Gilles Berger

Research in Drug Development (RD3)

Microbiology, Bioorganic and Macromolecular Chemistry

Research activities

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Top ten recent articles

Articles dans des revues avec comité de lecture

2024

Pseudodiproline (Pro-Cyp) Oligomers Fold into Helical Polyproline Type secondary structures

2023

An anti-glioblastoma gold( i )-NHC complex distorts mitochondrial morphology and bioenergetics to induce tumor growth inhibition

A new gold( i )-based therapeutic strategy to treat glioblastoma multiforme (GBM).

Halogen-Bonded Thiophene Derivatives Prepared by Solution and/or Mechanochemical Synthesis. Evidence of N···S Chalcogen Bonds in Homo- and Cocrystals

Thiophene, a key building block for the construction of conjugated materials, has been scarcely studied in halogen bonding (XB)-driven self-assemblies. In the present study, two thiophene derivatives modified at position 3 were (co-)crystallized using complementary XB donor/acceptor functional groups. Single-crystal X-ray diffraction analysis confirmed the presence of halogen and chalcogen bonding acting, in most cases, concomitantly. While the majority of the structures are governed by the conventional N···I motif, additional S···N and S···S contacts encouraged the cohesion of the supramolecular architectures. Density functional theory calculations shed the light on interaction energy, their respective contributions of the motifs to these non-covalent bonds, and the overall stability of these assemblies. To gain further insight into the formation and evidence of XB interactions, solution and mechanochemical syntheses of polymorphic adducts were performed, followed by 13C solid-state NMR analysis. Further, 1H and 19F{1H} solution-state NMR spectroscopy studies were carried out to highlight these interactions in the solution phase. The strength and directionality of halogen bonding thus reaffirm its role as a structure-directing agent for designing functional materials. The evidence of N···S chalcogen bonds in thiophene derivatives also broadens up the horizon of supramolecular chemistry in S-heterocycles, while necessitating further investigation for rational application in materials science.

Synthesis and biological activity of iron(II), iron(III), nickel(II), copper(II) and zinc(II) complexes of aliphatic hydroxamic acids

Aliphatic hydroxamic acids (HA) with varying numbers of carbon atoms, C2, C6, C8, C10, C12 and C17, and corresponding Fe(II), Fe(III), Ni(II), Cu(II) and Zn(II) complexes have been synthesized and characterized by various methods, including structural determination by single crystal X-ray diffraction and theoretical calculations. The biological activities of HA and their complexes have been assessed on a panel of pathogens, including eight bacteria strains and one fungus. The C12 aliphatic HA displayed the lowest minimum inhibitory concentrations (MIC) towards several microbial strains and a selective antifungal activity. This antifungal selectivity was further improved considering the Ni(II), Cu(II) and Zn(II) complexes of C12 HA showed higher IC50 values, thus less impact on the SiHa human cell line viability. This work warrants further investigation to understand the underlying mechanism of action and potential biological applications of HA and the derived metal complexes.

2022

A Pt(IV)-conjugated brain penetrant macrocyclic peptide shows pre-clinical efficacy in glioblastoma

Glioblastoma (GBM) is the most aggressive primary malignant brain tumor, with a median survival of approximately 15 months. Treatment is limited by the blood-brain barrier (BBB) which restricts the passage of most drugs to the brain. We previously reported the design and synthesis of a BBB-penetrant macrocyclic cell-penetrating peptide conjugate (M13) covalently linked at the axial position of a Pt(IV) cisplatin prodrug. Here we show the Pt(IV)-M13 conjugate releases active cisplatin upon intracellular reduction and effects potent in vitro GBM cell killing. Pt(IV)-M13 significantly increased platinum uptake in an in vitro BBB spheroid model and intravenous administration of Pt(IV)-M13 in GBM tumor-bearing mice led to higher platinum levels in brain tissue and intratumorally compared with cisplatin. Pt(IV)-M13 administration was tolerated in naïve nude mice at higher dosage regimes than cisplatin and significantly extended survival above controls in a murine GBM xenograft model (median survival 33 days for Pt(IV)-M13 vs 24 days for Pt(IV) prodrug, 22.5 days for cisplatin and 22 days for control). Increased numbers of γH2AX nuclear foci, biomarkers of DNA damage, were observed in tumors of Pt(IV)-M13-treated mice, consistent with elevated platinum levels. The present work provides the first demonstration that systemic injection of a Pt(IV) complex conjugated to a brain-penetrant macrocyclic peptide can lead to increased platinum levels in the brain and extend survival in mouse GBM models, supporting further development of this approach and the utility of brain-penetrating macrocyclic peptide conjugates for delivering non-BBB penetrant drugs to the central nervous system.

