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François Dufrasne

Research in Drug Development (RD3)

Microbiology, Bioorganic and Macromolecular Chemistry

Research activities

His main research interests focus on the design and synthesis of organic or inorganic molecules having potential therapeutic applications in health.

He is especially involved in solving problems related to the finding of new hits as receptor agonists/antagonists or enzyme inhibitors in collaboration with other teams working on molecular docking and protein crystallization in the University.

Further developments can be made in-house such as lead generation, toxicological testing and drug preformulation to achieve animal testing.

Articles dans des revues avec comité de lecture

2024

Immune Diseases: Challenges, Hopes and Recent Achievements

Dufrasne, F. (2024). Immune Diseases: Challenges, Hopes and Recent Achievements. Pharmaceuticals, 17(1), 97. doi:10.3390/ph17010097
https://dipot.ulb.ac.be/dspace/bitstream/2013/371574/1/doi_355218.pdf

2023

Antimycobacterial Activities of Hydroxamic Acids and Their Iron(II/III), Nickel(II), Copper(II) and Zinc(II) Complexes.

Yang, D., Zhang, Y., Sow, I. S., Liang, H., El Manssouri, N., Gelbcke, M., Dong, L., Chen, G., Dufrasne, F., Fontaine, V., & Li, R. (2023). Antimycobacterial Activities of Hydroxamic Acids and Their Iron(II/III), Nickel(II), Copper(II) and Zinc(II) Complexes. Microorganisms, 11(10), 2611. doi:10.3390/microorganisms11102611

Hydroxamic acid (HA) derivatives display antibacterial and antifungal activities. HA with various numbers of carbon atoms (C2, C6, C8, C10, C12 and C17), complexed with different metal ions, including Fe(II/III), Ni(II), Cu(II) and Zn(II), were evaluated for their antimycobacterial activities and their anti-biofilm activities. Some derivatives showed antimycobacterial activities, especially in biofilm growth conditions. For example, 20-100 µM of HA10Fe2, HA10FeCl, HA10Fe3, HA10Ni2 or HA10Cu2 inhibited Mycobacterium tuberculosis, Mycobacterium bovis BCG and Mycobacterium marinum biofilm development. HA10Fe2, HA12Fe2 and HA12FeCl could even attack pre-formed Pseudomonas aeruginosa biofilms at higher concentrations (around 300 µM). The phthiocerol dimycocerosate (PDIM)-deficient Mycobacterium tuberculosis H37Ra was more sensitive to the ion complexes of HA compared to other mycobacterial strains. Furthermore, HA10FeCl could increase the susceptibility of Mycobacterium bovis BCG to vancomycin. Proteomic profiles showed that the potential targets of HA10FeCl were mainly related to mycobacterial stress adaptation, involving cell wall lipid biosynthesis, drug resistance and tolerance and siderophore metabolism. This study provides new insights regarding the antimycobacterial activities of HA and their complexes, especially about their potential anti-biofilm activities.

https://dipot.ulb.ac.be/dspace/bitstream/2013/365568/1/doi_349212.pdf

Immunovirological and environmental screening reveals actionable risk factors for fatal COVID-19 during post-vaccination nursing home outbreaks.

Cuypers, L., Keyaerts, E., Hong, S. L., Gorissen, S., Menezes, S. M., Starick, M., Van Elslande, J., Weemaes, M., Wawina-Bokalanga, T., Marti-Carreras, J., Vanmechelen, B., Van Holm, B., Bloemen, M., Dogne, J.-M., Dufrasne, F., Durkin, K., Ruelle, J., De Mendonça, R., Wollants, E., Vermeersch, P., COVID-19 Genomics Belgium Consortium,, Boulouffe, C., Djiena, A., Broucke, C., Catry, B., Lagrou, K., Van Ranst, M., Neyts, J., Baele, G., Maes, P., André, E., Dellicour, S., Van Weyenbergh, J., et al. (2023). Immunovirological and environmental screening reveals actionable risk factors for fatal COVID-19 during post-vaccination nursing home outbreaks. Nature aging, 3(6), 722-733. doi:10.1038/s43587-023-00421-1

Coronavirus Disease 2019 (COVID-19) vaccination has resulted in excellent protection against fatal disease, including in older adults. However, risk factors for post-vaccination fatal COVID-19 are largely unknown. We comprehensively studied three large nursing home outbreaks (20-35% fatal cases among residents) by combining severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) aerosol monitoring, whole-genome phylogenetic analysis and immunovirological profiling of nasal mucosa by digital nCounter transcriptomics. Phylogenetic investigations indicated that each outbreak stemmed from a single introduction event, although with different variants (Delta, Gamma and Mu). SARS-CoV-2 was detected in aerosol samples up to 52 d after the initial infection. Combining demographic, immune and viral parameters, the best predictive models for mortality comprised IFNB1 or age, viral ORF7a and ACE2 receptor transcripts. Comparison with published pre-vaccine fatal COVID-19 transcriptomic and genomic signatures uncovered a unique IRF3 low/IRF7 high immune signature in post-vaccine fatal COVID-19 outbreaks. A multi-layered strategy, including environmental sampling, immunomonitoring and early antiviral therapy, should be considered to prevent post-vaccination COVID-19 mortality in nursing homes.

https://dipot.ulb.ac.be/dspace/bitstream/2013/366368/1/doi_350012.pdf

Crystal Structures of a Series of Hydroxamic Acids

Sow, I. S., Gelbcke, M., Dufrasne, F., & Robeyns, K. (2023). Crystal Structures of a Series of Hydroxamic Acids. Molbank, 2023, 1637.
https://dipot.ulb.ac.be/dspace/bitstream/2013/360179/3/SowetalMolbank.pdf

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

Sow, I. S., Gelbcke, M., Meyer, F., Vandeput, M., Marloye, M., Basov, S., Van Bael, M., Berger, G., Robeyns, K., Hermans, S., Yang, D., Fontaine, V., & Dufrasne, F. (2023). Synthesis and biological activity of iron(II), iron(III), nickel(II), copper(II) and zinc(II) complexes of aliphatic hydroxamic acids. Journal of coordination chemistry, 1-30. doi:10.1080/00958972.2023.2166407

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.

https://dipot.ulb.ac.be/dspace/bitstream/2013/355724/3/Sow_et_al_Article_revised.docxhttps://dipot.ulb.ac.be/dspace/bitstream/2013/355724/4/printversionJCC_XX_XXX.pdf

2022

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

Marloye, M., Inam, H., Moore, C. J., Mertens, T. R., Ingels, A., Koch, M., Nowicki, M. O., Mathieu, V., Pritchard, J. R., Awuah, S. G., Lawler, S. E., Meyer, F., Dufrasne, F., & Berger, G. (2022). Self-assembled ruthenium and osmium nanosystems display a potent anticancer profile by interfering with metabolic activity. Inorganic Chemistry Frontiers. doi:10.1039/D2QI00423B

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.

https://dipot.ulb.ac.be/dspace/bitstream/2013/343823/3/FRONTINORGCHEM_XX_XXX.pdf

Baloxavir marboxil: An original new drug against influenza

Dufrasne, F. (2022). Baloxavir marboxil: An original new drug against influenza. Pharmaceuticals, 15(1), 28, 11. doi:10.3390/ph15010028

Baloxavir marboxil is a new drug developed in Japan by Shionogi to treat seasonal flu infection. This cap-dependent endonuclease inhibitor is a prodrug that releases the biologically active baloxavir acid. This new medicine has been marketed in Japan, the USA and Europe. It is well tolerated (more than 1% of the patients experienced diarrhea, bronchitis, nausea, nasopharyngitis, and headache), and both influenza A and B viruses are sensitive, although the B strain is more resistant due to variations in the amino acid residues in the binding site. The drug is now in post-marketing pharmacovigilance phase, and its interest will be especially re-evaluated in the future during the annual flu outbreaks. It has been also introduced in a recent clinical trial against COVID-19 with favipiravir.

2021

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

Marloye, M., Inam, H., Moore, C. J., Debaille, V., Pritchard, J. J., Gelbcke, M., Meyer, F., Dufrasne, F., & Berger, G. (2021). Synthesis, structure and anticancer properties of new biotin- and morpholine-functionalized ruthenium and osmium half-sandwich complexes. JBIC. Journal of biological inorganic chemistry. doi:10.1007/s00775-021-01873-9

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.

https://dipot.ulb.ac.be/dspace/bitstream/2013/326656/3/Marloye2021_Article_SynthesisStructureAndAnticance.pdf

2020

On the Clinical Pharmacology of Reactive Oxygen Species.

