Janna Velder

Paraoxonase-1 is a major determinant of clopidogrel efficacy

Clinical efficacy of the antiplatelet drug clopidogrel is hampered by its variable biotransformation into the active metabolite. The variability in the clinical response to clopidogrel treatment has been attributed to genetic factors, but the specific genes and mechanisms underlying clopidogrel bioactivation remain unclear. Using in vitro metabolomic profiling techniques, we identified paraoxonase-1 (PON1) as the crucial enzyme for clopidogrel bioactivation, with its common Q192R polymorphism determining the rate of active metabolite formation. We tested the clinical relevance of the PON1 Q192R genotype in a population of individuals with coronary artery disease who underwent stent implantation and received clopidogrel therapy. PON1 QQ192 homozygous individuals showed a considerably higher risk than RR192 homozygous individuals of stent thrombosis, lower PON1 plasma activity, lower plasma concentrations of active metabolite and lower platelet inhibition. Thus, we identified PON1 as a key factor for the bioactivation and clinical activity of clopidogrel. These findings have therapeutic implications and may be exploited to prospectively assess the clinical efficacy of clopidogrel.

Enantioselective Cu-Catalyzed 1,4-Addition of Grignard Reagents to Cyclohexenone Using Taddol-Derived Phosphine–Phosphite Ligands and 2-Methyl-THF as a Solvent†

The 1,4-addition (conjugate addition) of C nucleophiles to a,b-unsaturated carbonyl compounds and related activated olefins belongs to the most powerful and reliable tools for C C bond formation. Accordingly, it is frequently exploited in the synthesis of natural products and other complex organic molecules. Three decades of research on asymmetric and, in particular, asymmetric catalytic versions of conjugate addition reactions have resulted in the development of a broad variety of methods. However, the important task of performing the 1,4-addition of simple Grignard reagents, the most common type of organometallic reagents, in an enantioselective fashion still remains a particular challenge. As recently reviewed, several Cu-based catalyst systems have been suggested in the past for the catalytic asymmetric 1,4-addition of Grignard reagents. Nevertheless, high enantioselectivities ( 90% ee) were achieved only in a few special cases, and the reported methods did not find much application owing to limited substrate scope, operational convenience, and accessibility of the chiral ligands required. In 2004, an important advance was made by Feringa and co-workers who, by screening a set of commercially available chiral P,P ligands, identified ferrocene-based diphosphines, in particular Taniaphos (1) and Josiphos (2), as promising ligands for such transformations.

Anti‐inflammatory AreneChromium Complexes Acting as Specific Inhibitors of NOD2 Signalling

Inflammation is a hallmark of microbial infection in mammals and is the result of a pathogen‐induced release of inflammatory effectors. In humans a variety of germ‐line encoded receptors, so‐called pattern‐recognition receptors, respond to conserved signatures on invading pathogens, which results in the transcriptional activation of pro‐inflammatory responses. Inflammation is often detrimental to the host and leads to tissue damage and/or systemic dysfunctions. Thus, specific inhibitors of these pathways are desirable for medical interventions. Herein we report on the synthesis and use of some chromium‐containing compounds (areneCr(CO)3 complexes) with a core structure related to anti‐inflammatory diterpenes produced by the sea whip Pseudopterogorgia elisabethae. By using cell‐based reporter assays we identified complexes with a potent inhibitory activity on tumour necrosis factor (TNF), Toll‐like receptor (TLR), and nucleotide binding domain, leucine‐rich repeat‐containing receptor (NLR) pathways. Moreover, we found one complex to be a specific inhibitor of inflammatory responses mediated by the NLR protein NOD2, a pivotal innate immune receptor involved in bacterial recognition. Synthesis and characterisation of a set of derivatives of this substance revealed structural requirements for NOD2 specificity. Taken together, our studies suggest this type of areneCr(CO)3 complex as a potential lead for the development of antiphlogistica and pharmacologically relevant NOD2 inhibitors.

Total Synthesis of Indole‐Derived Allocolchicine Analogues Exhibiting Strong Apoptosis‐Inducing Activity

A series of novel pyrrolo-allocolchicine derivatives (containing a 1-methyl-1H-indol-5-yl moiety replacing ring C) was synthesized. The tetracyclic ring system was constructed by Suzuki-Miyaura cross-coupling of a 1-methylindole-5-boronate with an ortho-iodo-dihydrocinnamic acid derivative and subsequent intramolecular Friedel-Crafts acylation. After reduction of the resulting ketone, the nitrogen functionality was introduced in a Mitsunobu-type reaction by using zinc azide followed by LiAlH(4) reduction. Structural assignments were supported by X-ray crystallography. The compounds synthesized were then tested against BJAB tumor cells and found to exhibit pronounced cytotoxic activity (proliferation inhibition and apoptosis induction). The ketone 24 b was even active at sub-nanomolar concentration. In addition, the antitumor potential of the compounds was confirmed by using B lymphoid cell lines.