STING activation promotes robust immune response and NK cell-mediated tumor regression in glioblastoma models

Immunotherapy has had a tremendous impact on cancer treatment in the past decade, with hitherto unseen responses at advanced and metastatic stages of the disease. However, the aggressive brain tumor glioblastoma (GBM) is highly immunosuppressive and remains largely refractory to current immunotherapeutic approaches. The stimulator of interferon genes (STING) DNA sensing pathway has emerged as a next-generation immunotherapy target with potent local immune stimulatory properties. Here, we investigated the status of the STING pathway in GBM and the modulation of the brain tumor microenvironment (TME) with the STING agonist ADU-S100. Our data reveal the presence of STING in human GBM specimens, where it stains strongly in the tumor vasculature. We show that human GBM explants can respond to STING agonist treatment by secretion of inflammatory cytokines. In murine GBM models, we show a profound shift in the tumor immune landscape after STING agonist treatment, with massive infiltration of the tumor-bearing hemisphere with innate immune cells including inflammatory macrophages, neutrophils, and natural killer (NK) populations. Treatment of established murine intracranial GL261 and CT-2A tumors by biodegradable ADU-S100-loaded intracranial implants demonstrated a significant increase in survival in both models and long-term survival with immune memory in GL261. Responses to treatment were abolished by NK cell depletion. This study reveals therapeutic potential and deep remodeling of the TME by STING activation in GBM and warrants further examination of STING agonists alone or in combination with other immunotherapies such as cancer vaccines, chimeric antigen receptor T cells, NK therapies, and immune checkpoint blockade.

Surprising Chemistry of 6-Azidotetrazolo[5,1-a]phthalazine: What a Purported Natural Product Reveals about the Polymorphism of Explosives

6-Azidotetrazolo[5,1-a]phthalazine (ATPH) is a nitrogen-rich compound of surprisingly broad interest. It is purported to be a natural product, yet it is closely related to substances developed as explosives and is highly polymorphic despite having a nearly planar structure with little flexibility. Seven solid forms of ATPH have been characterized by single-crystal X-ray diffraction. The structures show diverse patterns of molecular organization, including both stacked sheets and herringbone packing. In all cases, N···N and C-H···N interactions play key roles in ensuring molecular cohesion. The high polymorphism of ATPH appears to arise in part from the ability of virtually every atom of nitrogen and hydrogen in the molecule to take part in close N···N and C-H···N contacts. As a result, adjacent molecules can adopt many different relative orientations that are energetically similar, thereby generating a polymorphic landscape with an unusually high density of potential structures. This landscape has been explored in detail by the computational prediction of crystal structures. Studying ATPH has provided insights into the field of energetic materials, where access to multiple polymorphs can be used to improve performance and clarify how it depends on molecular packing. In addition, our work with ATPH shows how valuable insights into molecular crystallization, often gleaned from statistical analyses of structural databases, can also come from in-depth empirical and theoretical studies of single compounds that show distinctive behavior.

Self-assembled ruthenium and osmium nanosystems display a potent anticancer profile by interfering with metabolic activity

We disclose novel amphiphilic ruthenium and osmium complexes that auto-assemble into nanomedicines with potent antiproliferative activity by inhibition of mitochondrial respiration. The self-assembling units were rationally designed from the [M(p-cymene)(1,10-phenanthroline)Cl]PF6 motif (where M is either RuII or OsII) with an appended C16 fatty chain to achieve high cellular activity, nano-assembling and mitochondrial targeting. These amphiphilic complexes block cell proliferation at the sub-micromolar range and are particularly potent towards glioblastoma neurospheres made from patient-derived cancer stem cells. A subcutaneous mouse model using these glioblastoma stem cells highlights one of our C16 OsII nanomedicines as highly successful in vivo. Mechanistically, we show that they act as metabolic poisons, strongly impairing mitochondrial respiration, corroborated by morphological changes and damage to the mitochondria. A genetic strategy based on RNAi gave further insight on the potential involvement of microtubules as part of the induced cell death. In parallel, we examined the structural properties of these new amphiphilic metal-based constructs, their reactivity and mechanism.