Casas, A. I., Nogales, C., Mucke, H. H., Petraina, A., Cuadrado, A., Rojo, A. A., Ghezzi,, Jaquet, V., Augsburger, F., Dufrasne, F., Soubhye, J., Deshwal, S., Di Sante, M., Kaludercic, N., Di Lisa, F., & Schmidt, H. A. E. (2020). On the Clinical Pharmacology of Reactive Oxygen Species. Pharmacological reviews, 72(4), 801-828. doi:10.1124/pr.120.019422

Reactive oxygen species (ROS) have been correlated with almost every human disease. Yet clinical exploitation of these hypotheses by pharmacological modulation of ROS has been scarce to nonexistent. Are ROS, thus, irrelevant for disease? No. One key misconception in the ROS field has been its consideration as a rather detrimental metabolic by-product of cell metabolism, and thus, any approach eliminating ROS to a certain tolerable level would be beneficial. We now know, instead, that ROS at every concentration, low or high, can serve many essential signaling and metabolic functions. This likely explains why systemic, nonspecific antioxidants have failed in the clinic, often with neutral and sometimes even detrimental outcomes. Recently, drug development has focused, instead, on identifying and selectively modulating ROS enzymatic sources that in a given constellation cause disease while leaving ROS physiologic signaling and metabolic functions intact. As sources, the family of NADPH oxidases stands out as the only enzyme family solely dedicated to ROS formation. Selectively targeting disease-relevant ROS-related proteins is already quite advanced, as evidenced by several phase II/III clinical trials and the first drugs having passed registration. The ROS field is expanding by including target enzymes and maturing to resemble more and more modern, big data-enhanced drug discovery and development, including network pharmacology. By defining a disease based on a distinct mechanism, in this case ROS dysregulation, and not by a symptom or phenotype anymore, ROS pharmacology is leaping forward from a clinical underperformer to a proof of concept within the new era of mechanism-based precision medicine. SIGNIFICANCE STATEMENT: Despite being correlated to almost every human disease, nearly no ROS modulator has been translated to the clinics yet. Here, we move far beyond the old-fashioned misconception of ROS as detrimental metabolic by-products and suggest 1) novel pharmacological targeting focused on selective modulation of ROS enzymatic sources, 2) mechanism-based redefinition of diseases, and 3) network pharmacology within the ROS field, altogether toward the new era of ROS pharmacology in precision medicine.

https://dipot.ulb.ac.be/dspace/bitstream/2013/312522/1/doi_296166.pdf

A patent review of myeloperoxidase inhibitors for treating chronic inflammatory syndromes (focus on cardiovascular diseases, 2013-2019)

Soubhye, J., Van Antwerpen, P., & Dufrasne, F. (2020). A patent review of myeloperoxidase inhibitors for treating chronic inflammatory syndromes (focus on cardiovascular diseases, 2013-2019). Expert opinion on therapeutic patents. doi:10.1080/13543776.2020.1780210

Introduction: Myeloperoxidase (MPO) is an immune enzyme found in neutrophils and macrophages. It produces the highly oxidative compound HOCl from H2O2 and Cl− ions inside the phagosome of the neutrophil. Leakage of the enzyme outside the cell causes oxidative damages for the biomolecules promoting many inflammatory diseases such as atherosclerosis. Thus, there is a real interest to develop potent inhibitors of MPO as non-steroidal anti-inflammatory agents. This review highlights the several published MPO inhibitors, their activity, and the challenges met during the development of these compounds. Areas covered: This article covers the patent literature published on MPO inhibitors from 2013 to 2019, as well as the potential use of these compounds as therapeutics for inflammatory syndromes, especially that plays an important role in the initiation and progression of atherosclerosis. Expert opinion: To date, many MPO inhibitors with different structures have been studied, many of which have prominent inhibitory activities. Furthermore, the specificity of these drugs offers hope for the targeted therapy of inflammatory syndromes. Although many data have proved that MPO can contribute to several chronic inflammatory syndromes, the usefulness of MPO inhibitors in preventing and treating inflammatory disorders is still under investigation.

https://dipot.ulb.ac.be/dspace/bitstream/2013/311510/3/IETPA780210.pdf

2018

I3-Ag85 effect on phthiodiolone dimycocerosate synthesis

Rens, C., Laval, F., Wattiez, R., Lefèvre, P., Dufrasne, F., Daffé, M., & Fontaine, V. (2018). I3-Ag85 effect on phthiodiolone dimycocerosate synthesis. Tuberculosis, 108, 93-95. doi:10.1016/j.tube.2017.10.007

The multiplicity of drug resistant Mycobacterium tuberculosis (Mtb) strains is a growing health issue. New therapies are needed, acting on new targets. The I3-Ag85 was already reported to reduce the amount of trehalose dimycolate lipid of the mycobacterial cell wall. This inhibitor of Ag85C increased the mycobacterial wall permeability. We previously showed that M. tuberculosis strains, even multi-drug resistant and extensively-drug resistant strains, can be susceptible to vancomycin when concomitantly treated with a drug altering the cell envelope integrity. We investigated the effect of the I3-Ag85 on vancomycin susceptibility of M. tuberculosis. Although no synergy was observed, a new target of this drug was discovered: the production of phthiodiolone dimycocerosate (PDIM B).

Targeting Cytosolic Phospholipase A2α for Novel Anti-Inflammatory Agents.

Soubhye, J., Van Antwerpen, P., & Dufrasne, F. (2018). Targeting Cytosolic Phospholipase A2α for Novel Anti-Inflammatory Agents. Current medicinal chemistry. doi:10.2174/0929867325666180117103919

Group IV cytosolic phospholipase A2 (cPLA2α) plays a critical role in inflammatory processes. It produces arachidonic acid which is the main source of the pro-inflammatory eicosanoids mediators that are important in innate immune system. In some cases, these pro-inflammatory mediators cause damages to the host tissues and therefore promote autoimmune diseases. Consequently, development of potent inhibitors against cPLA2α could improve the therapy of inflammatory diseases. In the last two decades, intense efforts have been done to find potent cPLA2α inhibitors. Several scaffolds have been developed with the use of structure-activity relationship (SAR) studies, and potent inhibitors have been obtained. The poor absorption of these compounds from intestine was the main challenge for clinical application. This review illustrates the search for cPLA2α inhibitors, their SAR studies and biological effects.

2017

31ièmes Journées franco-belges de pharmacochimie: Meeting report

Frederick, R., Pochet, L., de Tullio, P., & Dufrasne, F. (2017). 31ièmes Journées franco-belges de pharmacochimie: Meeting report. Pharmaceuticals, 10(4), 94. doi:10.3390/ph10040094

The “Journées Franco-Belges de Pharmacochimie” is a recognized two-day annual meeting on Medicinal Chemistry that is renowned for the advanced science presented, conviviality, and outstanding opportunities for senior and young scientists to exchange knowledge. Abstracts of plenary lectures, oral communications, and posters presented during the meeting are collected in this report.

https://dipot.ulb.ac.be/dspace/bitstream/2013/263174/1/doi_246801.pdf

Discovery of Novel Potent Reversible and Irreversible Myeloperoxidase Inhibitors Using Virtual Screening Procedure

Soubhye, J., Chikh Alard, I., Aldib, I., Prévost, M., Gelbcke, M., De Carvalho, A., Furtmüller, P. G., Obinger, C., Flemmig, J., Tadrent, S., Meyer, F., Rousseau, A., Neve, J., Mathieu, V., Zouaoui Boudjeltia, K., Dufrasne, F., & Van Antwerpen, P. (2017). Discovery of Novel Potent Reversible and Irreversible Myeloperoxidase Inhibitors Using Virtual Screening Procedure. Journal of medicinal chemistry, 60(15), 6563-6586. doi:10.1021/acs.jmedchem.7b00285

The heme enzyme myeloperoxidase (MPO) participates in innate immune defense mechanism through formation of microbicidal reactive oxidants. However, evidence has emerged that MPO-derived oxidants contribute to propagation of inflammatory diseases. Because of the deleterious effects of circulating MPO, there is a great interest in the development of new efficient and specific inhibitors. Here, we have performed a novel virtual screening procedure, depending on ligand-based pharmacophore modeling followed by structure-based virtual screening. Starting from a set of 727842 compounds, 28 molecules were selected by this virtual method and tested on MPO in vitro. Twelve out of 28 compounds were found to have an IC50 less than 5 μM. The best inhibitors were 2-(7-methoxy-4-methylquinazolin-2-yl)guanidine (28) and (R)-2-(1-((2,3-dihydro-1H-imidazol-2-yl)methyl)pyrrolidin-3-yl)-5-fluoro-1H-benzo[d]imidazole (42) with IC50 values of 44 and 50 nM, respectively. Studies on the mechanism of inhibition suggest that 28 is the first potent mechanism-based inhibitor and inhibits irreversibly MPO at nanomolar concentration.

https://dipot.ulb.ac.be/dspace/bitstream/2013/259616/5/acs.jmedchem.7b00285.pdf https://dipot.ulb.ac.be/dspace/bitstream/2013/259616/4/_system_appendPDF_proof_hi.pdf

From Dynamic Combinatorial Chemistry to in Vivo Evaluation of Reversible and Irreversible Myeloperoxidase Inhibitors.

