Antimicrobial peptides constitute an important component of the mammalian innate immune response. Several types of antimicrobial peptides, including the -defensins, are produced at epithelial surfaces in response to infectious threats. Here we show that a class of small molecules, including L-isoleucine and several of its analogs, can specifically induce epithelial -defensin expression. This induction is transcriptional in nature and involves activation of the NF-B͞rel family of trans-activating factors. We hypothesize that these substances represent unique markers for the presence of pathogens and are recognized by innate immune pattern recognition receptors. Isoleucine or its analogs ultimately may have clinical utility as novel immunostimulants that could bolster the barrier defenses of mucosal surfaces.
A practical, safe, and high-yielding process for the cyclopropanation of a chiral epoxide has been developed using the inexpensive and nonhazardous reagents triethylphosphonoacetate and sodium tert-butoxide.
IntroductionCyclopropane ring systems are ubiquitous in nature and are contained in a large number of natural products, insecticides, and pharmaceutical drug candidates. 1 In conjunction with our work on the melatonergic agent 1 2 (Scheme 1), we needed to develop a cost-effective process for the large-scale preparation of the enantiomerically pure transcyclopropane carboxylic acid 2b.The reaction of epoxides with the anion of triethylphosphonoacetate (TEPA) in the synthesis of cyclopropane derivatives has been known for over four decades, 3 and there has been occasional additional application of the reaction between epoxides and phosphonates (either R-phosphono esters or phosphono ketones). 4 However, the utility of this reaction for the large-scale preparation of cyclopropane derivatives has not been explored. We were attracted toward developing the use of TEPA for the conversion of 3 to 2a due to its low cost, ease of availability and handling onscale. Most of the cited procedures use NaH as the base and afford the cyclopropane derivatives in fair yields (20-60%). Therefore, to make such a procedure scale-worthy, we needed to find a suitable substitute for NaH (dust hazard, hydrogen evolution, moisture sensitivity, etc.) and to identify reaction conditions to significantly improve the overall yield of the reaction.Herein, we wish to report the development of a safe, practical, and high-yielding process for the conversion of 3 to 2a by using the chemistry of TEPA anion and subsequent isolation of 2b.
A two-step telescoped synthesis of 4-vinyl-2,3-dihydrobenzofuran (2) was demonstrated using imidate ester chemistry and phase-transfer catalysis. Treatment of 2,3-bis(2-hydroxyethyl)phenol (1) with the Vilsmeier reagent resulted in an in situ generation of a bis-imidate intermediate 4, which was converted to 4-(2-chloroethyl)-2,3-dihydrobenzofuran (6) via a sequential ring closure and chloride displacement reactions. Further dehydrohalogenation of 6 using a phase-transfer catalyst provided an excellent, cost-effective method to prepare high quality 4-vinyl-2,3-dihydrobenzofuran (2). The yields for the two-step telescoped process ranged from 83 to 90%.
Relatively small cyclic peptides that contain functionalized side chains provide interesting model compounds for studying side chain‐side chain interactions, peptide backbone flexibility (especially if X‐Pro bonds are included), and as potential enzyme mimetics. In order to develop more efficient synthetic routes to compounds such as cyclo(Xxx‐Pro‐Gly‐Yyy‐Pro‐Gly), using the Merrifield method, we have investigated several orthogonal solid phase synthesis strategies and contrasted the use of two solid phase peptide‐resin cleavage techniques for preparing partially protected linear sequences. Phase transfer catalysis using tetrabutyl ammonium hydrogen sulfate in THF with saturated aqueous K2CO3 provides peptide acid salts in which most of the common protecting groups (Arg(NO2), Tyr(Bzl), Z‐Lys, Lys(Boc), and Glu(tBu)) are not affected. Using 500 MHz proton NMR, peptides having a cyclo (l‐l‐Gly‐l‐l‐Gly) sequence generally display two conformers in DMSO‐d6 with the major isomer being the bis‐cis conformer, while the minor form contains two δ turns. For peptides with a cyclo(d‐l‐Gly‐l‐l‐Gly) sequence, the major conformer contains one cis and one trans X‐Pro bond and one Type II δ turn, as previously predicted for related structure by Kopple and others.
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