Stable Au(I) catalysts for oxidant-free C-H Functionalization with Iodoarenes

The development of oxidant-free gold-catalyzed cross coupling reactions involving aryl halides have been hamstrung by the lack of gold catalysts capable of performing oxidative addition at Au(I) centers. Herein, we report the development of novel tricoordinate Au(I) catalysts supported by N,N-bidentate ligands and ligated by phosphine or arsine ligands for C-H functionalization without external oxidants to form biaryls with no homocoupling. The unsymmetrical character of the Au(I) catalyst is critical to facilitating this necessary orthogonal transformation. This study unveils yet another potential of Au(I) catalysis in biaryl synthesis.

Effect of Revascularization on Intramuscular Vascular Endothelial Growth Factor Levels in Peripheral Arterial Disease

Vascular endothelial growth factor (VEGF) is a potent driver of angiogenesis, which may help to relieve ischemia in peripheral arterial disease (PAD). We aimed to investigate the role of intramuscular VEGF in ischemic and non-ischemic skeletal muscle in PAD patients before and after surgical or endovascular revascularization and different stages of PAD. Biopsies of the gastrocnemius and vastus muscles from twenty PAD patients with stenosis or occlusion of the superficial femoral artery were obtained both during revascularization and 8 weeks postoperatively. The gastrocnemius muscle was considered ischemic, while vastus muscle biopsies served as intraindividual controls. The levels of vascular endothelial growth factor in muscle lysates were then determined by ELISA. Preoperative VEGF levels were significantly higher in ischemic muscles compared to the controls (98.07 ± 61.96 pg/mL vs. 55.50 ± 27.33 pg/mL, p = 0.004). Postoperative values decreased significantly (p = 0.010) to 54.83 ± 49.60 pg/mL in gastrocnemius biopsies. No significant change was observed in vastus muscle biopsies, with mean postoperative VEGF values found at 54.16 ± 40.66 pg/mL. Since all patients still had indications for revascularization, impairment of angiogenesis mechanisms can be assumed. More research about angiogenesis in PAD is needed with the ultimate goal to improve conservative treatment.

Catalytic properties of 4,5-bridged proline methano- and ethanologues in the Hajos-Parrish intramolecular aldol reaction

The catalysis of the Hajos-Parrish reaction by cis- and trans-4,5-ethano-proline was explored experimentally and computationally with DFT (ωB97X-D and MN15) and DLPNO-CCSD(T). Both of the new catalysts are as active as proline or cis- and trans-4,5-methano-proline, with the trans-ethano-proline being as enantioselective as proline. A thorough theoretical analysis of the electronic factors influencing catalysis is reported. This journal is

2021

Reduction Mechanisms of Anticancer Osmium(VI) Complexes Revealed by Atomic Telemetry and Theoretical Calculations

Resonant X-ray emission spectroscopy (RXES) has developed in the past decade as a powerful tool to probe the chemical state of a metal center and in situ study chemical reactions. We have used it to monitor spectral changes associated with the reduction of osmium(VI) nitrido complexes to the osmium(III) ammine state by the biologically relevant reducing agent, glutathione. RXES difference maps are consistent with the proposed DFT mechanism and the formation of two stable osmium(IV) intermediates, thereby supporting the overall pathway for the reduction of these high-valent anticancer metal complexes for which reduction by thiols within cells may be essential to the antiproliferative activity.

Synthesis, structure and anticancer properties of new biotin- and morpholine-functionalized ruthenium and osmium half-sandwich complexes.

Ruthenium (Ru) and osmium (Os) complexes are of sustained interest in cancer research and may be alternative to platinum-based therapy. We detail here three new series of ruthenium and osmium complexes, supported by physico-chemical characterizations, including time-dependent density functional theory, a combined experimental and computational study on the aquation reactions and the nature of the metal-arene bond. Cytotoxic profiles were then evaluated on several cancer cell lines although with limited success. Further investigations were, however, performed on the most active series using a genetic approach based on RNA interference and highlighted a potential multi-target mechanism of action through topoisomerase II, mitotic spindle, HDAC and DNMT inhibition.

2020

Halogen bonding for molecular recognition: new developments in materials and biological sciences

This review highlights recent developments of halogen bonding in materials and biological sciences with a short discussion on the nature of the interaction.

Design and Synthesis of Backbone-Fused, Conformationally Constrained Morpholine-Proline Chimeras

We report the synthesis of two novel bridged morpholine-proline chimeras 4 and 5, which represent rigid conformationally locked three-dimensional structures wherein the lone pairs of electrons on oxygen and nitrogen are oriented in spatially different “east-west” and “north-west” directions, respectively. In combination with the presence of a carboxylic acid, the electronic features of these compounds may be useful in the context of peptidomimetic design of biologically relevant compounds. Quantitative estimates of the basicity of the nitrogen atoms were obtained using conceptual density functional theory analysis.