Soubhye, J., Gelbcke, M., Van Antwerpen, P., Dufrasne, F., Boufadi, Y. M., Neve, J., Furtmüller, P. G., Obinger, C., Zouaoui Boudjeltia, K., & Meyer, F. (2017). From Dynamic Combinatorial Chemistry to in Vivo Evaluation of Reversible and Irreversible Myeloperoxidase Inhibitors. ACS Medicinal Chemistry Letters, 8(2), 206-210. doi:10.1021/acsmedchemlett.6b00417

The implementation of dynamic combinatorial libraries allowed the determination of highly active reversible and irreversible inhibitors of myeloperoxidase (MPO) at the nanomolar level. Docking experiments highlighted the interaction between the most active ligands and MPO, and further kinetic studies defined the mode of inhibition of these compounds. Finally, in vivo evaluation showed that one dose of irreversible inhibitors is able to suppress the activity of MPO after inducing inflammation.

2016

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

Marloye, M., Berger, G., Gelbcke, M., & Dufrasne, F. (2016). A survey of the mechanisms of action of anticancer transition metal complexes. Future Medicinal Chemistry, 8(18), 2263-2286. doi:10.4155/fmc-2016-0153

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.

Characterization of chemical features of potent myeloperoxidase inhibitors.

Soubhye, J., Meyer, F., Furtmüller, P. G., Obinger, C., Dufrasne, F., & Van Antwerpen, P. (2016). Characterization of chemical features of potent myeloperoxidase inhibitors. Future Medicinal Chemistry, 8(11), 1163-1177. doi:10.4155/fmc-2016-0031

Despite its important role in the immune system, myeloperoxidase (MPO) is implicated in a wide range of inflammatory syndromes due to its oxidative product HOCl. The oxidative damages caused by MPO make it a new target for developing promising anti-inflammatory agents. In this paper, we tried to understand the mechanism of MPO inhibition in order to facilitate the drug design, to develop more accurate virtual tests and to understand the structure-activity relationship.

https://dipot.ulb.ac.be/dspace/bitstream/2013/239321/3/f.pdf

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

Aldib, I., Gelbcke, M., Soubhye, J., Prévost, M., Furtmüller, P. G., Obinger, C., Elfving, B., Chikh Alard, I., Roos, G., Delporte, C., Berger, G., Dufour, D., Zouaoui Boudjeltia, K., Neve, J., Dufrasne, F., & Van Antwerpen, P. (2016). Novel bis-arylalkylamines as myeloperoxidase inhibitors: Design, synthesis, and structure-activity relationship study. European journal of medicinal chemistry, 123, 746-762. doi:10.1016/j.ejmech.2016.07.053

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).

https://dipot.ulb.ac.be/dspace/bitstream/2013/235321/4/Elsevier_218948.pdf

Myeloperoxidase as a Target for Treatment of Inflammatory Syndromes: Mechanisms and Structure Activity Relationships of Inhibitors.

Soubhye, J., Aldib, I., Delporte, C., Prévost, M., Dufrasne, F., & Van Antwerpen, P. (2016). Myeloperoxidase as a Target for Treatment of Inflammatory Syndromes: Mechanisms and Structure Activity Relationships of Inhibitors. Current medicinal chemistry. doi:10.2174/0929867323666160607111806

Inflammation is the initial response of the body to the harmful stimuli and it is achieved by the increased movement of leukocytes (especially granulocytes) from blood into injured tissues. It is required for healing wounds and infections. Despite their indispensable role in microbial killing, the inflammation reactions may also cause diseases to a host such as hay fever, atherosclerosis, and rheumatoid arthritis. The enzymes and oxidizing species released during the inflammatory process can cause damages to the host tissues which lead to inflammatory syndromes. The role of myeloperoxidase (MPO) in the inflammatory reactions is well documented. It contributes in killing the pathogens but it is also implicated in several inflammatory syndromes such as Parkinson's disease, Alzheimer's disease and atherosclerosis. Thus, this enzyme attracted more and more attention of the scientists and it became a target for drug designing. In the last decade, several reversible and irreversible MPO inhibitors were identified as very high potent inhibitors such as fluoroalkylindole, aromatic hydroxamic acid, thioxanthine and benzoic acid hydrazide derivatives. In this review, we tried to illustrate the MPO inhibitors and highlight their structure activity relationship (SAR). In this paper we also discussed the mechanism of the inhibitory effect of the most potent compounds.

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

Sá, J., Czapla-Masztafiak, J., Lipiec, E., Kayser, Y., Fernandes, D. L. A., Szlachetko, J., Dufrasne, F., & Berger, G. (2016). Resonant X-ray emission spectroscopy of platinum(ii) anticancer complexes. Analyst, 141(4), 1226-1232. doi:10.1039/c5an02490k

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.

2015

29ièmes journées Franco-Belges de Pharmacochimie: Meeting report

Frederick, R., Pochet, L., de Tullio, P., & Dufrasne, F. (2015). 29ièmes journées Franco-Belges de Pharmacochimie: Meeting report. Pharmaceuticals, 8(4), 758-777. doi:10.3390/ph8040758

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

Sá, J., Fernandes, D. L. A., Szlachetko, J., Czapla-Masztafiak, J., Lipiec, E., Kayser, Y., Kwiatek, W., Wood, B., Deacon, G. G., Berger, G., & Dufrasne, F. (2015). The use of Resonant X-ray Emission Spectroscopy (RXES) for the electronic analysis of metal complexes and their interactions with biomolecules. Drug Discovery Today: Technologies, 16, 1-6. doi:10.1016/j.ddtec.2015.07.001

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.

https://dipot.ulb.ac.be/dspace/bitstream/2013/226726/1/Elsevier_210353.pdf

Technologies to develop new metal medicines

Dufrasne, F. (2015). Technologies to develop new metal medicines. Drug Discovery Today: Technologies, 16, 31-32. doi:10.1016/j.ddtec.2015.10.001
https://dipot.ulb.ac.be/dspace/bitstream/2013/226780/1/Elsevier_210407.pdf

Type 2 17-β hydroxysteroid dehydrogenase as a novel target for the treatment of osteoporosis

Soubhye, J., Chikh Alard, I., Van Antwerpen, P., & Dufrasne, F. (2015). Type 2 17-β hydroxysteroid dehydrogenase as a novel target for the treatment of osteoporosis. Future Medicinal Chemistry, 7(11), 1431-1456. doi:10.4155/fmc.15.74

Low estradiol level in postmenopausal women is implicated in osteoporosis, which occurs because of the high bone resorption rate. Estrogen formation is controlled by 17-β hydroxysteroid dehydrogenase 17-β HSD enzymes, where 17-β HSD type 1 contributes in the formation of estradiol, while type 2 catalyzes its catabolism. Inhibiting 17-β HSD2 can help in increasing estradiol concentration. Several promising 17-β HSD2 inhibitors that can act at low nanomolar range have been identified. However, there are some specific challenges associated with the application of these compounds. Our review provides an up-to-date summary of the current status and recent progress in the production of 17-β HSD2 inhibitors as well as the future challenges in their clinical application.

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

Berger, G., Fusaro, L., Luhmer, M., Czapla-Masztafiak, J., Lipiec, E., Szlachetko, J., Kayser, Y., Fernandes, D. L. A., Sá, J., Dufrasne, F., & Bombard, S. (2015). Insights into the structure-activity relationships of chiral 1,2-diaminophenylalkane platinum(II) anticancer derivatives. JBIC. Journal of biological inorganic chemistry. doi:10.1007/s00775-015-1270-6

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.

