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.

Molecular hazardous materials transport: Enzyme‐triggered CO‐releasing molecules (ET‐CORMs) offer new options for the delivery of CO. The cleavage of dienylester iron tricarbonyl complexes by an esterase under mild oxidative conditions generates CO, which causes a strong inhibiting activity of the compounds to inducible nitric oxide synthase as shown in a cellular assay.

The stilbene phytochemicals resveratrol and piceatannol have been reported to possess substantial antitumorigenic and antileukemic activities, respectively. Although recent experimental data revealed the proapoptotic potency of resveratrol, the molecular mechanisms underlying the antileukemic activity have not yet been studied in detail. In the present study, we show that resveratrol, as well as the hydroxylated analog piceatannol, are potent inducers of apoptotic cell death in BJAB Burkittlike lymphoma cells with an ED 50 concentration of 25 M. Further experiments revealed that treatment of BJAB cells with both substances led to a concentration-dependent activation of caspase-3 and mitochondrial permeability transition. Using BJAB cells overexpressing a dominant-negative mutant of the Fas-associated death domain (FADD) adaptor protein to block death receptor-mediated apoptosis, we demonstrate that resveratrol-and piceatannol-induced cell death in these cells is independent of the CD95/Fas signaling pathway. To explore the antileukemic properties of both compounds in more detail, we extended our study to primary, leukemic lymphoblasts. Interestingly, piceatannol but not resveratrol is a very efficient inducer of apoptosis in this ex vivo assay with leukemic lymphoblasts of 21 patients suffering from childhood lymphoblastic leukemia (ALL). Leukemia (2001Leukemia ( ) 15, 1735Leukemia ( -1742

Highly substituted furans are found as key structural elements in many bioactive natural products and important pharmaceuticals. They also represent versatile building blocks for the synthesis of more elaborate heterocyclic compounds. [1, 2] The search for efficient general routes to substituted furans is an important, continuing goal of organic synthesis. Several studies have focused on metal-catalyzed methods for furan synthesis (Scheme 1). These include the cyclization of allenyl ketones, [3] 3-alkyn-1-ones, [4] or 2-(1-alkynyl)-2-alken-1-ones [5] through nucleophilic attack of the carbonyl oxygen atom to a transition-metal-coordinated C À C double or triple bond (Mode A, Scheme 1). Alternatively, alkylidene cyclopropyl ketones [6] or cyclopropenyl ketones [7] are prone to metalcatalyzed cycloisomerization to afford furans through (regioselective) cleavage of the three-membered ring and subsequent cyclization (Mode B, Scheme 1).As cyclopropanes are readily accessible and reactive because of their ring strain, [8,9] we designed 1-(1-alkynyl)-cyclopropyl ketones 1 (Scheme 2) that contain both an alkyne and a cyclopropane unit as starting materials for cyclization reactions catalyzed by transition metals. Although both modes A and B (to form 2,3-dihydrofurans [10] ) are potentially possible pathways for metal-mediated reactions involving 1, we envisioned that furan formation through attack of the carbonyl oxygen atom on the alkyne (Mode A) seemed to be particularly feasible.Herein, we present a mild and efficient method for the synthesis of multiply substituted furans starting from compounds of type 1. In particular, we show that the atomeconomical gold(I)-catalyzed cascade process allows access to condensed ring systems (for example, furo[b]cycloheptenes) under ring expansion.First, we examined the reaction of (racemic) ketone 2 a using different metal catalysts (5 mol %) with MeOH (2 equiv) in CH 2 Cl 2 (Table 1). Remarkably, the ringexpanded bicyclic cycloheptafuran 3 aa was formed regiose-

Colchicine, the major alkaloid of the meadow saffron, is one of the most prominent natural products and, like other tubulin-binding natural products (e.g. taxol and the epothilones), exhibits great pharmaceutical potential. The first syntheses in the late 1950s were milestones in natural product synthesis. But even today this structurally supposedly simple molecule poses a challenge to synthetic chemists. Only in the last years have syntheses been developed that are efficient enough to provide novel structurally modified colchicine analogues. The comparative examination of all known colchicine total syntheses undertaken in this Review not only reveals the tremendous progress in synthetic organic methodology over the past decades, but also shows how the unique synthetic problems posed by this molecule can be solved in an exceptionally creative manner. Only a few target molecules have been synthesized in such multifaceted ways.