Methyl arachidonyl fluorophosphonate inhibits Mycobacterium tuberculosis thioesterase TesA and globally affects vancomycin susceptibility.

Phthiocerol dimycocerosates and phenolic glycolipids (PGL) are considered as major virulence elements of Mycobacterium tuberculosis, in particular because of their involvement in cell wall impermeability and drug resistance. The biosynthesis of these waxy lipids involves multiple enzymes, including thioesterase A (TesA). We observed that purified recombinant M. tuberculosis TesA is able to dimerize in the presence of palmitoyl-CoA and our 3D structure model of TesA with this acyl-CoA suggests hydrophobic interaction requirement for dimerization. Furthermore, we identified that methyl arachidonyl fluorophosphonate, which inhibits TesA by covalently modifying the catalytic serine, also displays a synergistic antimicrobial activity with vancomycin further warranting the development of TesA inhibitors as valuable antituberculous drug candidates.

2019

Current patent and clinical status of stimulator of interferon genes (STING) agonists for cancer immunotherapy

Pharmacological Modulation of the STING Pathway for Cancer Immunotherapy

The advent of immunotherapy in recent years has shown the potential to revolutionize the treatment of cancer. Unleashing antitumor T cell responses via immune checkpoint blockade has led to remarkable responses in previously untreatable tumors. The master regulator of interferon-mediated antiviral responses - stimulator of interferon genes (STING) - has now emerged as a critical mediator of innate immune sensing of cancer, and is a promising target for local immunostimulation, promoting intratumoral inflammation, and facilitating antitumor T cell responses. Pharmacological activation of the STING pathway can lead to T cell-mediated tumor regression in preclinical tumor models, and novel STING activating small molecules are now being tested in clinical trials. Here we will introduce the STING pathway and review the current state of drug development.

Direct intramolecular carbon(sp2)-nitrogen(sp2) reductive elimination from gold(III)

The reactivity of bidentate Au III -Cl species, [(C^N)AuCl 2 ], with a bisphosphine or carbon donor ligands results in reductive elimination. Combined experimental and computational investigations lead to the first evidence of a direct intramolecular C(sp 2 )-N(sp 2 ) bond formation from a monomeric [(C^N)AuCl 2 ] gold(iii) complex. We show that bidentate ligated Au(iii) systems bypass transmetallation to form C(sp 2 )-N(sp 2 ) species and NHC-Au-Cl. Mechanistic investigations of the reported transformation reveal a ligand-induced reductive elimination via a key Au III intermediate. Kinetic studies of the reaction support a second-order rate process.

2018

Novel non-nucleotidic STING agonists for cancer immunotherapy

Crystal packing and theoretical analysis of halogen- and hydrogen-bonded hydrazones from pharmaceuticals. Evidence of type I and II halogen bonds in extended chains of dichloromethane

The supramolecular assembly of halogenated and hydroxyl hydrazones derived from two well known pharmaceuticals, isoniazid (IsX, where X = I, Br, OH) and hydralazine (HyX, where X = I, Br, OH), was studied by X-ray crystallography and theoretical methods. Crystal packing of IsI and HyI shows weak I…N and I…π halogen bonds, whereas the hydrogen bonds are dominant in the brominated scaffolds IsBr and HyBr. Although the calculated I…N interaction strength appears almost three times weaker than the O—H…N contacts in the isoniazid-based hydrazones, the higher directionality of the halogen bonds induces a linear and planar architecture of self-complementary tectons, observed only with the help of a bridging water molecule in the case of IsOH. Finally, the X-ray structure of HyOH is characterized by an unexpected linear arrangement of clathrated dichloromethane molecules bound through type I and II halogen bonds. This rare phenomenon, observed in less than ten structures, was studied by coupled cluster-based energy decomposition.

Anticancer activity of osmium(VI) nitrido complexes in patient-derived glioblastoma initiating cells and in vivo mouse models.

