to-good yields. When spontaneous precipitation of the disubstituted product does not occur, purification from [Ru(L1)] can be rather easily accomplished by column chromatography or solvent extraction. By comparison, under the same conditions, compound is much less selective, thus demonstrating that locking the geometry of the precursor through the introduction of O-O in the coordination sphere of Ru is a valid strategic approach. By virtue of its proton-sensitive nature, facile and quantitative replacement of O-O in [Ru(L1)(O-O)] by L2, selectively affording [Ru(L1)(L2)], was accomplished in refluxing ethanol in the presence of a slight excess of trifluoroacetic acid or HPF.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.inorgchem.1c00240DOI Listing
April 2021

Polymeric Encapsulation of a Ru(II)-Based Photosensitizer for Folate-Targeted Photodynamic Therapy of Drug Resistant Cancers.

J Med Chem 2021 Apr 5;64(8):4612-4622. Epub 2021 Apr 5.

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

The currently used photodynamic therapy (PDT) photosensitizers (PSs) are generally associated with a poor cancer cell selectivity, which is responsible for some undesirable side effects. To overcome these problems, there is an urgent need for a selective drug delivery system for PDT PSs. Herein, the encapsulation of a promising Ru(II) polypyridine complex in a polymer with terminal folate groups to form nanoparticles is presented. While the Ru(II) complex itself has a cytotoxic effect in the dark, the encapsulation is able to overcome this drawback. Upon light exposure, the nanoparticles were found to be highly phototoxic in 2D monolayer cells as well as 3D multicellular tumor spheroids upon 480 or 595 nm irradiation. Importantly, the nanoparticles demonstrated a high selectivity for cancerous cells over noncancerous cells and were found to be active in drug resistant cancer cells lines, indicating that they are able to overcome drug resistances.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jmedchem.0c02006DOI Listing
April 2021

Enzymatic construction of metal-mediated nucleic acid base pairs.

Metallomics 2021 04;13(4)

Institut Pasteur, Department of Structural Biology and Chemistry, Laboratory for Bioorganic Chemistry of Nucleic Acids, CNRS UMR3523, 28 rue du Docteur Roux, 75724 Paris Cedex 15, France.

Artificial metal base pairs have become increasingly important in nucleic acids chemistry due to their high thermal stability, water solubility, orthogonality to natural base pairs, and low cost of production. These interesting properties combined with ease of chemical and enzymatic synthesis have prompted their use in several practical applications, including the construction of nanomolecular devices, ions sensors, and metal nanowires. Chemical synthesis of metal base pairs is highly efficient and enables the rapid screening of novel metal base pair candidates. However, chemical synthesis is limited to rather short oligonucleotides and requires rather important synthetic efforts. Herein, we discuss recent progress made for the enzymatic construction of metal base pairs that can alleviate some of these limitations. First, we highlight the possibility of generating metal base pairs using canonical nucleotides and then describe how modified nucleotides can be used in this context. We also provide a description of the main analytical techniques used for the analysis of the nature and the formation of metal base pairs together with relevant examples of their applications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/mtomcs/mfab016DOI Listing
April 2021

Efficient Amino-Sulfhydryl Stapling on Peptides and Proteins Using Bifunctional NHS-Activated Acrylamides.

Angew Chem Int Ed Engl 2021 05 1;60(19):10850-10857. Epub 2021 Apr 1.

Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal.