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))

Berger, G., Gelbcke, M., Neve, J., Dufrasne, F., Cauet, E., & Luhmer, M. (2015). 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)). Tetrahedron letters, 56(2), 485. doi:10.1016/j.tetlet.2014.11.086
https://dipot.ulb.ac.be/dspace/bitstream/2013/204875/1/Elsevier_188502.pdf

2014

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

Berger, G., Leclercqz, H., Derenne, A., Gelbcke, M., Goormaghtigh, E., Neve, J., Mathieu, V., & Dufrasne, F. (2014). Synthesis and in vitro characterization of platinum(II) anticancer coordinates using FTIR spectroscopy and NCI COMPARE: A fast method for new compound discovery. Bioorganic & medicinal chemistry, 22(13), 3527-3536. doi:10.1016/j.bmc.2014.04.017

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.

https://dipot.ulb.ac.be/dspace/bitstream/2013/179462/1/Elsevier_163089.pdf

Hybrid molecules inhibiting myeloperoxidase activity and serotonin reuptake: a possible new approach of major depressive disorders with inflammatory syndrome.

Soubhye, J., Aldib, I., Prévost, M., Elfving, B., Gelbcke, M., Podrecca, M., Conotte, R., Colet, J.-M., Furtmüller, P. G., Delporte, C., Rousseau, A., Vanhaeverbeek, M., Neve, J., Obinger, C., Zouaoui Boudjeltia, K., Van Antwerpen, P., & Dufrasne, F. (2014). Hybrid molecules inhibiting myeloperoxidase activity and serotonin reuptake: a possible new approach of major depressive disorders with inflammatory syndrome. Journal of Pharmacy and Pharmacology, 66(8), 1122-1132. doi:10.1111/jphp.12236

Major depressive disorder (MDD) is accompanied with an imbalance in the immune system and cardiovascular impairments, such as atherosclerosis. Several mechanisms have been pointed out to underlie this rather unexpected association, and among them the activity of myeloperoxidase (MPO). The aim of our study was to find compounds that inhibit both MPO and serotonin transporter (SERT) for treating MDD associated with cardiovascular diseases.

https://dipot.ulb.ac.be/dspace/bitstream/2013/159760/1/Hybrid-molecs_MPO_SERT.pdfhttps://dipot.ulb.ac.be/dspace/bitstream/2013/159760/4/159760.pdf

The antiapoptotic effect of remifentanil on the immature mouse brain: An ex vivo study

Tourrel, F., Laudenbach, V., Gonzalez, B. J., Jégou, S., De Lendeu, P. K., Abily-Donval, L., Chollat, C., Marret, S., Dufrasne, F., Compagnon, P., Ramdani, Y., & Dureuil, B. (2014). The antiapoptotic effect of remifentanil on the immature mouse brain: An ex vivo study. Anesthesia and analgesia, 118(5), 1041-1051. doi:10.1213/ANE.0000000000000159

BACKGROUND: The use of remifentanil in a context of potential prematurity led us to explore ex vivo the opioid effects on the immature mouse brain. Remifentanil enhances medullary glutamatergic N-methyl-d-aspartate (NMDA) receptor activity. Furthermore, in neonatal mouse cortex, NMDA was previously shown to exert either excitotoxic or antiapoptotic effects depending on the cortical layers. With the use of a model of acute cultured brain slices, we evaluated the potential necrotic and apoptotic effects of remifentanil, alone or associated with its glycine vehicle (commercial preparation of remifentanil, C.P. remifentanil), on the immature brain. METHODS: Cerebral slices from postnatal day 2 mice were treated up to 5 hours with the different compounds, incubated alone or in the presence of NMDA. The necrotic effect was studied by measuring lactate dehydrogenase activity and 7-Aminoactinomycin D labeling. Apoptotic death was evaluated by measurement of caspase-3 activity and cleaved caspase-3 protein levels, using Western blot and immunohistochemistry. Extrinsic and intrinsic apoptotic pathways were investigated by measuring caspase-8, caspase-9 activities, Bax protein levels, and mitochondrial integrity. RESULTS: C.P. remifentanil was ineffective on necrotic death, whereas it significantly reduced caspase-3 activity and cortical cleaved caspase-3 levels. C.P. remifentanil inhibited cortical Bax protein expression, caspase-9 activity, and preserved mitochondrial integrity, whereas it had no effect on caspase-8 activity. Its action targeted the neocortex superficial layers, and it was reversed by the opioid receptors antagonist naloxone and the NMDA antagonist MK801. Remifentanil and glycine acted synergistically to inhibit apoptotic death. In addition, C.P. remifentanil enhanced the antiapoptotic effect of NMDA, whereas it did not improve NMDA excitotoxicity in brain slices. CONCLUSION: The present data indicate that at a supraclinical concentration C.P. remifentanil had no pronecrotic effect but exerted ex vivo antiapoptotic action on the immature mouse brain, involving the opioid and NMDA receptors, and the mitochondrial-dependent apoptotic pathway. Assessment of the impact of the antiapoptotic effect of remifentanil in in vivo neonatal mouse models of brain injury will also be essential to measure its consequences on the developing brain.

2013

Structure-Activity Relationship Analysis of Bufadienolide-Induced in Vitro Growth Inhibitory Effects on Mouse and Human Cancer Cells.

Moreno Y Banuls, L., Urban, E., Gelbcke, M., Dufrasne, F., Kopp, B., Kiss, R., & Zehl, M. (2013). Structure-Activity Relationship Analysis of Bufadienolide-Induced in Vitro Growth Inhibitory Effects on Mouse and Human Cancer Cells. Journal of natural products, 76(6), 1078-1084. doi:10.1021/np400034d

The in vitro growth inhibitory effects of 27 bufadienolides and eight degradation products, with two cardenolides (ouabain and digoxin) chosen as reference compounds, were analyzed by means of an MTT colorimetric assay in six human and two mouse cancer cell lines. A structure-activity analysis was then performed to highlight the most important substituents relating to the in vitro growth inhibitory activity of bufadienolides in cancer cells. Thus, the current study revealed that various bufadienolides, including gamabufotalin rhamnoside (1a), bufotalin (2a), and hellebrin (3a), displayed higher growth inhibitory activities for various human cancer cell lines when compared to ouabain and digoxin. Gamabufotalin rhamnoside (1a) was the only compound that displayed growth inhibitory effects of <1 μM in mouse cancer cells that expressed mutated forms of the Na(+),K(+)-ATPase α-1 subunit. In addition, all genins and degradation products displayed weaker (if any) in vitro growth inhibitory effects on cancer cells when compared to their respective glycosylated homologue, with the exception of hellebrigenin (3b), which was as active as hellebrin (3a).

Design, synthesis, and structure-activity relationship studies of novel 3-alkylindole derivatives as selective and highly potent myeloperoxidase inhibitors.

Soubhye, J., Aldib, I., Elfving, B., Gelbcke, M., Furtmüller, P. G., Podrecca, M., Conotte, R., Colet, J.-M., Rousseau, A., Reye, F., Sarakbi, A., Vanhaeverbeek, M., Kauffmann, J.-M., Obinger, C., Neve, J., Prévost, M., Zouaoui Boudjeltia, K., Dufrasne, F., & Van Antwerpen, P. (2013). Design, synthesis, and structure-activity relationship studies of novel 3-alkylindole derivatives as selective and highly potent myeloperoxidase inhibitors. Journal of medicinal chemistry, 56(10), 3943-3958. doi:10.1021/jm4001538

Due to its production of potent antimicrobial oxidants including hypochlorous acid, human myeloperoxidase (MPO) plays a critical role in innate immunity and inflammatory diseases. Thus MPO is an attractive target in drug design. (Aminoalkyl)fluoroindole derivatives were detected to be very potent MPO inhibitors; however, they also promote inhibition of the serotonin reuptake transporter (SERT) at the same concentration range. Via structure-based drug design, a new series of MPO inhibitors derived from 3-alkylindole were synthesized and their effects were assessed on MPO-mediated taurine chlorination and low-density lipoprotein oxidation as well as on inhibition of SERT. The fluoroindole compound with three carbons in the side chain and one amide group exhibited a selectivity index of 35 (Ki/IC50) with high inhibition of MPO activity (IC50 = 18 nM), whereas its effect on SERT was in the micromolar range. Structure-function relationships, mechanism of action, and safety of the molecule are discussed.

https://dipot.ulb.ac.be/dspace/bitstream/2013/145698/1/Alkylindole-derivatives-MPO-inhibitors.pdf

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

Berger, G., Gelbcke, M., Cauet, E., Luhmer, M., Neve, J., & Dufrasne, F. (2013). Synthesis of 15N-labeled vicinal diamines through N-activated chiral aziridines: tools for the NMR study of platinum-based anticancer compounds. Tetrahedron letters, 54(6), 545-548. doi:10.1016/j.tetlet.2012.11.079

