The Erythrina alkaloids [1] have received considerable attention over the past few decades owing to their intriguing biological activity [2] and characteristic polycondensed structures, which provide an opportunity to develop a new ringforming methodology. [3] This family of alkaloids are classified into two groups according to their structural features: those whose D rings are aromatic, and those whose D rings contain an unsaturated lactone. Although a wide variety of methods have already been developed for the synthesis of the group containing an aromatic D ring, [1,3] the synthesis of their counterparts with non-aromatic D rings is limited to that of (AE )-cocculolidine by Kitahara and co-workers.[3p] Herein, we describe the first total synthesis of (+)-b-erythroidine (1), a non-aromatic dienoid-type Erythrina alkaloid isolated from several species of the Erythrina genus together with aerythroidine. [4,5] Recently, we developed an efficient method [3j, 6] for the construction of the erythrinan skeleton which relies on ringclosing metathesis [7,8] of a dienyne. On the basis of this methodology, we envisaged dienyne 2 as a precursor of 1 and postulated that this intermediate could be accessed from bketo ester 3, which would be available from 5 through 4 by Nalkylation followed by Dieckmann condensation (Scheme 1). In this synthetic plan, another key issue which must be addressed is the enantiocontrolled construction of ethynylated amino acid fragment 5, which contains a quaternary center.The required amino acid fragment was synthesized as 18 in enantiocontrolled manner by taking advantage of the method [9] that we previously developed for the construction of quaternary amino acids (Scheme 2). Thus, according to the procedure developed by Kotsuki et al., [10] triflate 7, which is readily available from 2,3-O-isopropylidene-d-threitol (6) through the corresponding monotosylate, [11] was treated with lithiated propargyl tetrahaydropyranyl ether to give tosylate 8. Iodination of 8 followed by reductive cleavage of the resulting iodide gave alcohol 10. Methylation of 10 and subsequent removal of the THP protecting group afforded propargyl alcohol 11. Successive treatment [12] of 11 with NaH 2 Al(OCH 2 CH 2 OMe) 2 and iodine allowed stereo-and regioselective formation of Z-iodoalkene 12. Upon Sonogashira coupling [13] of 12 with trimethylsilylacetylene, the acetylene functionality was cleanly introduced and, after desilylation, Z-allylic alcohol 13 was obtained quantitatively. Although subsequent epoxidation of 13 proceeded with poor diastereoselectivity under Katsuki-Sharpless catalytic asymScheme 1. Retrosynthetic analysis of b-erythroidine (1).
The transanal endorectal pull-through (TAEPT) procedure is now widely performed for Hirschsprung's disease (HD), however, the colorectal function after TAEPT has not yet been adequately assessed. We evaluated the postoperative clinical outcome and colorectal function based on lower colonic manometry after TAEPT. Twenty-one cases of HD underwent TAEPT from 1998 to 2005. We examined the clinical outcome based on the requirement of enemas/suppositories, the number of defecations per day, the severity of perianal erosion, and the incidence of enterocolitis requiring hospital stay. Using a three-channel Dentsleeve catheter and UPS-2020 measuring device, we performed postoperative colonic manometry at three locations: (1) the anal canal, (2) 5 cm proximal to the anal canal, and (3) 10 cm proximal to the anal canal, during defecation, and then we measured the appearance of high-amplitude contraction (HAC) (duration >/=10 s, amplitude >/=100 cmH(2)O). Four of 21 cases were treated with enemas/suppositories no longer than 1 year. The number of defecations decreased gradually from 4 to 5 per day in the early postoperative period, reaching 2 to 3 per day about 1 year postoperatively. Perianal erosion was noted in 3 of 21 cases but it disappeared within three postoperative years. Two cases had enterocolitis. Lower colon manometry was performed in eight cases. Manometry during defecation was successfully monitored in six cases. HAC occurred in five of six cases (83.3%). The clinical outcomes after TAEPT were satisfactory in almost all cases. These good outcomes were possibly due to the occurrence of HAC during defecation, though HAC did not fill the definition of high amplitude propagated contractions (HAPCs). The occurrence of HAC after TAEPT might be caused by keeping any damage to the mesenteric ascending cholinergic nerve to a minimum during surgery. Further long-term observations are still required to make an adequate assessment of such cases.
Growing evidence suggests persistent mitochondrial permeability transition pore (mPTP) opening is a key pathophysiological event in cell death underlying a variety of diseases. While it has long been clear the mPTP is a druggable target, current agents are limited by off-target effects and low therapeutic efficacy. Therefore identification and development of novel inhibitors is necessary. To rapidly screen large compound libraries for novel mPTP modulators, a method was exploited to cryopreserve large batches of functionally active mitochondria from cells and tissues. The cryopreserved mitochondria maintained respiratory coupling and ATP synthesis, Ca2+ uptake and transmembrane potential. A high-throughput screen (HTS), using an assay of Ca2+-induced mitochondrial swelling in the cryopreserved mitochondria identified ER-000444793, a potent inhibitor of mPTP opening. Further evaluation using assays of Ca2+-induced membrane depolarisation and Ca2+ retention capacity also indicated that ER-000444793 acted as an inhibitor of the mPTP. ER-000444793 neither affected cyclophilin D (CypD) enzymatic activity, nor displaced of CsA from CypD protein, suggesting a mechanism independent of CypD inhibition. Here we identified a novel, CypD-independent inhibitor of the mPTP. The screening approach and compound described provides a workflow and additional tool to aid the search for novel mPTP modulators and to help understand its molecular nature.
Glucagon-like peptide 2 (GLP-2) is an intestinotropic peptide that binds to GLP-2 receptor (GLP-2R), a class-B G protein-coupled receptor. The GLP-2R antagonist GLP-2(3-33) has relatively high partial agonistic activity, and there are as yet no ideal known potent GLP-2R antagonists. We therefore prepared several truncated forms of human GLP-2 and characterized them by binding and reporter assays to find antagonists more potent than GLP-2(3-33). We found that GLP-2(11-33) was the most potent orthosteric GLP-2R antagonist, with binding activity almost equal to those of GLP-2 and GLP-2(3-33) and weaker intrinsic agonistic activity than GLP-2(3-33). GLP-2(11-33) retained weak agonistic activity toward human, cynomolgus monkey, dog, and Syrian hamster GLP-2Rs. However, it had no agonistic activity toward rat GLP-2R. GLP-2(11-33) potentiated the agonistic activity of an ago-allosteric modulator of GLP-2R, compound 1 (N-[1-(2,5-dichlorothiophen-3-yl)-2-(phenylsulfanyl)ethylidene]hydroxylamine), synergistically toward human GLP-2R. In the case of rat GLP-2R, GLP-2(11-33) decreased the agonistic activity of compound 1, although GLP-2 and GLP-2(3-33) increased this activity additively. These findings suggest that the binding sites of the ago-allosteric modulator and GLP-2 overlap, at least in rat GLP-2R. GLP-2(11-33) is a novel, useful tool for analyzing the mode of action of agonists and ago-allosteric modulators of GLP-2R.
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