Widely used reagents in the peptide functionalization toolbox, Michael acceptors and N-hydroxysuccinimide (NHS) activated esters, are combined in NHS-activated acrylamides for efficient chemoselective amino-sulfhydryl stapling on native peptides and proteins. NHS-activated acrylamides allow for a fast functionalization of N-terminal cysteines (k =1.54±0.18×10  M  s ) under dilute aqueous conditions, enabling selectivity over other nucleophilic amino acids. Additionally, the versatility of these new bioconjugation handles was demonstrated in the cross-linking of in-chain or C-terminal cysteines with nearby lysine residues. NHS-activated acrylamides are compatible with the use of other cysteine selective reagents, allowing for orthogonal dual-modifications. This strategy was successfully applied to the late-stage functionalization of peptides and proteins with a PEG unit, fluorescent probe, and cytotoxic agent. The level of molecular control offered by NHS-activated acrylamides is expected to promote amino-sulfhydryl stapling technology as a powerful strategy to design functional bioconjugates.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/anie.202016936DOI Listing
May 2021

Unveiling the Potential of Transition Metal Complexes for Medicine: Translational in Situ Activation of Metal-Based Drugs from Bench to in Vivo Applications.

Chembiochem 2021 Jan 28. Epub 2021 Jan 28.

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

The development of metal-based anticancer drugs has been hampered, among other reasons, by their lack of selectivity for cancer cells. In a recent article, Zou and co-workers presented the successful intracellular activation of organogold(I) complexes for potential cancer treatment through Pd(II)-mediated transmetallation, overcoming some off-target activity of novel gold-based drugs. This unique strategy builds the perfect bridge between metallodrug usage and bioorthogonal intracellular catalysis for more advanced and selective therapies. Such an approach will hopefully pave the way for forthcoming studies in medicinal inorganic chemistry.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cbic.202100015DOI Listing
January 2021

Polymeric Encapsulation of a Ruthenium Polypyridine Complex for Tumor Targeted One- and Two-Photon Photodynamic Therapy.

ACS Appl Mater Interfaces 2020 Dec 25;12(49):54433-54444. Epub 2020 Nov 25.

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

Photodynamic therapy is a medical technique, which is gaining increasing attention to treat various types of cancer. Among the investigated classes of photosensitizers (PSs), the use of Ru(II) polypyridine complexes is gaining momentum. However, the currently investigated compounds generally show poor cancer cell selectivity. As a consequence, high drug doses are needed, which can cause side effects. To overcome this limitation, there is a need for the development of a suitable drug delivery system to increase the amount of PS delivered to the tumor. Herein, we report the encapsulation of a promising Ru(II) polypyridyl complex into polymeric nanoparticles with terminal biotin groups. Thanks to this design, the particles showed much higher selectivity for cancer cells in comparison to noncancerous cells in a 2D monolayer and 3D multicellular tumor spheroid model. As a highlight, upon intravenous injection of an identical amount of the Ru(II) polypyridine complex of the nanoparticle formulation, an improved accumulation inside an adenocarcinomic human alveolar basal epithelial tumor of a mouse up to a factor of 8.7 compared to the Ru complex itself was determined. The nanoparticles were found to have a high phototoxic effect upon one-photon (500 nm) or two-photon (800 nm) excitation with eradication of adenocarcinomic human alveolar basal epithelial tumor inside a mouse model. Overall, this work describes, to the best of our knowledge, the first study demonstrating the cancer cell selectivity of a very promising Ru(II)-based PDT photosensitizer encapsulated into polymeric nanoparticles with terminal biotin groups.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acsami.0c16119DOI Listing
December 2020

Critical discussion of the applications of metal complexes for 2-photon photodynamic therapy.

J Biol Inorg Chem 2020 12 4;25(8):1035-1050. Epub 2020 Nov 4.

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

Photodynamic therapy is a light-activated medical technique, which has received increasing attention within the last decade to treat various diseases including bacterial, viral or fungal infections as well as cancer. To overcome the limitations of the currently clinically applied photosensitizers based on a tetrapyrrolic scaffold, metal complexes are sought to be an interesting alternative. While these complexes show attractive photophysical and biological properties, the majority of these compounds are excited using visible light, which is associated with a poor tissue penetration. To circumvent this drawback, increasing attention has been devoted towards the use of 2-Photon instead of 1-Photon irradiation. In this mini-review, the metal complexes prepared in view of 2P-PDT are reviewed and the requirements these compounds need to fulfil to be of interest are critically discussed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00775-020-01829-5DOI Listing
December 2020

Studying the cellular distribution of highly phototoxic platinated metalloporphyrins using isotope labelling.