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.

https://dipot.ulb.ac.be/dspace/bitstream/2013/136202/1/Berger_TetrahedronLett_2012_InPress.pdf

2012

Evaluation of new scaffolds of myeloperoxidase inhibitors by rational design combined with high-throughput virtual screening

Aldib, I., Soubhye, J., Zouaoui Boudjeltia, K., Vanhaeverbeek, M., Rousseau, A., Furtmüller, P. G., Obinger, C., Dufrasne, F., Neve, J., Van Antwerpen, P., & Prévost, M. (2012). Evaluation of new scaffolds of myeloperoxidase inhibitors by rational design combined with high-throughput virtual screening. Journal of medicinal chemistry, 55(16), 7208-7218. doi:10.1021/jm3007245

Myeloperoxidase (MPO) is a major player of the innate immune defense system of human neutrophils and catalyzes the prodn. of strong oxidizing and halogenating antimicrobial products. Because of its role in pathogenesis of many (inflammatory) diseases, there is great interest in the development of efficient and specific inhibitors. Here, using the X-ray structure of MPO, high-throughput mol. docking of 1350000 compds. was performed. From this virtual screening process, 81 were tested for inhibition of the chlorination activity of MPO, finally ending up with eight inhibiting candidates of different chem. structures. These were tested for inhibiting MPO-mediated low-d. lipoprotein oxidn. and for interacting with the relevant redox intermediates of MPO. The best inhibitors were bis-2,2'-[(dihydro-1,3(2H,4H)-pyrimidinediyl)bis(methylene)]phenol and 8-[(2-aminoethyl)amino]-3,7-dihydro-3-methyl-7-(3-phenoxypropyl)-1H-purine-2,6-dione. Both did not irreversibly inactivate the enzyme but efficiently trapped it in its compd. II state. We discuss the mechanism of inactivation as well as pros and cons of the performed selection process.

https://dipot.ulb.ac.be/dspace/bitstream/2013/126049/1/JMC_55_7208.pdf

Trivanillic polyphenols with anticancer cytostatic effects through the targeting of multiple kinases and intracellular Ca 2+ release

Lamoral-Theys, D., Wauthoz, N., Heffeter, P., Mathieu, V., Jungwirth, U., Lefranc, F., Neve, J., Dubois, J., Dufrasne, F., Amighi, K., Berger, W., Gailly, P., & Kiss, R. (2012). Trivanillic polyphenols with anticancer cytostatic effects through the targeting of multiple kinases and intracellular Ca 2+ release. Journal of Cellular and Molecular Medicine, 16(7), 1421-1434. doi:10.1111/j.1582-4934.2011.01403.x.
https://dipot.ulb.ac.be/dspace/bitstream/2013/126042/1/JCMM_16_1421.pdf

Na+/K+-ATPase and cancer

Mijatovic, T., Dufrasne, F., & Kiss, R. (2012). Na+/K+-ATPase and cancer. Pharmaceutical patent analyst, 1(1), 91-106. doi:10.4155/ppa.12.3

The sodium pump, Na+/K+-ATPase, could be an important target for the development of anticancer drugs as it serves as a versatile signal transducer, plays a key role in cell adhesion and has abnormal expression and activity that are implicated in the development and progression of different cancers. Several publications have reported differing expression of Na+/K+-ATPase α- and β-subunits in malignant tissues compared with their normal tissue counterparts, thus offering a powerful diagnostic tool. A growing number of patent applications claim the invention or discovery of Na+/K+-ATPase inhibitors (e.g., cardiac glycosides) to be used to effectively treat certain cancers that are refractory to conventional chemotherapy or radiotherapy. The aims of this review are to provide an overview of the most significant patents that highlight Na+/K+-ATPase as a valuable target in anticancer therapy and which report on novel Na+/K+-ATPase inhibitors and ligands designed as potential anticancer agents.

https://dipot.ulb.ac.be/dspace/bitstream/2013/126047/1/CMC_19_627.pdf

Cardiotonic Steroids-Mediated Targeting of the Na+/K+-ATPase to Combat Chemoresistant Cancers.

Mijatovic, T., Dufrasne, F., & Kiss, R. (2012). Cardiotonic Steroids-Mediated Targeting of the Na+/K+-ATPase to Combat Chemoresistant Cancers. Current medicinal chemistry, 19, 627-646. doi:10.2174/092986712798992075

A large proportion of cancer patients fail to respond to conventional chemotherapy because of the intrinsic resistance of their cancer to pro-apoptotic stimuli and/or the acquisition of a multidrug resistant (MDR) phenotype during chronic chemotherapy. A new angle in chemotherapeutics against these cancer types associated with dismal prognoses would be the targeting of specific ion channels and pumps over expressed by cancer cells as compared to normal cells. Several reports suggest that the alpha subunits of the Na+/K+-ATPase (referred as sodium pump from now on) could be such targets, using cardiotonic steroids (CS) including cardenolides and bufadienolides. A significant proportion of non-small-cell-lung cancers (NSCLCs), glioblastomas (GBMs), melanomas and kidney cancers overexpresses the alpha-1 subunit of the sodium pump as compared to corresponding normal tissues, while colon cancers overexpress the alpha-3 subunit. Thus, a deeper knowledge of the structure-activity relationship (SAR), in terms of CS-mediated anticancer effects, to the sodium pump alpha subunits might enable the identification of potent anticancer agents with limited cardiotoxicity. The current review provides an in depth SAR analysis with respect to cardenolide- versus bufadienolide-mediated anticancer effects. Moreover, pharmacological data from in vitro and in vivo experiments, as well as pre-clinical and clinical trials regarding cardenolides to combat cancers associated with dismal prognoses are presented.

DYRK1A Kinase Inhibitors with Emphasis on Cancer.

Ionescu, A., Dufrasne, F., Gelbcke, M., Jabin, I., Kiss, R., & Lamoral-Theys, D. (2012). DYRK1A Kinase Inhibitors with Emphasis on Cancer. Mini-reviews in medical chemistry, 12(13), 1315-1329.

Various types of cancers (including gliomas, melanomas, and esophageal, pancreas and non-small-cell lung cancers) display intrinsic resistance to pro-apoptotic stimuli, such as conventional chemotherapy and radiotherapy, and/or the activation of a multidrug resistance phenotype, which are major barriers to effective treatment and lead to poor patient prognosis. The DYRK1A kinase is directly implicated in the resistance of cancer cells to pro-apoptotic stimuli and drives several pathways that enhance proliferation, migration, and the reduction of cell death, leading to very aggressive biological behavior in cancer cell populations. The DYRK1A kinase is also implicated in neurological diseases and in neoangiogenic processes. Thus, the DYRK1A kinase is of great interest for both cancer and neuroscience research. During the last decade, numerous compounds that inhibit DYRK1A have been synthesized. The present review discusses the available molecules known to interfere with DYRK1A activity and the implications of DYRK1A in cancer and other diseases and serves as a rational analysis for researchers who aim to improve the anti-DYRK1A activity of currently available compounds.

2011

In vitro anticancer activity, toxicity and structure-activity relationships of phyllostictine A, a natural oxazatricycloalkenone produced by the fungus Phyllosticta cirsii.

Le Calve, B., Lallemand, B., Perrone, C., Lenglet, G., Depauw, S., Van Goietsenoven, G., Bury, M., Vurro, M., Herphelin, F., Andolfi, A., Zonno, M. C., Mathieu, V., Dufrasne, F., Van Antwerpen, P., Poumay, Y., David-Cordonnier, M.-H., Evidente, A., & Kiss, R. (2011). In vitro anticancer activity, toxicity and structure-activity relationships of phyllostictine A, a natural oxazatricycloalkenone produced by the fungus Phyllosticta cirsii. Toxicology and applied pharmacology, 254(1), 8-17. doi:10.1016/j.taap.2011.03.027

The in vitro anticancer activity and toxicity of phyllostictine A, a novel oxazatricycloalkenone recently isolated from a plant-pathogenic fungus (Phyllosticta cirsii) was characterized in six normal and five cancer cell lines. Phyllostictine A displays in vitro growth-inhibitory activity both in normal and cancer cells without actual bioselectivity, while proliferating cells appear significantly more sensitive to phyllostictine A than non-proliferating ones. The main mechanism of action by which phyllostictine displays cytotoxic effects in cancer cells does not seem to relate to a direct activation of apoptosis. In the same manner, phyllostictine A seems not to bind or bond with DNA as part of its mechanism of action. In contrast, phyllostictine A strongly reacts with GSH, which is a bionucleophile. The experimental data from the present study are in favor of a bonding process between GSH and phyllostictine A to form a complex though Michael attack at C=C bond at the acrylamide-like system. Considering the data obtained, two new hemisynthesized phyllostictine A derivatives together with three other natural phyllostictines (B, C and D) were also tested in vitro in five cancer cell lines. Compared to phyllostictine A, the two derivatives displayed a higher, phyllostictines B and D a lower, and phyllostictine C an almost equal, growth-inhibitory activity, respectively. These results led us to propose preliminary conclusions in terms of the structure-activity relationship (SAR) analyses for the anticancer activity of phyllostictine A and its related compounds, at least in vitro.

https://dipot.ulb.ac.be/dspace/bitstream/2013/98234/1/Elsevier_77297.pdf

Quinone methides and their prodrugs: a subtle equilibrium between cancer promotion, prevention, and cure.