Studies towards the total synthesis of mumbaistatin: synthesis of highly substituted benzophenone and anthraquinone building blocks

Abstract Model compounds and building blocks for a planned total synthesis of the highly potent glucose-6-phosphate (G6P) translocase inhibitor mumbaistatin ( 1 ) and structural analogs were elaborated: compound 1 represents a lead structure in the development of potential new antidiabetic drugs. With the model substrate 20 it was demonstrated that highly functionalized, tetra-ortho-substituted benzophenones can be prepared by nucleophilic addition of an aryllithium-building block to a benzaldehyde followed by oxidation. For compound 37 , a potential precursor of the anthraquinone part of mumbaistatin, various approaches via aryne/phthalide annulations were developed and evaluated. The required functionalized arenes were prepared exploiting, among others, regioselective bromination and ortho-lithiation reactions. Coupling reactions of the anthracene–carbaldehyde 44 derived from 37 with various metalated arenes proved to be unexpectedly difficult and failed so far.

Lipophilic prodrugs of a triazole-containing colchicine analogue in liposomes: Biological effects on human tumor cells

Colchicine site binders—blockers of tubulin polymerization—are potential antimitotic agents for anticancer therapy. To reduce their systemic toxicity and improve biodistribution, encapsulation in nanosized liposomes may be employed. Liposomes present a convenient means for preparation of injectable for-mulations of hydrophobic compounds, however colchicine as such is known to leak through the lipid bilayer. In this study, newly synthesized triazole-containing analogues of colchicine and allocolchicine, and their palmitic and oleic esters (lipophilic prodrugs) were tested for anti-proliferative activity and apoptosis-inducing potential. In contrast to colchicine conjugates, whose activities ranged with those of colchicine, allocolchicine derivatives exhibited drastically lower effects and were discarded. Liposomes of about 100 nm in diameter composed of egg phosphatidylcholine-yeast phosphatidylinositol-palmitic or oleic prodrug, 8: 1: 1, by mol, were prepared by standard extrusion technique and tested in a panel of four human tumor cell lines. Liposome formulations preserved the biological activities of the parent colchicinoid the most towards human epithelial tumor cells. Moreover, liposomal form of the oleoyl bearing colchicinoid inhibited cell proliferation more efficiently than free lipophilic prodrug. Due to substantial loading capacity of the liposomes, the dispersions contain sufficient concentration of the active agent to test wide dose range in experiments on systemic administration to animals.

Reply to: "Paraoxonase-1 and clopidogrel efficacy"

Jordi Camps1, Jorge Joven1, Bharti Mackness1, Michael Mackness1, Dan Tawfik2, Dragomir Draganov3, Lucio G Costa4, György Paragh5, Ildikó Seres5, Sven Horke6, Richard James7, Antonio Hernández8, Srinivasa Reddy9, Diana Shih9, Mohamed Navab9, Daniel Rochu10 & Michael Aviram11 1Centre de Recerca Biomèdica, Institut d’Investigació Sanitària Pere Virgili, Universitat Rovira i Virgili, C. Sant Joan, Reus, Spain. 2Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel. 3WIL Research Laboratories, Ashland, Ohio, USA. 4Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington, USA. 5Department of Internal Medicine, University of Debrecen, Hungary. 6Institute of Pharmacology, University Medical Center, Meinz, Obere Zahlbacher, Meinz, Germany. 7Department of Internal Medicine, University of Geneva, Switzerland. 8Department of Toxicology, University of Granada, Granada, Spain. 9Division of Cardiology, University of California–Los Angeles, Los Angeles, California, USA. 10Département de Toxicologie, Centre de Recherches du Service de Santé des Armées, La Tronche Cedex, France. 11The Lipid Research Laboratory, Technion Faculty of Medicine, Rambam Medical Center, Haifa, Israel. e-mail: jcamps@grupsagessa.cat

Hydrophenalene–Cr(CO)3 complexes as anti-inflammatory agents based on specific inhibition of NOD2 signalling: a SAR study

Small molecules, which specifically inhibit NOD2 signalling, are of high interest in the search for new anti-inflammatory drugs. In this context, the previously discovered hydrophenalene–Cr(CO)3 complex 1 was taken as a lead and new structural analogues were prepared by means of chemical synthesis. The NOD2-inhibiting activity of the compounds was determined with cell-based reporter assays employing human embryonic kidney cells. As a result of the study, some clear structure activity relationships (SARs) could be identified. The best compounds were active at low μM concentration.

trans-Ethyl­enedi-p-phenyl­ene diacetate

The centrosymmetric title compound, C18H26O4, was prepared in high yield from 4-acetoxystyrene via Ru-catalysed homo-olefin metathesis. Exclusive formation of the E-configurated isomer was observed. In the crystal, a strong C—H⋯π intermolecular interaction links the molecules together.

trans-1,2-Bis(3,5-dimethoxy-phen-yl)ethene.

The title compound, C18H20O4, was prepared in high yield from 3,5-dimethoxystyrene via a Ru-catalysed homo-olefin metathesis. Exclusive formation of the E-configurated isomer was observed. Interestingly, one symmetric unit contains two molecules adopting an s-syn-anti and and an all-s-anti conformation.