Chem Commun (Camb) 2020 Nov;56(92):14373-14376

Department of Chemistry, University of Zurich, Zurich CH 8057, Switzerland.

Novel tetraplatinated metalloporphyrin-based photosensitizers (PSs) are reported, which show excellent phototoxic indexes (PIs) up to 5800 against HeLa cells, which is, to the best of our knowledge, the highest value reported for any porphyrin so far. Furthermore, 67Zn isotope labelling allowed the determination of the ratio of zinc to platinum inside the cells using ICP-MS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/d0cc05196aDOI Listing
November 2020

Enzymatic Formation of an Artificial Base Pair Using a Modified Purine Nucleoside Triphosphate.

ACS Chem Biol 2020 11 22;15(11):2872-2884. Epub 2020 Oct 22.

Institut Pasteur, Department of Structural Biology and Chemistry, Laboratory for Bioorganic Chemistry of Nucleic Acids, CNRS UMR3523, 28, rue du Docteur Roux, 75724 Paris Cedex 15, France.

The expansion of the genetic alphabet with additional, unnatural base pairs (UBPs) is an important and long-standing goal in synthetic biology. Nucleotides acting as ligands for the coordination of metal cations have advanced as promising candidates for such an expansion of the genetic alphabet. However, the inclusion of artificial metal base pairs in nucleic acids mainly relies on solid-phase synthesis approaches, and very little is known about polymerase-mediated synthesis. Herein, we report the selective and high yielding enzymatic construction of a silver-mediated base pair (dIm-Ag-dPur) as well as a two-step protocol for the synthesis of DNA duplexes containing such an artificial metal base pair. Guided by DFT calculations, we also shed light into the mechanism of formation of this artificial base pair as well as into the structural and energetic preferences. The enzymatic synthesis of the dIm-Ag-dPur artificial metal base pair provides valuable insights for the design of future, more potent systems aiming at expanding the genetic alphabet.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acschembio.0c00396DOI Listing
November 2020

Incorporation of Ru(II) Polypyridyl Complexes into Nanomaterials for Cancer Therapy and Diagnosis.

Adv Mater 2020 Nov 19;32(47):e2003294. Epub 2020 Oct 19.

Chimie ParisTech, PSL University, CNRS, Institut de Recherche de Chimie Paris, Paris, 75005, France.

Ru(II) polypyridyl complexes are compounds of great interest in cancer therapy due to their unique photophysical, photochemical, and biological properties. For effective treatment, they must be able to penetrate tumor cells effectively and selectively. The development of nanoscale carriers capable of delivering Ru(II) polypyridyl complexes has the potential to passively or selectively enhance their cellular uptake in tumor cells. Many different strategies have been explored to incorporate Ru(II) polypyridyl complexes into a variety of nanosized constructs, ranging from organic to inorganic materials. Herein, recent developments in nanomaterials loaded with Ru(II) polypyridyl complexes are highlighted. Their rational design, preparation, and physicochemical properties are described, and their potential applications in cancer therapy are eventually discussed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/adma.202003294DOI Listing
November 2020

Encapsulation of a Ru(II) Polypyridyl Complex into Polylactide Nanoparticles for Antimicrobial Photodynamic Therapy.

Pharmaceutics 2020 Oct 13;12(10). Epub 2020 Oct 13.

