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.

Professor Helmut Schwarz zum 65. Geburtstag gewidmetThe 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 À C bond formation. Accordingly, it is frequently exploited in the synthesis of natural products and other complex organic molecules.[1] Three decades of research on asymmetric [2] and, in particular, asymmetric catalytic [3] versions of conjugate addition reactions have resulted in the development of a broad variety of methods.[1-3] 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, [4a] several Cu-based catalyst systems have been suggested in the past for the catalytic asymmetric 1,4-addition of Grignard reagents.[4] 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) [5] and Josiphos (2), [6] as promising ligands for such transformations. [7] For instance, the reaction of n-alkyl Grignard reagents with cyclohexenone (3) proceeded smoothly in the presence of 5 mol % of a catalyst generated in situ from 1 and CuCl to give the 1,4-addition products 4 with excellent enantioselectivity (up to 96 % ee) and good regioselectivity (4/5 ! 4:1) (Scheme 1). [4,7] Furthermore, Feringa and co-workers were able to apply this catalytic system to other substrates and in the synthesis of natural products. [8] However, the reaction of 3 with other relevant Grignard reagents such as iPrMgBr or PhMgBr proceeded only with low selectivity under these conditions, and also with an alternative catalyst (formed from 2 and CuBr-SMe 2 ) ee values did not exceed 54 % (R = iPr) and 40 % (R = Ph). Thus, the challenge remained open.Considering that chiral diphosphine ligands possess an obvious potential for the Cu-catalyzed 1,4-addition of Grignard reagents [7,8] we wondered whether phosphinephosphite ligands of type 7[9] (developed in our laboratory) would also be suited for this purpose.[10] These ligands are efficiently prepared from o-bromophenols 6 and chiral diols (such as Binol (2,2'-dihydroxy-1,1'-binaphthyl) [11] and Taddol (a,a,a'-tetraaryl-2,2-dimethyl-1,3-dioxolan-4,5-dimethanol) [12] ), and the modular synthesis facilitates structural variation and optimization (Scheme 2). We herein report that compounds of this class indeed represent highly useful ligands for the Cu-catalyzed 1,4-addition of various Grignard Scheme 1. Cu-catalyzed 1,4-addition of Grignard reagents to cyclohexenone according to Feringa .[7]Scheme 2. Modular ph...

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.

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An efficient and modular approach to bidentate phosphine-phosphite ligands formally derived from a 6-alkyl-2-phosphanylphenol, a chiral diol and phosphorus trichloride has been developed. In a key step, a borane-protected phosphinite, prepared from an o-bromophenol by O-phosphanylation, is reacted with n-butyllithium to afford the corresponding ortho-phosphanylphenol (as the stable borane adduct) through bromine-lithium exchange and anionic migration rearrangement. Treatment with phosphorus trichloride in the presence of a base and subsequent reaction of the in situ formed dichlorophosphite with a chiral diol (such as TADDOL or BINOL) affords the target P,P ligands in good overall yield (up to 60% over 4 steps). In contrast to an earlier approach, the new methodology is very general and tolerates bulky ortho-substituents. The reliability of the operationally convenient protocol was demonstrated in the synthesis of a library of 16 new phosphine-phosphite ligands, starting from different ortho-alkylphenols. The modular concept opens a rapid access to a broad variety of ligands and might be useful in the search for and structural optimization of suitable ligands for specific chirogenic transition metal-catalyzed transformations.