Glioblastoma is the most prevalent and lethal primary intrinsic brain tumor with a median patient survival of less than two years, even with the optimal standard of care, namely, surgical resection followed by radiotherapy with adjuvant temozolomide chemotherapy. Long-term survival is extremely rare and there is a tremendous need for novel GBM therapies. Following our prior reports on the anticancer activity of osmium(VI) nitrido compounds and their effectiveness against cancer initiating cells, we investigated the efficacy of Os(VI) on GBM initiating cells in vitro and in vivo. Conventional MTT and 3D cytotoxicity assays revealed that patient-derived GBM models were sensitive to cisplatin, TMZ, and two Os(IV) derivatives. Rapid cell death occurred at low micromolar concentrations of the Os(IV) compounds. Cell cycle analysis, Os uptake studies, and cellular distribution experiments provided further insight into the anticancer properties of these compounds, indicating differential uptake for both compounds and a modest G2/M arrest after treatment. Moreover, in vivo experiments showed a significant increase in survival after a single intracranial chemotherapeutic injection, results that warrant further studies using this approach.

Speciation of Phenanthriplatin and Its Analogs in the Core of Tobacco Mosaic Virus

2017

Metal Coordination Controlled and Bifunctional H-Bonded Catalysis in Stereoselective Intramolecular Aldol Cyclizations toward Carbocyclic Tertiary beta-Ketols

The principle of bifunctional catalysis is shown in the highly regio- and stereoselective intramolecular aldolization of 2-methyl-1,3-cyclopentanedione, C2-substituted with a methyl ethyl ketone group, to provide [3.2.1]-bicyclooctanol diones in the presence of catalytic amounts of either LiBr and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), or 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD). Mechanistic investigations corroborated by DFT calculations show that LiBr engages in a bifunctional coordination of two carbonyl moieties and leads to the preorganization of the reactive enolate intermediate for a base-mediated intramolecular aldol cyclization. On the other hand, TBD catalysis of the triketone substrate proceeds through a bifunctional H-bonded mechanism to give the same aldol product as the major diastereomer. The LiBr and TBD-catalyzed highly stereocontrolled intramolecular aldol cyclizations can be extended to other di- and triketones to give carbocyclic and carbobicyclic products as single diastereomers.

Triple-stimuli responsive polymers with fine tuneable magnetic responses

The formation of multi-stimuli responsive polymers exhibiting magnetic, pH and light sensitivity is reported. After quaternization of tertiary amines along poly(2-(N,N-dimethylamino) ethyl methacrylate) (PDMAEMA) with varied alkyl and benzyl halides, a series of tetrahalogenoferrate(iii) salts were obtained by anion metathesis, conferring tailored and high magnetic responses. Experimental and theoretical Raman analyses allowed one to distinguish between the different magnetic anions present in the materials. This strategy was then implemented to the formation of multi-responsive compounds, by using random copolymers that incorporate various amounts of DMAEMA (∼40, 65 and 80%) and diazobenzene units. Partial or total quaternization of the dimethylamino end groups (10, 50 and 100%) followed by magnetic anion exchange afforded the magnetic-responsive copolymers, as evidenced by their magnetic susceptibility. Free ternary amino groups and diazobenzene moieties further brought pH and light sensitivity, giving rise to triple-stimuli responsive materials. This simple and rapid procedure offers the opportunity to fine tune the magnetic properties of remotely controlled smart devices.

Properties of the Amide Bond Involving Proline 4,5-methanologues: an Experimental and Theoretical Study

Herein we disclose a combined experimental and theoretical study on the conformational properties of amide bonds involving diastereomeric 4,5-methano-L-proline congeners as N-acetyl ethyl esters and dimeric amide ethyl esters as substrates for cyclization to diketopiperazines. The results are discussed in light of density functional theory calculations aimed at delineating the importance of the n→π* stabilization of the trans-amide conformations. The transitions states for the cyclization of diastereomeric 4,5-methano-L-proline ethyl esters to diketopiperazines were calculated and correlated to the experimental studies.

2016

A survey of the mechanisms of action of anticancer transition metal complexes

Metal complexes have been the subject of numerous investigations in oncology but, despite the plethora of newly synthesized compounds, their precise mechanisms of action remain generally unknown or, for the best, incompletely determined. The continuous development of efficient and sensitive techniques in analytical chemistry and molecular biology gives scientists new tools to gather information on how metal complexes can be effective toward cancer. This review focuses on recent findings about the anticancer mechanism of action of metal complexes and how the ligands can be used to tune their pharmacological and physicochemical properties.

Novel bis-arylalkylamines as myeloperoxidase inhibitors: Design, synthesis, and structure-activity relationship study.