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

Antimicrobial photodynamic therapy (aPDT) also known as photodynamic inactivation (PDI) is a promising strategy to eradicate pathogenic microorganisms such as Gram-positive and Gram-negative bacteria. This therapy relies on the use of a molecule called photosensitizer capable of generating, from molecular oxygen, reactive oxygen species including singlet oxygen under light irradiation to induce bacteria inactivation. Ru(II) polypyridyl complexes can be considered as potential photosensitizers for aPDT/PDI. However, to allow efficient treatment, they must be able to penetrate bacteria. This can be promoted by using nanoparticles. In this work, ruthenium-polylactide () nanoconjugates with different tacticities and molecular weights were prepared from a Ru(II) polypyridyl complex, . Narrowly-dispersed nanoparticles with high ruthenium loadings (up to 53%) and an intensity-average diameter < 300 nm were obtained by nanoprecipitation, as characterized by dynamic light scattering (DLS). Their phototoxicity effect was evaluated on four bacterial strains (, and ) and compared to the parent compound . and the nanoparticles were found to be non-active towards Gram-negative bacterial strains. However, depending on the tacticity and molecular weight of the nanoconjugates, differences in photobactericidal activity on Gram-positive bacterial strains have been evidenced whereas remained non active.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/pharmaceutics12100961DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7602071PMC
October 2020

Head-to-head comparison of DFO* and DFO chelators: selection of the best candidate for clinical Zr-immuno-PET.

Eur J Nucl Med Mol Imaging 2021 Mar 5;48(3):694-707. Epub 2020 Sep 5.

Radiology & Nuclear Medicine, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, De Boelelaan, 1117, Amsterdam, The Netherlands.

Purpose: Almost all radiolabellings of antibodies with Zr currently employ the hexadentate chelator desferrioxamine (DFO). However, DFO can lead to unwanted uptake of Zr in bones due to instability of the resulting metal complex. DFO*-NCS and the squaramide ester of DFO, DFOSq, are novel analogues that gave more stable Zr complexes than DFO in pilot experiments. Here, we directly compare these linker-chelator systems to identify optimal immuno-PET reagents.

Methods: Cetuximab, trastuzumab and B12 (non-binding control antibody) were labelled with Zr via DFO*-NCS, DFOSq, DFO-NCS or DFO*Sq. Stability in vitro was compared at 37 °C in serum (7 days), in formulation solution (24 h ± chelator challenges) and in vivo with N87 and A431 tumour-bearing mice. Finally, to demonstrate the practical benefit of more stable complexation for the accurate detection of bone metastases, [Zr]Zr-DFO*-NCS and [Zr]Zr-DFO-NCS-labelled trastuzumab and B12 were evaluated in a bone metastasis mouse model where BT-474 breast cancer cells were injected intratibially.

Results: [Zr]Zr-DFO*-NCS-trastuzumab and [Zr]Zr-DFO*Sq-trastuzumab showed excellent stability in vitro, superior to their [Zr]Zr-DFO counterparts under all conditions. While tumour uptake was similar for all conjugates, bone uptake was lower for DFO* conjugates. Lower bone uptake for DFO* conjugates was confirmed using a second xenograft model: A431 combined with cetuximab. Finally, in the intratibial BT-474 bone metastasis model, the DFO* conjugates provided superior detection of tumour-specific signal over the DFO conjugates.

Conclusion: DFO*-mAb conjugates provide lower bone uptake than their DFO analogues; thus, DFO* is a superior candidate for preclinical and clinical Zr-immuno-PET.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00259-020-05002-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8036225PMC
March 2021

Classification of Metal-based Drugs According to Their Mechanisms of Action.

Chem 2020 Jan 7;6(1):41-60. Epub 2019 Nov 7.

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

Metal-based drugs and imaging agents are extensively used in the clinic for the treatment and diagnosis of cancers and a wide range of other diseases. The current clinical arsenal of compounds operate via a limited number of mechanisms, whereas new putative compounds explore alternative mechanisms of action, which could potentially bring new chemotherapeutic approaches into the clinic. In this review, metal-based drugs and imaging agents are characterized according to their primary mode of action and the key properties and features of each class of compounds are defined, wherever possible. A better understanding of the roles played by metal compounds at a mechanistic level will help to deliver new metal-based therapies to the clinic, by providing an alternative, targeted and rational approach, to supplement non-targeted screening of novel chemical entities for biological activity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.chempr.2019.10.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7451962PMC
January 2020

Multidisciplinary Preclinical Investigations on Three Oxamniquine Analogues as New Drug Candidates for Schistosomiasis*.