Dufrasne, F., Gelbcke, M., Neve, J., Kiss, R., & Kraus, J.-L. (2011). Quinone methides and their prodrugs: a subtle equilibrium between cancer promotion, prevention, and cure. Current medicinal chemistry, 18(26), 3995-4011. doi:10.2174/092986711796957301

The importance of reactive drug metabolites in the pathogenesis of drug-induced toxicity has been investigated since the early 1950s, mainly to reveal the link between toxic metabolites and chemical carcinogenesis. This review mainly focuses on biologically active compounds, which generate reactive quinone methide (QM) intermediates either directly or after bioactivation. Several examples of anticancer drugs acting through the generation of QM electrophiles are given. The use of those drugs for chemotherapeutic purposes is also discussed. The key feature of those QM-generating drugs is their reactivity toward specific nucleophilic biological targets. Modulation of their reactivity represents a challenge for medicinal chemists because, depending on the reactivity of these QM intermediates, their interaction with critical proteins can alter the function of these key proteins and induce a wide variety of responses with functional consequences. Among the possible consequences, antiproliferative effects could be exploited for chemotherapeutic purposes. Information on how such QM-generating drugs can affect individual target proteins and their functional consequences are required to help the medicinal chemist in the design of more specific QM-generating molecules for chemotherapeutic use.

https://dipot.ulb.ac.be/dspace/bitstream/2013/107342/1/CMC_18_3995.pdf

2010

Structure-based design, synthesis, and pharmacological evaluation of 3-(Aminoalkyl)-5-fluoroindoles as myeloperoxidase inhibitors.

Soubhye, J., Prévost, M., Van Antwerpen, P., Zouaoui Boudjeltia, K., Rousseau, A., Furtmüller, P. G., Obinger, C., Vanhaeverbeek, M., Ducobu, J., Neve, J., Gelbcke, M., & Dufrasne, F. (2010). Structure-based design, synthesis, and pharmacological evaluation of 3-(Aminoalkyl)-5-fluoroindoles as myeloperoxidase inhibitors. Journal of medicinal chemistry, 53(24), 8747-8759. doi:10.1021/jm1009988

Oxidized low-density lipoproteins (LDLs) accumulate in the vascular wall and promote local inflammation, which contributes to the progression of the atheromatous plaque. The key role of myeloperoxidase (MPO) in this process is related to its ability to modify APO B-100 in the intima and at the surface of endothelial cells. A series of 3-(aminoalkyl)-5-fluoroindole analogues was designed and synthesized by exploiting the structure-based docking of 5-fluorotryptamine, a known MPO inhibitor. In vitro assays were used to study the effects of these compounds on the inhibition of MPO-mediated taurine chlorination and oxidation of LDLs. The kinetics of the interaction between the MPO redox intermediates, Compounds I and II, and these inhibitors was also investigated. The most potent molecules possessed a 4- or 5-carbon aminoalkyl side chain and no substituent on the amino group. The mode of binding of these analogues and the mechanism of inhibition is discussed with respect to the structure of MPO and its halogenation and peroxidase cycles.

https://dipot.ulb.ac.be/dspace/bitstream/2013/74263/1/JMC_53_8747.pdf

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

Berger, G., Gasper, R., Lamoral-Theys, D., Wellner, A., Gelbcke, M., Gust, R., Neve, J., Kiss, R., Goormaghtigh, E., & Dufrasne, F. (2010). Fourier transform infrared (FTIR) spectroscopy to monitor the cellular impact of newly synthesized platinum derivatives. International journal of oncology, 37(3), 679-686. doi:10.3892/ijo-00000717

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.

Simple di- and trivanillates exhibit cytostatic properties toward cancer cells resistant to pro-apoptotic stimuli

Lamoral-Theys, D., Pottier, L., Kerff, F., Dufrasne, F., Proutiere, F., Wauthoz, N., Neven, P., Ingrassia, L., Van Antwerpen, P., Lefranc, F., Gelbcke, M., Pirotte, B., Kraus, J.-L., Neve, J., Kornienko, A., Kiss, R., & Dubois, J. (2010). Simple di- and trivanillates exhibit cytostatic properties toward cancer cells resistant to pro-apoptotic stimuli. Bioorganic & medicinal chemistry, 18(11), 3823-3833. doi:10.1016/j.bmc.2010.04.047
https://dipot.ulb.ac.be/dspace/bitstream/2013/129469/1/BMC_18_3823.pdf

Natural polyphenols that display anticancer properties through inhibition of kinase activity.

Lamoral-Theys, D., Pottier, L., Dufrasne, F., Neve, J., Dubois, J., Kornienko, A., Kiss, R., & Ingrassia, L. (2010). Natural polyphenols that display anticancer properties through inhibition of kinase activity. Current medicinal chemistry, 17(9), 812-825. doi:10.2174/092986710790712183

Over eleven hundred publications reporting anticancer activities of polyphenols have appeared in the peer-reviewed literature. In addition, a search of the PubMed database using "polyphenols - cancer - review" as keywords produced over 320 hits for review articles (July 2009). Polyphenol anticancer activities include, among others, anti-oxidative, pro-apoptotic, DNA damaging, anti-angiogenic, and immunostimulatory effects. Targeting specific protein kinases to combat cancer represents a major focus of oncology research within the so-called targeted therapy approach. An exhaustive search of the PubMed database (July 2009) using "polyphenols - cancer - kinases" as keywords resulted in more than 130 hits, half of them having been published within the past five years. Furthermore, the PubMed database contains 25 reviews on the subject of anti-kinase activity of some specific polyphenols, including mainly curcumin and the green tea polyphenol (-)-epigallocatechin 3-gallate (EGCG). However, no attempt has been made yet to review this area of research in a comprehensive, general manner. The current review therefore aims to highlight those anticancer polyphenols that target specific kinases in various types of cancer. The present review also provides an in-depth analysis of polyphenol structure- activity relationships in relation to their anticancer activities and specific kinase targeting. Lastly, a number of polyphenols are identified as potential antitumor agents that could be used to combat biologically aggressive cancers, including metastasizing cancers, through the targeting of specific kinases.

https://dipot.ulb.ac.be/dspace/bitstream/2013/70172/1/CMC_17_812.pdf

2008

Development and validation of a screening procedure for the assessment of inhibition using a recombinant enzyme.

Van Antwerpen, P., Moreau, P., Zouaoui Boudjeltia, K., Babar, S., Dufrasne, F., Moguilevsky, N., Vanhaeverbeek, M., Ducobu, J., & Neve, J. (2008). Development and validation of a screening procedure for the assessment of inhibition using a recombinant enzyme. Talanta, 75(2), 503-510. doi:10.1016/j.talanta.2007.11.040

Myeloperoxidase (MPO, E.C. 1.1.11.7) is a heme-containing enzyme that catalyses the synthesis of hypochlorous acid (HOCl) in the presence of hydrogen peroxide (H2O2) and chlorine anions. The production of HOCl is kept under strict control of neutrophils. However, in several pathological conditions, MPO is leaked in the extracellular fluid, which involves an over-production of reactive oxygen species like HOCl and promotes the damages caused by neutrophils. As a consequence, the inhibition of MPO by various agents has been investigated and a variety of molecules have been evaluated for this activity in different models. The present study aims to describe and validate a rapid screening method based on the taurine assay and using a recombinant MPO. After validation of the stock solutions used during the experiments, the amount of MPO for the completion of the reaction was measured and fixed to an optimal value. The inhibiting concentration at 50% of flufenamic acid (taken as a reference molecule) was then assessed in both a simple tube test and a microplate test and delivered similar results (1.3+/-0.2 microM vs 1.4+/-0.2 microM, P=0.2). Finally, different molecules able to inhibit MPO were evaluated in this rapid assay system providing results comparable to literature. The high throughput screening is undoubtedly a first line assessment method which affords the selection of inhibitors and permits to reduce the number of candidates for a further elucidation of the mechanism of MPO inhibition.