Human myeloperoxidase (MPO) plays an important role in innate immunity but also aggravates tissue damage by oxidation of biomolecules at sites of inflammation. As a result from a recent high-throughput virtual screening approach for MPO inhibitors, bis-2,2'-[(dihydro-1,3(2H,4H) pyrimidinediyl)bis(methylene)]phenol was detected as a promising lead compound for inhibition of the MPO-typical two-electron oxidation of chloride to hypochlorous acid (IC50 = 0.5 μM). In the present pharmacomodulation study, 37 derivatives of this lead compound were designed and synthesized driven by comprehensive docking studies and the impact on the chlorination activity of MPO. We describe the structural requirements for optimum (i) binding to the heme periphery and (ii) inhibition capacity. Finally, the best three inhibitors (bis-arylalkylamine derivatives) were probed for interaction with the MPO redox intermediates Compound I and Compound II. Determined apparent bimolecular rate constants together with determination of reduction potential and nucleophilicity of the selected compounds allowed us to propose a mechanism of inhibition. The best inhibitor was found to promote the accumulation of inactive form of MPO-Compound II and has IC50 = 54 nM, demonstrating the successful approach of the drug design. Due to the similarity of ligand interactions between MPO and serotonine transporter, the selectivity of this inhibitor was also tested on the serotonin transporter providing a selectivity index of 14 (KiSERT/IC50MPO).

Strategies toward the Total Synthesis of Calyciphylline B-type Alkaloids: A Computational Perspective Aided by DFT Analysis

Herein we describe synthetic efforts toward the total synthesis of calyciphylline B-type alkaloids. In the process, we disclose a detailed DFT study of equilibrium geometries and transition states that explains the stereochemical outcome during the formation of critical intermediates. X-ray crystallographic analysis reveals interesting conformational features in the naturally occurring deoxycalyciphylline B and its synthetic congeners.

Resonant X-ray emission spectroscopy of platinum(ii) anticancer complexes.

Platinum-based drugs are commonly used in cancer treatment. The biological activity of a metallodrug is obviously closely related to its chemical and stereochemical characteristics. An overlooked aspect is the effect of the ligand to the electronic structure of the metal atom (coordinated atom). We report herein a Resonant X-ray Emission Spectroscopy (RXES) study on the chemical speciation of chiral platinum complexes in which diastereomers are distinguished on the basis of their metal electronic configuration. This demonstrates RXES high chemical speciation capabilities, a necessary property to further investigate the reactivity of the Pt atom towards nucleophiles or bionucleophiles, and an important complement the previously reported RXES abilities, namely that it can be employed for in situ studies at physiological concentrations.

Total Synthesis of Isodaphlongamine H: A Possible Biogenetic Conundrum.

Herein we describe the first synthetic efforts toward the total synthesis of isodaphlongamine H, a calyciphylline B-type alkaloid. The strategy employs a chemoenzymatic process for the preparation of a functionalized cyclopentanol with a quaternary center. This molecule is elaborated to form an enantiopure 1-aza-perhydrocyclopentalene core, representing rings A and E of all calyciphylline B-type alkaloids. Further transformations involve the formation of a cyclic enaminone, 1,4-conjugate addition with a cyclopentenyl subunit, and intramolecular aldol cyclization to achieve a pentacyclic intermediate, ultimately forming isodaphlongamine H in a total of 24 steps from the commercially available compound 2-carbethoxycyclopentanone. Isodaphlongamine H exhibits promising inhibitory activity against a panel of human cancer cell lines.

Halogen bonding in multi-connected 1,2,2-triiodo-alkene involving geminal and/or vicinal iodines: A crystallographic and DFT study

Four halogen-bonded arrangements of (1,2,2 - triiodovinyl) benzene involving geminai and/or vicinal iodine atoms were studied both by X-ray diffraction and density functional theory (DFT). Crystallographic data show weaker XB-type interactions for the iodine atom geminal to the phenylring, which is corroborated by DFT-optimized structures of 1:1, 1:2 and 1:3 (1,2,2-triiodovinyl)benzene/pyridine complexes. In addition, a theoretical model reflects an interplay existing between these conjugated and multi-connected sites, highlighting the weakening of the halogen bonds when the number of partners is increased.