Chemistry 2020 Nov 22;26(66):15232-15241. Epub 2020 Oct 22.

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

Schistosomiasis is a disease of poverty affecting millions of people. Praziquantel (PZQ), with its strengths and weaknesses, is the only treatment available. We previously reported findings on three lead compounds derived from oxamniquine (OXA), an old antischistosomal drug: ferrocene-containing (Fc-CH -OXA), ruthenocene-containing (Rc-CH -OXA) and benzene-containing (Ph-CH -OXA) OXA derivatives. These derivatives showed excellent in vitro activity against both Schistosoma mansoni larvae and adult worms and S. haematobium adult worms, and were also active in vivo against adult S. mansoni. Encouraged by these promising results, we conducted additional in-depth preclinical studies and report in this investigation on metabolic stability studies, in vivo studies on S. haematobium and juvenile S. mansoni, computational simulations, and formulation development. Molecular dynamics simulations supported the in vitro results on the target protein. Though all three compounds were poorly stable within an acidic environment, they were only slightly cleared in the in vitro liver model. This is likely the reason why the promising in vitro activity did not translate into in vivo activity on S. haematobium. This limitation could not be overcome by the formulation of lipid nanocapsules as a way to improve the in vivo activity. Further studies should focus on increasing the compound's bioavailability, to reach an active concentration in the microenvironment of the parasite.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/chem.202002856DOI Listing
November 2020

One- and Two-Photon Phototherapeutic Effects of Ru Polypyridine Complexes in the Hypoxic Centre of Large Multicellular Tumor Spheroids and Tumor-Bearing Mice*.

Chemistry 2021 Jan 17;27(1):362-370. Epub 2020 Nov 17.

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

During the last decades, photodynamic therapy (PDT), an approved medical technique, has received increasing attention to treat certain types of cancer. Despite recent improvements, the treatment of large tumors remains a major clinical challenge due to the low ability of the photosensitizer (PS) to penetrate a 3D cellular architecture and the low oxygen concentrations present in the tumor center. To mimic the conditions found in clinical tumors, exceptionally large 3D multicellular tumor spheroids (MCTSs) with a diameter of 800 μm were used in this work to test a series of new Ru polypyridine complexes as one-photon and two-photon PSs. These metal complexes were found to fully penetrate the 3D cellular architecture and to generate singlet oxygen in the hypoxic center upon light irradiation. While having no observed dark toxicity, the lead compound of this study showed an impressive phototoxicity upon clinically relevant one-photon (595 nm) or two-photon (800 nm) excitation with a full eradication of the hypoxic center of the MCTSs. Importantly, this efficacy was also demonstrated on mice bearing an adenocarcinomic human alveolar basal epithelial tumor.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/chem.202003486DOI Listing
January 2021

Enzymatic Construction of Artificial Base Pairs: The Effect of Metal Shielding.

Chembiochem 2020 Dec 2;21(23):3398-3409. Epub 2020 Sep 2.

Institut Pasteur, Department of Structural Biology and Chemistry, Laboratory for Bioorganic Chemistry of Nucleic Acids, CNRS UMR3523, 28, rue du Docteur Roux, 75724, Paris Cedex 15, France.