https://dipot.ulb.ac.be/dspace/bitstream/2013/67960/1/Elsevier_45022.pdf

Conception of myeloperoxidase inhibitors derived from flufenamic acid by computational docking and structure modification

Van Antwerpen, P., Prévost, M., Zouaoui Boudjeltia, K., Babar, S., Legssyer, I., Moreau, P., Moguilevsky, N., Vanhaeverbeek, M., Ducobu, J., Neve, J., & Dufrasne, F. (2008). Conception of myeloperoxidase inhibitors derived from flufenamic acid by computational docking and structure modification. Bioorganic & medicinal chemistry, 16(4), 1702-1720. doi:10.1016/j.bmc.2007.11.025

The development of myeloperoxidase (MPO) inhibitors has been conducted using flufenamic acid as a lead compound. Computational docking of the drug and its analogs in the MPO active site was first attempted. Several molecules were then synthesized and assessed using three procedures for the measurement of their inhibiting activity: (i) the taurine assay, (ii) the accumulation of compound II, and (iii) the LDL oxidation by ELISA. Most of the synthesized molecules had an activity in the same range as flufenamic acid but none of them were able to inhibit the MPO-dependent LDL oxidation. The experiments however gave some useful indications for a rational conception of MPO inhibitors. © 2007 Elsevier Ltd. All rights reserved.

https://dipot.ulb.ac.be/dspace/bitstream/2013/67972/1/Elsevier_45034.pdf

2007

Inhibition of the myeloperoxidase chlorinating activity by non-steroidal anti-inflammatory drugs: flufenamic acid and its 5-chloro-derivative directly interact with a recombinant human myeloperoxidase to inhibit the synthesis of hypochlorous acid.

Van Antwerpen, P., Dufrasne, F., Lequeux, M., Zouaoui Boudjeltia, K., Lessgyer, I., Babar, S., Moreau, P., Moguilevsky, N., Vanhaeverbeek, M., Ducobu, J., & Neve, J. (2007). Inhibition of the myeloperoxidase chlorinating activity by non-steroidal anti-inflammatory drugs: flufenamic acid and its 5-chloro-derivative directly interact with a recombinant human myeloperoxidase to inhibit the synthesis of hypochlorous acid. European journal of pharmacology, 570(1-3), 235-243. doi:10.1016/j.ejphar.2007.05.057

The present in vitro study was designed to assess the inhibition of the myeloperoxidase (MPO)/H(2)O(2)/Cl(-) system by several non steroidal anti-inflammatory drugs (NSAIDs) of the oxicam family and of nimesulide and to compare their effect with flufenamic acid in order to investigate their influence on the chlorinating activity of MPO as a protective mechanism during chronic inflammatory syndromes. The inhibition of the system was assessed by measurement of the taurine chlorination while the accumulation of compound II was used to investigate the mechanism of inhibition. The oxidation products of NSAIDs by the MPO/H(2)O(2)/Cl(-) system were identified and flufenamic acid and derivatives were also assessed in the inhibition of LDL oxidation in two models. Flufenamic acid (IC(50) = 1.1+/-0.3 microM) is the most efficient inhibitor of the MPO/H(2)O(2)/Cl(-) system and nimesulide (IC(50) = 2.1+/-0.3 microM) is more active than the other NSAIDs of the oxicam family (IC(50) = 8-12 microM). The accumulation of compound II revealed that flufenamic acid acts as an electron donor while the other NSAIDs are antagonists of chloride anions. The identification of the oxidation products confirms that flufenamic behaves like an electron donor and is directly oxidized in the 5-hydroxy-derivative but gives also the 5-chloro-derivative which similarly inhibits the MPO/H(2)O(2)/Cl(-) system. Flufenamic acid has the best inhibiting activity towards the MPO/H(2)O(2)/Cl(-) system. However, in models that assess the LDL oxidation, flufenamic acid and its derivatives were unable to properly inhibit MPO activity as the enzyme is adsorbed on macrostructures such as LDL molecules.

https://dipot.ulb.ac.be/dspace/bitstream/2013/67981/1/Elsevier_45044.pdf

The relation between stereochemistry and biological activity of platinum(II) complexes chelated with chiral diamine ligands: an intricate problem.

Dufrasne, F., & Galanski, M. (2007). The relation between stereochemistry and biological activity of platinum(II) complexes chelated with chiral diamine ligands: an intricate problem. Current pharmaceutical design, 13(27), 2781-2794. doi:10.2174/138161207781757060

The origin of activity differences between stereoisomers of anticancer platinum(II) complexes chelated with chiral diamine ligands has been almost exclusively explained by diastereoselective interactions with DNA. Although this model has been widely accepted in vitro and in vivo experiments showed some conflicting results, leading to the conclusion that other biomolecules might be responsible for this stereoselectivity as well. These compounds, called bionucleophiles, are in most instances amino acids or proteins present in biological fluids. As these chiral molecules are very reactive towards the platinum complexes, they may contribute to stereoselectivity, but also to resistance and toxicity. This review gives a general survey of chiral platinum(II) complexes and their interactions with DNA. The bionucleophiles which have been identified and the consequences of their reaction with platinum(II) complexes are discussed. Analytical techniques used to investigate interactions between established and potential chiral platinum drugs and bionucleophiles are presented.

https://dipot.ulb.ac.be/dspace/bitstream/2013/74265/1/CPD_13_2781.pdf

2006

Signal separation and determination of the enantiomeric purity of primary amines with (-)-myrtenal - a 13C NMR study

Dufrasne, F., Gelbcke, M., & Galanski, M. (2006). Signal separation and determination of the enantiomeric purity of primary amines with (-)-myrtenal - a 13C NMR study. Spectrochimica acta. Part A: Molecular and biomolecular spectroscopy, 65(3-4), 869-873. doi:10.1016/j.saa.2006.01.020

The applicability of (-)-myrtenal as a chiral derivatizing agent in combination with 13C NMR spectroscopy was investigated. 13C NMR was found to be a valuable tool for the identification and enantiomer differentiation of primary amines including β-amino alcohols and vicinal diamines. The enantiomeric excess could be determined via automated deconvolution and integration, and was found to be in good accordance with the expected values even in the cases, when enantiomer differentiation was not possible in 1H NMR spectra. © 2006 Elsevier B.V. All rights reserved.

https://dipot.ulb.ac.be/dspace/bitstream/2013/171086/1/Elsevier_154716.pdf

Synthesis and cytotoxicity of enantiomerically pure [1,2-diamino-1-(4-fluorophenyl)-3-methylbutane]platinum(II) complexes.

Dullin, A., Dufrasne, F., Gelbcke, M., & Gust, R. (2006). Synthesis and cytotoxicity of enantiomerically pure [1,2-diamino-1-(4-fluorophenyl)-3-methylbutane]platinum(II) complexes. ChemMedChem, 1(6), 644-653. doi:10.1002/cmdc.200600032

A series of leaving group derivatives of enantiomerically pure [1,2-diamino-1-(4-fluorophenyl)-3-methylbutane]platinum(II) complexes were synthesized and tested for cytotoxicity. The enantiomeric purity was determined by 1H NMR spectroscopy on the final diamines after derivation with (1R)-myrtenal. For coordination to platinum, the diamines were reacted with K2PtI4. The treatment of diiodoplatinum(II) complexes (4F-Ph/iProp-PtI2) with Ag2SO4 resulted in the sulfatoplatinum(II) complexes (4F-Ph/iProp-PtSO4), which can be easily transformed to dichloroplatinum(II) complexes (4F-Ph/iProp-PtCl2) with 2 n HCl. The importance of the leaving groups and the configuration at the diamine ligand on the antiproliferative effects was evaluated on the hormone-dependent MCF-7 and the hormone-independent MDA-MB 231 breast cancer cell lines as well as the LNCaP/FGC prostate cancer cell line. (R,R)-4F-Ph/iProp-PtCl2 was identified as the most active platinum(II) complex. The 3-methyl group increased antiproliferative effects relative to the [1,2-diamino-1-(4-fluorophenyl)butane]platinum(II) complexes described in an earlier study.

https://dipot.ulb.ac.be/dspace/bitstream/2013/74266/1/CHEMMEDCHEM_1_644.PDF

2005

Effects of remifentanil on N-methyl-D-aspartate receptor: an electrophysiologic study in rat spinal cord.

