Living organisms employ glycans as recognition elements because of their large structural information density. Well-defined sugar structures are needed to fully understand and take advantage of glycan functions, but sufficient quantities of these compounds cannot be readily obtained from natural sources and have to be synthesized. Among the bottlenecks in the chemical synthesis of complex glycans is the preparation of suitably protected monosaccharide building blocks. Thus, easy, rapid, and efficient methods for building-block acquisition are desirable. Herein, we describe routes directly starting from the free sugars toward notable monosaccharide derivatives through microwave-assisted one-pot synthesis. The procedure followed the in situ generation of per-O-trimethylsilylated monosaccharide intermediates, which provided 1,6-anhydrosugars or thioglycosides upon treatment with either trimethylsilyl trifluoromethanesulfonate or trimethyl(4-methylphenylthio)silane and ZnI2, respectively, under microwave irradiation. We successfully extended the methodology to regioselective protecting group installation and manipulation toward a number of thioglucosides and the glycosylation of persilylated derivatives, all of which were conducted in a single vessel. These developed approaches open the possibility for generating arrays of suitably protected building blocks for oligosaccharide assembly in a short period with minimal number of purification stages.
Objective— PAR4 (protease-activated receptor 4), one of the thrombin receptors in human platelets, has emerged as a promising target for the treatment of arterial thrombotic disease. Previous studies implied that thrombin exosite II, known as a binding site for heparin, may be involved in thrombin-induced PAR4 activation. In the present study, a heparin octasaccharide analog containing the thrombin exosite II–binding domain of heparin was chemically synthesized and investigated for anti-PAR4 effect. Approach and Results— PAR4-mediated platelet aggregation was examined using either thrombin in the presence of a PAR1 antagonist or γ-thrombin, which selectively activates PAR4. SCH-28 specifically inhibits PAR4-mediated platelet aggregation, as well as the signaling events downstream of PAR4 in response to thrombin. Moreover, SCH-28 prevents thrombin-induced β-arrestin recruitment to PAR4 but not PAR1 in Chinese Hamster Ovary-K1 cells using a commercial enzymatic complementation assay. Compared with heparin, SCH-28 is more potent in inhibiting PAR4-mediated platelet aggregation but has no significant anticoagulant activity. In an in vitro thrombosis model, SCH-28 reduces thrombus formation under whole blood arterial flow conditions. Conclusions— SCH-28, a synthetic small-molecular and nonanticoagulant heparin analog, inhibits thrombin-induced PAR4 activation by interfering with thrombin exosite II, a mechanism of action distinct from other PAR4 inhibitors that target the receptor. The characteristics of SCH-28 provide a new strategy for targeting PAR4 with the potential for the treatment of arterial thrombosis.
An efficient procedure for the regiocontrolled synthesis of a-phenylseleno ketones has been developed, making use of the lithium naphthalenide induced reductive selenenylation of the a-cyano ketone system as a key operation. Moreover, seleno ketones thus generated in situ, upon subsequent treatment with hydrogen peroxide and acetic acid, could be further converted into the corresponding enones with a high degree of regioselectivity, presumably due to the lithium salt mediated selenoxide syn-elimination process.a-Phenylseleno ketones are of great importance in synthetic chemistry where they are commonly used as the substrates for preparation of a,b-unsaturated ketones 1 or the intermediates for synthesizing polycyclic compounds via a free-radical cyclization process. 2 In addition to their synthetic versatility, a specific series of a-phenylseleno ketones as reported by Cotgreave et al. 3 has been shown to possess glutathione peroxidase-like biological properties, indicating that a-phenylseleno ketones might have potential to serve as anticancer, antiviral and anti-inflammatory agents, 4 and/or as the selenium source of selenoproteins, which are essential for human immune system and known to play a critical role in reducing the incidence of a wide variety of cancers, particularly that of the prostate. 5,6 While a number of procedures are accessible to provide aphenylseleno ketones, an efficient control over the regioselectivity remains problematic for unsymmetrical ketones with the a and a¢ carbons to a ketone carbonyl equally susceptible to selenenylation. 7-11 Herein, we wish to report that a convenient synthetic method, making use of the lithium naphthalenide (LN) 12 induced reductive selenenylation of a-cyano ketones as a key operation, has been developed to facilitate the formation of the corresponding a-phenylseleno ketones with complete regioselectivity. It was found that a-cyano ketones could be readily reduced with LN under mild conditions (-40°C) to give the corresponding ketone enolates. 13 When the reduction was followed by the addition of a phenylselenenylating agent, a-selenenylation was effected, resulting in the specific replacement of the cyano group with a phenylseleno group. A typical experiment is depicted in Scheme 1. 14 However, it is noteworthy that among several phenylselenenylating agents investigated, phenylselenyl bromide is superior to its counterparts such as phenylselenyl chloride (65% yield) and diphenyl diselenide (52% yield) in offering compound 2. Scheme 1This reductive selenenylation process proved to be general as outlined in Table 1. In all cases examined, the reactions proceeded smoothly and the desired products were obtained in synthetically useful yields (75-92%). Substrates 1 and 3-9 are prepared by alkylation of the corresponding a-cyano ketones using an appropriate alkylating agent and lithium hydride (LiH) in THF at room temperature for 24 hours, which are readily accessible via the Thorpe-Ziegler reaction, 15 the base-induced rearrangement of isoxazoles 16 or the a-cya...
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