Development of Controlled-Release Cisplatin Dry Powders for Inhalation against Lung Cancers

The present study focuses on the development of dry powders for inhalation as adjuvant chemotherapy in lung cancer treatment. Cisplatin was chosen as a potential candidate for a local treatment as it remains the main platinum component used in conventional chemotherapies, despite its high and cumulative systemic toxicities. Bulk cisplatin was reduced to submicron sizes using high-pressure homogenization, mixed with a solubilized lipid and/or PEGylated component and then spray-dried to produce controlled-release dry powder formulations. The obtained formulations were characterized for their physicochemical properties (particle size and morphology), aerodynamic performance and release profiles. Cisplatin content and integrity were assessed by electrothermal atomic absorption spectrometry and 195Pt nuclear magnetic resonance spectroscopy. DPI formulations with cisplatin contents ranging from 48.5 to 101.0% w/w exhibited high fine particle fractions ranging from 37.3% to 51.5% of the nominal dose. Formulations containing cisplatin microcrystals dispersed in solid lipid microparticles based on acceptable triglycerides for inhalation and PEGylated excipients showed a controlled-release for more than 24 h and a limited burst effect. These new formulations could provide an interesting approach to increasing and prolonging drug exposure in the lung while minimizing systemic toxicities.

2015

Structural Properties and Stereochemically Distinct Folding Preferences of 4,5-cis and trans-Methano- L -Proline Oligomers: The Shortest Crystalline PPII-Type Helical Proline-Derived Tetramer

The synthesis, structural properties, and folding patterns of a series of L-proline methanologues represented by cis- and trans-4,5-methano-L-proline amides and their oligomers are reported as revealed by X-ray crystallography, circular dichroism measurements, and DFT calculations. We disclose the first example of a crystalline tetrameric proline congener to exhibit a polyproline II helical conformation. Experimental evidence of PPII-type helical arrangement (both in solution and in the solid state) of cis-4,5-methano-L-proline oligomers is supported by theoretical calculations reflecting the extent of n→π∗ stabilization of the trans-amide conformation.

The use of Resonant X-ray Emission Spectroscopy (RXES) for the electronic analysis of metal complexes and their interactions with biomolecules

This review presents a new application of Resonant X-ray Emission Spectroscopy (RXES) to study the mechanism of action of metal containing anticancer derivatives and in particular platinum in situ and in vivo. The technique is an example of a photon-in photon-out X-ray spectroscopic approach, which enables chemical speciation of drugs to be determined and therefore to derive action mechanisms, and to determine drug binding rates under physiological conditions and therapeutic concentrations. This is made feasible due to the atomic specificity and high penetration depth of RXES. The review presents examples of the three main types of information that can be obtained by RXES and establishes an experimental protocol to perfect the measurements within cells.

Insights into the structure-activity relationships of chiral 1,2-diaminophenylalkane platinum(II) anticancer derivatives.

The structure-activity relationships of chiral 1,2-diaminophenylalkane platinum(II) anticancer derivatives are studied, including interactions with telomeric- and genomic-like DNA sequences, the pKa of their diaqua species, structural properties obtained from DFT calculations and resonant X-ray emission spectroscopy. The binding modes of the compounds to telomeric sequences were elucidated, showing no major differences with conventional cis-platinum(II) complexes like cisplatin, supporting that the cis-square planar geometry governs the binding of small Pt(II) complexes to G4 structures. Double-stranded DNA platination kinetics and acid-base constants of the diaqua species of the compounds were measured and compared, highlighting a strong steric dependence of the DNA-binding kinetics, but independent to stereoisomerism. Structural features of the compounds are discussed on the basis of dispersion-corrected DFT, showing that the most active series presents conformers for which the platinum atom is well devoid of steric hindrance. If reactivity indices derived from conceptual DFT do not show evidences for different reactivity between the compounds, RXES experiments provide new insight into the availability of platinum orbitals for binding to nucleophiles.

Halogen bonding in polymer science: From crystal engineering to functional supramolecular polymers and materials

Halogen bonding (XB) is commonly defined as a non-covalent bond where halogen atoms (X

Erratum:Corrigendum to "synthesis of 15N-labeled vicinal diamines through N-activated chiral aziridines: Tools for the NMR study of platinum-based anticancer compounds" (Tetrahedron Letters (2013) 54 (545-548) doi:10.1016/j.tetlet.2014.11.086))

2014

Synthesis of alpha-CF3 azanorbornene and azetidines by aza Diels-Alder or iodine-mediated cyclizations: Application in ROMP and ligand design

We report the synthesis of several new α-trifluoromethylated nitrogen heterocycles, among which azanorbornene and azetidine derivatives, by aza Diels-Alder or iodine-mediated cyclizations. These building blocks were used as starting materials for the formation of fluorinated polymers by ROMP or for ligand design through substitution and click reactions.

Synthesis and in vitro characterization of platinum(II) anticancer coordinates using FTIR spectroscopy and NCI COMPARE: A fast method for new compound discovery.