Th formation of metal base pairs is a versatile method for the introduction of metal cations into nucleic acids that has been used in numerous applications including the construction of metal nanowires, development of energy, charge-transfer devices and expansion of the genetic alphabet. As an alternative, enzymatic construction of metal base pairs is an alluring strategy that grants access to longer sequences and offers the possibility of using such unnatural base pairs (UBPs) in SELEX experiments for the identification of functional nucleic acids. This method remains rather underexplored, and a better understanding of the key parameters in the design of efficient nucleotides is required. We have investigated the effect of methylation of the imidazole nucleoside (dIm TP) on the efficiency of the enzymatic construction of metal base pairs. The presence of methyl substituents on dImTP facilitates the polymerase-driven formation of dIm -Ag -dIm and dIm TP-Cr -dIm base pairs. Steric factors rather than the basicity of the imidazole nucleobase appear to govern the enzymatic formation of such metal base pairs. We also demonstrate the compatibility of other metal cations rarely considered in the construction of artificial metal bases by enzymatic DNA synthesis under both primer extension reaction and PCR conditions. These findings open up new directions for the design of nucleotide analogues for the development of metal base pairs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cbic.202000402DOI Listing
December 2020

Radiolabelling of the octadentate chelators DFO* and oxoDFO* with zirconium-89 and gallium-68.

J Biol Inorg Chem 2020 08 13;25(5):789-796. Epub 2020 Jul 13.

Ludwig Boltzmann Institute Applied Diagnostics, General Hospital of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.

In recent years, clinical imaging with zirconium-89 (Zr)-labelled monoclonal antibodies (Ab) by positron emission tomography (immunoPET) has been gaining significant importance in nuclear medicine for the diagnosis of different types of cancer. For complexation of the radiometal Zr and its attachment to the Ab, chelating agents are required. To date, only the hexadentate chelator desferrioxamine (DFO) is applied in the clinic for this purpose. However, there is increasing preclinical evidence that the [Zr]Zr-DFO complex is not sufficiently stable and partly releases the radiometal in vivo due to the incomplete coordination sphere of the metal. This leads to unfavourable unspecific uptake of the osteophilic radiometal in bones, hence decreasing the signal-to-noise-ratio and leading to an increased dose to the patient. In the past, several new chelators with denticities > 6 have been published, notably the octadentate DFO derivative DFO*. DFO*, however, shows limited water solubility, wherefore an oxygen containing analogue, termed oxoDFO*, was developed in 2017. However, no data on the suitability of oxoDFO* for radiolabelling with Zr has yet been reported. In this proof-of-concept study, we present the first radiolabelling results of the octadentate, water-soluble chelator oxoDFO*, as well as the in vitro stability of the resulting complex [Zr]Zr-oxoDFO* in comparison to the analogous octadentate, but less water-soluble derivative DFO* and the current "standard" chelator DFO. In addition, the suitability of DFO* and oxoDFO* for radiolabeling with the short-lived PET metal gallium-68 is discussed. The water-soluble, octadentate chelator oxoDFO* provides stable complexes with the positron emitter Zirconium-89. The radiolabelling can be performed at room temperature and neutral pH and thus, oxoDFO* represents a promising chelator for applications in immunoPET.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00775-020-01800-4DOI Listing
August 2020

Rationally designed ruthenium complexes for 1- and 2-photon photodynamic therapy.

Nat Commun 2020 06 26;11(1):3262. Epub 2020 Jun 26.

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

The use of photodynamic therapy (PDT) against cancer has received increasing attention over recent years. However, the application of the currently approved photosensitizers (PSs) is limited by their poor aqueous solubility, aggregation, photobleaching and slow clearance from the body. To overcome these limitations, there is a need for the development of new classes of PSs with ruthenium(II) polypyridine complexes currently gaining momentum. However, these compounds generally lack significant absorption in the biological spectral window, limiting their application to treat deep-seated or large tumors. To overcome this drawback, ruthenium(II) polypyridine complexes designed in silico with (E,E')-4,4'-bisstyryl-2,2'-bipyridine ligands show impressive 1- and 2-Photon absorption up to a magnitude higher than the ones published so far. While nontoxic in the dark, these compounds are phototoxic in various 2D monolayer cells, 3D multicellular tumor spheroids and are able to eradicate a multiresistant tumor inside a mouse model upon clinically relevant 1-Photon and 2-Photon excitation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-020-16993-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7320011PMC
June 2020

First Workshop on Metals in Medicine (2019): Translational Research in Medicinal Bioinorganic Chemistry.

