There is a grave need for safer antiplatelet therapeutics to prevent heart attack and stroke. Agents targeting the interaction of platelets with the diseased vessel wall could impact vascular disease with minimal effects on normal hemostasis. We targeted integrin ␣2␤1, a collagen receptor, because its overexpression is associated with pathological clot formation whereas its absence does not cause severe bleeding. Structure-activity studies led to highly potent and selective small-molecule inhibitors. Responses of integrin ␣2␤1 mutants to these compounds are consistent with a computational model of their mode of inhibition and shed light on the activation mechanism of I-domain-containing integrins. A potent compound was proven efficacious in an animal model of arterial thrombosis, which demonstrates in vivo efficacy for inhibition of this platelet receptor. These results suggest that targeting integrin ␣2␤1 could be a potentially safe, effective approach to long-term therapy for cardiovascular disease.I-domain ͉ platelet ͉ thrombosis ͉ integrin ͉ alpha(2) beta(1)

The ␣2␤1 integrin receptor plays a key role in angiogenesis. Here we investigated the effects of small molecule inhibitors (SMIs) designed to disrupt integrin ␣2 I or ␤1 I-like domain function on angiogenesis. In unchallenged endothelial cells, fibrillar collagen induced robust capillary morphogenesis. In contrast, tube formation was significantly reduced by SMI496, a ␤1 I-like domain inhibitor and by function-blocking anti-␣2␤1 but not -␣1␤1 antibodies. Endothelial cells bound fluorescein-labeled collagen I fibrils, an interaction specifically inhibited by SMI496. Moreover, SMI496 caused cell retraction and cytoskeletal collapse of endothelial cells as well as delayed endothelial cell wound healing. SMI activities were examined in vivo by supplementing the growth medium of zebrafish embryos expressing green fluorescent protein under the control of the vascular endothelial growth factor receptor-2 promoter. SMI496, but not a control compound, interfered with angiogenesis in vivo by reversibly inhibiting sprouting from the axial vessels. We further characterized zebrafish ␣2 integrin and discovered that this integrin is highly conserved, especially the I domain. Notably, a similar vascular phenotype was induced by morpholino-mediated knockdown of the integrin ␣2 subunit. By live videomicroscopy, we confirmed that the vessels were largely nonfunctional in the absence of ␣2␤1 integrin. Collectively , our results provide strong biochemical and genetic evidence of a central role for ␣2␤1 integrin in experimental and developmental angiogenesis.

Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. . The crystal structure of 2a reveals that only one quadrant is blocked. Asymmetric hydrogenation of acrylic esters and enamides using 3a and 3b as catalysts show that the phenylene-backboned diphosphine gives a more efficient catalyst in terms of asymmetric induction than the more flexible ferrocene-backboned diphosphine.The best results, which were obtained with 3a and enamide substrates, exceeded those obtained with Duphos catalysts. The rate of hydrogenation of the enamides with 3a was 10 times faster than with [Rh(Duphos)(diene)][BF 4 ]. A quadrant diagram can be used to predict the configuration of the major product, provided it is assumed to be derived from the less sterically congested intermediate.

The first catalytic, enantioselective addition of organozinc reagents to α-aldiminoesters is described. The use of a Lewis acid/Lewis base containing bifunctional catalyst preorganizes both reactive substrates to promote enantioselective addition over the racemic background reaction and alternative addition modes. Alcohol additives were found to enhance the enantioselection. The addition product was also found to cyclize with remaining substrate to provide imidazolidines.Optically active natural and nonnatural amino acids are versatile building blocks for a range of biologically important molecules. 1 Enantioselective addition to α-iminoesters as a route to the synthesis of important chiral amino acids has been achieved 2 via the iminoene reaction, 3 Friedel Crafts reaction, 4 enol ether addition 5 and enolisable ketone 6 and aldehyde 7 addition.In comparison, the enantioselective addition of unstabilized anions to α-iminoesters which provides entry to key congeners of α-amino acids has not been reported. While related diastereomeric processes have been forthcoming, 8 the enantioselective processes have proven more difficult. To date only enantioselective additions of stoichiometric allyl zinc reagents have appeared. 9 On the other hand, the corresponding aldimine additions have met with greater success. 10 α-Iminoesters are significantly more challenging due to their higher reactivity and the presence of a bicoordinate metal binding site ( Figure 1); both factors lead to substantial racemic background processes.We have previously reported the enantioselective addition of Et 2 Zn to α-ketoesters using salen-derived independent Lewis acid/Lewis base bifunctional catalysts. 11 In these systems, the electrophile coordinates to the Lewis acid, while the electronically decoupled Lewis base activates the nucleophile. These independent moieties facilitate enantioselective addition (Figure 2). Here we report the first enantioselective addition of organozinc reagents to α-iminoesters using these bifunctional catalysts. Our initial experiments showed that the addition of Et 2 Zn to α-ketiminoesters (Figure 3, R ≠ H) proceeded with poor regioselectivity, yielding 1,2-addition, 1,4-addition and reduction. A survey of prior work revealed similar regioselectivity problems. Mg, Al and Cu mediated alkylations have resulted in 1,4-additions, whereas Zn mediated additions lead to mainly 1,2-additions ( Figure 3). 12Upon screening aldiminoester substrates (Figure 3, R = H) against metal adducts of bifunctional salens 1-4, we found that PMP (para-methoxyphenyl) protected aldiminoester 6 gave only 1,2-addition (eq 1) and was chosen for further exploration. Pure 6 can be synthesized on a large scale by condensation of ethylglyoxylate and para-methoxyaniline and subsequent distillation. 13Importantly, treating 6 with Et 2 Zn at −40°C in the absence of catalyst led to the formation of significant racemic addition product within 2 h. Thus, these substrates are much more challenging than most aldehydes (no background reaction) ...

To examine patterns of strategy choice and discovery during problem-solving of a novel locomotor task, 13.5- and 18-month-old infants were placed at the top of a staircase and encouraged to descend. Spontaneous stair descent strategy choices were documented step by step and trial by trial to provide a microgenetic account of problem-solving in action. Younger infants tended to begin each trial walking, were more likely to choose walking with each successive step, and were more likely to lose their balance and have to be rescued by an experimenter. Conversely, older infants tended to begin each trial scooting, were more likely to choose scooting with each successive step, and were more likely to use a handrail to augment balance on stairs. Documenting problem-solving microgenetically across age groups revealed striking similarities between younger infants' strategy development and older children's behaviour on more traditionally cognitive tasks, including using alternative strategies, mapping prior experiences with strategies to a novel task, and strengthening new strategies. As cognitive resources are taxed during a challenging task, resources available for weighing alternatives or inhibiting a well-used strategy are reduced. With increased motor experience, infants can more easily consider alternative strategies and maintain those solutions over the course of the trial.