Guntz, E., Dumont, H., Roussel, C., Gall, D., Dufrasne, F., Cuvelier, L., Blum, D., Schiffmann, S. N., & Sosnowski, M. (2005). Effects of remifentanil on N-methyl-D-aspartate receptor: an electrophysiologic study in rat spinal cord. Anesthesiology, 102(6), 1235-1241.

BACKGROUND: Remifentanil hydrochloride contained in Ultiva (GlaxoSmithKline, Genval, Belgium) has been incriminated in difficult postoperative pain management, promotion of hyperalgesia, and direct N-methyl-D-aspartate (NMDA) receptor activation, but the involved mechanisms have remained unclear. In the current study, the authors investigated the effects of remifentanil hydrochloride, with and without its vehicle, glycine, on the activation of NMDA receptors and the modulation of NMDA-induced current on neurons inside the lamina II from the dorsal horn of rat spinal cord. METHODS: To test these effects, whole cell patch clamp recordings were conducted on acute rat lumbar spinal cord slices. Considering that both components of Ultiva (remifentanil hydrochloride and glycine) could be involved in NMDA receptor activation, experiments were performed first with remifentanil hydrochloride, second with glycine, and third with the two components within Ultiva. RESULTS: Remifentanil hydrochloride does not induce any current, whereas 3 mm glycine induced a current that was abolished by the specific NMDA glutamate site antagonist D-2-amino-5-phosphonovalerate. Ultiva (remifentanil hydrochloride with its vehicle, glycine) also evoked an inward current that was abolished by D-2-amino-5-phosphonovalerate and not significantly different from the glycine-induced current. Application of remifentanil hydrochloride potentiated the NMDA-induced inward current, and this potentiation was abolished by the mu-opioid receptor antagonist naloxone. CONCLUSION: These results show that remifentanil hydrochloride does not directly activate NMDA receptors. The NMDA current recorded after application of Ultiva is related to the presence of glycine. Induced NMDA current is potentiated by application of remifentanil hydrochloride through a pathway involving the mu-opioid receptor.

https://dipot.ulb.ac.be/dspace/bitstream/2013/51845/1/ANESTHESIOLOGY_102_1235.pdf

Synthesis of 1,2-diamino-1-phenylpropane diastereoisomers from u-N-trifluoroacetyl-2-amino-1-phenylpropan-1-ol

Dufrasne, F., & Neve, J. (2005). Synthesis of 1,2-diamino-1-phenylpropane diastereoisomers from u-N-trifluoroacetyl-2-amino-1-phenylpropan-1-ol. Monatshefte fuer Chemie, 136(5), 739-746. doi:10.1007/s00706-004-0266-7
https://dipot.ulb.ac.be/dspace/bitstream/2013/112485/1/MONATSCHEFTEFURCHEMIE_136_739.pdf

2004

Enantiomerically pure [1,2-diamino-1-(4-fluorophenyl)butane]platinum(II) complexes: Synthesis and antitumor activity against MCF-7 and MDA-MB 231 breast cancer and LnCaP/FGC prostate cancer cell lines

Dullin, A., Dufrasne, F., Gelbcke, M., & Gust, R. (2004). Enantiomerically pure [1,2-diamino-1-(4-fluorophenyl)butane]platinum(II) complexes: Synthesis and antitumor activity against MCF-7 and MDA-MB 231 breast cancer and LnCaP/FGC prostate cancer cell lines. Archiv der Pharmazie, 337(12), 654-667. doi:10.1002/ardp.200400621

A series of leaving group derivs. of enantiomerically pure [1,2-diamino-1-(4-fluorophenyl)-3-methylbutane]platinum(II) complexes were synthesized and tested for cytotoxicity. The enantiomeric purity was detd. by 1H NMR spectroscopy on the final diamines after derivation with (1R)-myrtenal. For coordination to platinum, the diamines were reacted with K2Ptl4. The treatment of diiodoplatinum(II) complexes (4F-Ph/iProp-Ptl2) with Ag2SO4 resulted in the sulfatoplatinum(II) complexes (4F-Ph/iProp-PtSO4), which can be easily transformed to dichloroplatinum(II) complexes (4F-Ph/iProp-PtCl2) with 2 N HCl. The importance of the leaving groups and the configuration at the diamine ligand on the antiproliferative effects was evaluated on the hormone-dependent MCF-7 and the hormone-independent MDA-MB 231 breast cancer cell lines as well as the LNCaP/FGC prostate cancer cell line. (R,R)-4F-Ph/iProp-PtCl2 was identified as the most active platinum(II) complex. The 3-Me group increased antiproliferative effects relative to the [1,2-diamino-1-(4-fluorophenyl)butane]platinum(II) complexes described in an earlier study.

https://dipot.ulb.ac.be/dspace/bitstream/2013/107339/4/107339.pdf https://dipot.ulb.ac.be/dspace/bitstream/2013/107339/1/ARCHPHARMPHARMMEDCHEM_337_654.pdf

2003

1H-nuclear magnetic resonance determination of the enantiomeric purity of aliphatic primary amines, β-aminoalcohols, β-diamines and α-amino-acids with 1R-(-)-myrtenal: Scope and limitations

Dufrasne, F., Gelbcke, M., & Neve, J. (2003). 1H-nuclear magnetic resonance determination of the enantiomeric purity of aliphatic primary amines, β-aminoalcohols, β-diamines and α-amino-acids with 1R-(-)-myrtenal: Scope and limitations. Spectrochimica acta. Part A: Molecular and biomolecular spectroscopy, 59(6), 1239-1245. doi:10.1016/S1386-1425(02)00305-0

1R-(-)-myrtenal was tested as a chiral derivatising agent for the determination of the enantiomeric purity of aliphatic primary amines, β-aminoalcohols, β-diamines and α-amino-acids. Derivatisation procedure consists in mixing one equivalent each of the amine and 1R-(-)-myrtenal directly into the nuclear magnetic resonance (NMR) tube before addition of the appropriate deuterated solvent and, for α-amino-acids, one equivalent of NaOH was added to neutralise the acidic function. Diastereoisomeric imines were completely formed after 12 h and analysed by 1H-NMR except for N-methyl β-diamines for which imidazolidines were obtained. The method gave satisfactory results only for α- and β-arylalkylamines for which CDCl3 could be advantageously replaced by C6D6 or pyridine-d5 in order to increase the difference between the chemical shifts. The main advantage of the procedure is its simplicity as it does not involve steps such as activation, heating, solvent evaporation and isolation of the product. Its limitations are the limited series of compounds susceptible to be analysed and the small difference between the chemical shifts of the diastereoisomeric imines obtained. © 2002 Elsevier Science B.V. All rights reserved.

https://dipot.ulb.ac.be/dspace/bitstream/2013/112469/1/Elsevier_92836.pdf

2002

Synthesis and antitumor activity of enantiomerically pure [1,2-diamino-1-(4-fluorophenyl)propane]dichloroplatinum(II) complexes.

Dufrasne, F., Gelbcke, M., Schnurr, B., & Gust, R. (2002). Synthesis and antitumor activity of enantiomerically pure [1,2-diamino-1-(4-fluorophenyl)propane]dichloroplatinum(II) complexes. Archiv der Pharmazie, 335(5), 229-239. doi:10.1002/1521-4184(200205)335:5<229::AID-ARDP229>3.0.CO;2-Q

Enantiomerically pure 1, 2-diamino-1-(4-fluorophenyl)propanes were synthesized by stereospecific and stereoselective procedures by use of the (1R, 2S)- and (1S, 2R)-2-amino-1-(4-fluorophenyl)propanols (12a) as intermediates. The enantiomeric purity was determined by (1)H NMR spectroscopy after conversion of the propanolamines and the diamines with (1R)-myrtenal into mono- and diimines. For the coordination to platinum the diamines were reacted with K(2)PtCl(4). The resulting dichloroplatinum(II) complexes 4F-Ph/Me-PtCl(2) were tested for antiproliferative activity on the MCF-7 breast cancer cell line. (SS)- and (RR)-4F-Ph/Me-PtCl(2) produced the strongest inhibitory effect. Both complexes showed cytocidal effects, (SS)-4F-Ph/Me-PtCl(2) even in a concentration of 1 microM. The (1S, 2R)- and (1R, 2S)-configurated complexes were far less active (SS > RR > RS = SR) and comparable in this respect with the standard cisplatin.

https://dipot.ulb.ac.be/dspace/bitstream/2013/74268/4/74268.pdf https://dipot.ulb.ac.be/dspace/bitstream/2013/74268/1/ARCHPHARMPHARMMEDCHEM_335_229.pdf