Platinum-based drugs have been used for several decades to treat various cancers successfully. Cisplatin is the original compound in this class; it cross-links DNA, resulting in cell cycle arrest and cell death via apoptosis. Cisplatin is effective against several tumor types but exhibits toxic side effects; in addition, tumors often develop resistance. An original in vitro approach is proposed to determine whether platinum-based research compounds are good candidates for further study by comparing them to marketed drugs using FTIR spectroscopy and the COMPARE analysis from the NCI. Both methods can produce fingerprints and highlight differences between the compounds, classifying the candidates and revealing promising derivatives.

Interplay between halogen bonding and lone pair-Pi interactions: A computational and crystal packing study

The supramolecular organization of modified thiophenes resulting from N⋯I halogen bonding (XB) has been studied. X-ray diffraction analyses of two polymorphs of the same supramolecular complex showed an arrangement controlled by halogen-bonded pyridyl and tetrafluoroiodobenzene rings, one case with and the other without the presence of two different lone pair (lp)⋯π interactions, namely O⋯pyridyl and I⋯ tetrafluoroiodobenzene contacts. To shed light on the interplay between these interactions, quantum mechanical calculations were performed at the ωB97X-D/6-31+G(d,p) level on both systems in the gas phase. The longer N⋯I distance observed in the crystal structure without lp⋯π interactions was also corroborated by dispersion-corrected DFT. These results represent the first case in which a synergy between lp⋯π interactions and XB is observed experimentally and confirmed by calculations. Getting organized: X-ray diffraction analyses of two polymorphs of a supramolecular thiophene complex show an arrangement controlled by N⋯I halogen bonding (XB), one case with and the other without the presence of two different lone pair (lp)⋯π interactions, namely O⋯pyridyl and I⋯tetrafluoroiodobenzene contacts (see figure). Quantum mechanical calculations confirm the interplay between concomitant XB and lp⋯π interactions. Copyright © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

2013

Using conceptual density functional theory to rationalize regioselectivity: A case study on the nucleophilic ring-opening of activated aziridines

Density functional theory calculations have been performed to rationalize the regiochemistry of the nucleophilic ring opening of activated aziridines. Atomic charges, lowest unoccupied molecular orbitals, Fukui functions and Fukui indices were calculated at the B3LYP/6-311G++(2d,2p) level of theory. Frontier molecular orbital theory, as well as the Fukui function were able to explain the experimentally observed ratios of opening products and a surprising change in regioselectivity upon nitrobenzenesulfonyl activation on the nitrogen. In addition, robustness of atomic charges and Fukui indices to the basis set quality was assessed. © 2013 Elsevier B.V.

Synthesis of 15N-labeled vicinal diamines through N-activated chiral aziridines: tools for the NMR study of platinum-based anticancer compounds

A new method for the synthesis of 15N-labeled chiral beta-diamines from a common precursor, either optically pure amino acids or anti-beta-amino alcohols, is reported. The two diastereomeric series of vicinal diamines are produced through the nucleophilic ring opening of activated chiral aziridines. 15N was introduced by means of [15N]-benzylamine, prepared from 15NH4Cl. The final compounds are highly valuable because [1H-15N] NMR is considered a powerful tool for studying the chemical properties of platinum-based complexes.

2010

Fourier transform infrared (FTIR) spectroscopy to monitor the cellular impact of newly synthesized platinum derivatives.

Platinum complexes remain widely used to combat various types of cancers. Three platinum complexes, cisplatin, carboplatin and oxaliplatin, are marketed for various oncological purposes. Additionally, nedaplatin, lobaplatin and heptaplatin have gained regionally limited approval for oncology purposes. Furthermore, various platinum derivatives are currently under clinical trials. More than 40 years after their discovery, however, the precise mechanism of action of platinum antitumor complexes remains elusive, partly because these compounds display numerous intracellular targets. Structure-activity-relationship analyses are therefore difficult to conduct to optimize the synthesis of novel platinum derivatives. The aim of the present study is to illustrate the potential of using Fourier Transform Infrared (FTIR) analyses to monitor the cellular modifications induced by the new platinum derivatives that we have synthesized. We show in the present study the advantages of combining an in vitro assay to determine the IC50 growth inhibition concentrations of a series of compounds belonging to a given chemical series and FTIR analyses carried out at the IC50 concentrations for each compound to identify potential hits within this series of compounds. The original pharmacological approach proposed here could, therefore, avoid large-scale pharmacological experiments to find hits within a given chemical series.