Chembiochem 2020 10 26;21(19):2706-2707. Epub 2020 Jun 26.

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

On the 14-15th November 2019, the first workshop on Metals in Medicine took place in Paris at Chimie ParisTech, PSL University. Organised with the aim of having invited speakers share their experience in bringing metal-based drugs to (pre-)clinical trials, this event gathered 135 attendees from six continents to Paris. A special collection on this event has now been published in ChemBioChem, combining more than 20 articles on different topics related to metals in medicine.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cbic.202000329DOI Listing
October 2020

Increased Lipophilicity of Halogenated Ruthenium(II) Polypyridyl Complexes Leads to Decreased Phototoxicity in vitro when Used as Photosensitizers for Photodynamic Therapy.

Chembiochem 2020 10 7;21(20):2966-2973. Epub 2020 Jul 7.

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

In the fight against cancer, photodynamic therapy is generating great interest thanks to its ability to selectively kill cancer cells without harming healthy tissues. In this field, ruthenium(II) polypyridyl complexes, and more specifically, complexes with dipyrido[3,2-a:2',3'-c]phenazine (dppz) as a ligand are of particular interest due to their DNA-binding and photocleaving properties. However, ruthenium(II) polypyridyl complexes can sometimes suffer from low lipophilicity, which hampers cellular internalisation through passive diffusion. In this study, four new [Ru(dppz-X ) ] complexes (X=H, F, Cl, Br, I) were synthesized and their lipophilicity (logP), cytotoxicity and phototoxicity on cancerous and noncancerous cell lines were assessed. This study shows that, counterintuitively, the phototoxicity of these complexes decreases as their lipophilicity increases; this could be due solely to the atomic radius of the halogen substituents.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cbic.202000289DOI Listing
October 2020

Synthesis, characterization and antiparasitic activity of organometallic derivatives of the anthelmintic drug albendazole.

Dalton Trans 2020 May;49(20):6616-6626

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

Helminthiases, a group of neglected tropical diseases, affect more than one billion people mainly in tropical and subtropical regions. Moreover, major intestinal protozoa have a significant impact on global public health. Albendazole (ABZ) is a broad-spectrum anthelmintic recommended by the World Health Organisation (WHO). However, drug resistance is emerging due to its widespread use. In order to tackle this problem, taking into account the spectacular results obtained with ferroquine, an organometallic derivatization of the antimalarial drug chloroquine, we have prepared, in this study, a series of new ferrocenyl and ruthenocenyl derivatives of the organic drug ABZ and assessed their activity against different helminths and protozoans, namely Trichuris muris, Heligmosomoides polygygrus, Schistosoma mansoni, Giardia lamblia, Haemonchus contortus and Toxoplasma gondii. The ferrocene-containing ABZ analogue 2d exhibited over 70% activity against T. muris adults in vitro at 200 μM and no toxicity to mammalian cells (IC50 >100 μM). H. polygyrus adults were not affected by any of the derivatives tested. Against T. gondii, the ferrocene-containing ABZ analogues 1a and 2d showed better in vitro activity than ABZ and low toxicity to the host cells. The activity of the analogous ruthenocenyl compound 2b against S. mansoni and T. gondii in vitro might be attributed to its toxicity towards the host cells rather than a specific antiparasitic activity. These results demonstrate that the derivatives show a species specific in vitro activity and the choice of the organometallic moieties attached to the organic drug is playing a very important role. Two of our organometallic compounds, namely 1b and 2d, were tested in T. muris infected mice. At a 400 mg kg-1 dose, the compounds showed moderate worm burden reductions but low worm expulsion rates. Overall, this work, which is one of the first studies reporting the potential of organometallic compounds on a very broad range of parasitic helminths and protozoan, is a clear confirmation of the potential of organometallic complexes against parasites of medical and veterinary importance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/d0dt01107jDOI Listing
May 2020

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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).
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/chem.201904877DOI Listing
April 2020

A Multi-action and Multi-target Ru -Pt Conjugate Combining Cancer-Activated Chemotherapy and Photodynamic Therapy to Overcome Drug Resistant Cancers.

Angew Chem Int Ed Engl 2020 04 11;59(18):7069-7075. Epub 2020 Mar 11.

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

Pt complexes are commonly used to treat cancer. To reduce their side effects and improve their pharmacological properties, Pt complexes are being developed as prodrug candidates that are activated by reduction in cancer cells. Concomitantly, Ru polypyridine complexes have gained much attention as photosensitizers for use in photodynamic therapy due to their attractive characteristics. In this article, a novel Pt -Ru conjugate, which combines cancer activated chemotherapy with PDT, is presented. Upon entering the cancer cell, the Pt centre is reduced to Pt and the axial ligands including the Ru complex and phenylbutyrate are released. As each component has its individual targets, the conjugate exerts a multi-target and multi-action effect with (photo-)cytotoxicity values upon irradiation up to 595 nm in the low nanomolar range in various (drug resistant) 2D monolayer cancer cells and 3D multicellular tumour spheroids.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/anie.201916400DOI 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/chem.201905686DOI Listing
May 2020

A Luminescent NOTA-Based Terbium(III) "Turn-Off" Sensor for Copper.

Inorg Chem 2020 Jan 20;59(1):669-677. Epub 2019 Dec 20.

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

A bimacrocyclic luminescent terbium(III) sensor is reported for the selective "turn-off" detection of Cu ions in aqueous solutions. The current sensor differentiates from previous sensors in that it offers the use of (1) time-gated luminescence detection to remove the background signal, (2) a longer excitation wavelength of up to 350 nm for increased biocompatibility, and (3) a practically irreversible detection as a form of probing Cu ions with an extremely low limit of detection of about 1.7 nM.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.inorgchem.9b02934DOI Listing
January 2020

Note of Caution for the Aqueous Behaviour of Metal-Based Drug Candidates.

ChemMedChem 2020 02 21;15(4):345-348. Epub 2020 Jan 21.

INRS-Centre Armand-Frappier Santé Biotechnologie, Organometallic Chemistry Laboratory for the Design of Catalysts and Therapeutics, Université du Québec, 531 boul. des Prairies Laval, Québec, H7V 1B7, Canada.

Poor aqueous solubility is one of the recurrent drawbacks of many compounds in medicinal chemistry. To overcome this limitation, the dilution of drug candidates from stock solutions of an organic solvent is common practice. However, the precise characterisation of these compounds in aqueous solutions is often neglected, leading to some uncertainties regarding the nature of the actual active species. In this communication, we demonstrate that two ruthenium complexes previously reported by our group for their chemotherapeutic potential against cancer, namely [Ru(DIP) (sq)](PF ) and [Ru(DIP) (3-methoxysq)](PF ), where DIP is 4,7-diphenyl-1,10-phenanthroline, sq=semiquinonate and 3-methoxysq=3-methoxysemiquinonate, form colloids in water-DMSO (1 % v/v) mixtures that are invisible to the naked eyes. [Ru(DIP) (3-methoxysq)](PF ) was found to form a highly stable and monodispersed colloid with nanoaggregates of ∼25 nm. In contrast, [Ru(DIP) (sq)](PF ) was found to form large reticulates of mostly spherical aggregates which size was found to increase over time. The difference in size and shape distribution of drug candidates is of tremendous significance as the study of their biological activity might be severely affected. Overall, we strongly believe that these observations should be taken into account by the scientific community working on the development of metal-based drugs with poor water solubility.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cmdc.201900677DOI Listing
February 2020