Protecting Group-Free Total Synthesis of (-)-Boscartin H.

Herein, we report the first protecting group-free total synthesis of (-)-boscartin H, which features a 5-12-5-fused tricyclic structure. The key steps, which include a diastereoselective THF-ring-forming/aldol reaction sequence and ring-closing metathesis, afforded high stereoselectivity with (-)-boscartin H obtained in 3.6% overall yield using a 11-step long linear sequence. In addition, X-ray crystallography clearly confirmed the stereochemistry of boscartin H.

Discovery of Novel 11-Membered Templates as Squalene Synthase Inhibitors.

Squalene synthase is one of the most promising pharmaceutical targets to treat hyperlipidemia. Inhibition of the squalene synthase causes a decrease in the hepatic cholesterol concentration. We have already reported the design and synthesis of highly potent benzhydrol-type squalene inhibitors. Although these templates showed unique and potent cyclic active conformations via intramolecular hydrogen bonds, the in vivo cholesterol-lowering efficacy was insufficient. We attempted to improve their potential as an orally active medicine. In our medicinal chemistry effort, cyclized 11-membered ring templates were acquired. The novel series of compounds exhibited potent squalene synthase inhibitory activity, and one of the derivatives, isomer A-(1S, 3R)-14i, showed plasma lipid-lowering efficacy in hamster and marmoset repeated-dose studies. Our findings provide valuable insights into the design and development of novel and unique 11-membered ring-type highly potent squalene synthase inhibitors.

Total synthesis of 14-membered ring ß-resorcylic acid lactone (+)-monocillin II.

This study outlines the total synthesis of (+)-monocillin II, wherein a cis-isomer selectively produces a trans-isomer during the ring-closing metathesis. The Mitsunobu reaction conducted at -60 °C, facilitating the formation of an ester bond, was the key to completing the total synthesis, which was accomplished in the longest linear sequence of 10 steps with an overall yield of 9.3%.

Enantioselective Total Syntheses of (+)-Ganocin A and (-)-Cochlearol B.

Herein, we report the total syntheses of (+)-ganocin A and (-)-cochlearol B, featuring pentacyclic skeletons, in optically active forms. We utilized asymmetric Corey-Bakshi-Shibata reduction, phenolic oxidative cyclization, the intramolecular radical cyclization-benzylic oxidative cyclization sequence, and intramolecular [2 + 2] photocycloaddition. These key steps enabled enantioselective access with the longest linear sequence of 17 steps and 9% overall yield for (+)-ganocin A and with 16 steps and 9% overall yield for (-)-cohlearol B.

Total syntheses of Ganoderma-derived meroterpenoids, (-)-oregonensin A, (-)-chizhine E, (-)-applanatumol U, and (-)-ent-fornicin A.

In this study, we report the total syntheses of Ganoderma-derived meroterpenoids, (-)-oregonensin A, (-)-chizhine E, (-)-applanatumol U, and (-)-ent-fornicin A. The 3-alkyl-5-aryl-γ-butenolide skeleton, a common motif of these meroterpenoids, was constructed through the enantioselective reductive lactonization of the γ-keto ester, alkylation, and sulfoxide-ß-syn-elimination. This flexible approach enabled enantioselective access to these meroterpenoids with the longest linear sequence of 6-8 steps, and in 21-36% overall yield, respectively.

Total Synthesis of (-)-Lamellodysidine A via an Intramolecular Diels-Alder Reaction.

In this study, we achieved an eight-step enantioselective synthesis of (-)-lamellodysidine A, a structurally intriguing sesquiterpene natural product featuring a 5/5/6/6-fused tetracyclic skeleton that was obtained from the marine sponge Lamellodysidea herbacea. The key to the synthesis is a cascade reaction that includes an intramolecular Diels-Alder reaction. In addition, single-crystal X-ray crystallographic analysis of the synthetic (-)-lamellodysidine A clearly confirmed the proposed stereochemistry and absolute configuration.

Total Synthesis of Cochlearol†B via Intramolecular [2+2] Photocycloaddition.

Herein, we describe the first total synthesis of cochlearol B, a meroterpenoid natural product featuring a 4/5/6/6/6-fused pentacyclic structure. Key steps, oxidative cyclization and subsequent intramolecular [2+2] photocycloaddition, which constructed the pentacyclic structure in highly stereoselective manner, allowed efficient access to cochlearol B with the longest linear sequence of 16 steps, and in 9 % overall yield. Single-crystal X-ray crystallographic analysis clearly confirmed the stereochemistry of cochlearol B.

Convergent total synthesis of corallocin A.

The first total synthesis of corallocin A is described herein. The Suzuki coupling reaction as a key step proceeded with high stereoselectivity and in good yield. Robust transformations, including Vilsmeier-Haack formylation and Wittig reaction, allowed for effective access to corallocin A.

Further investigation of the rapid-onset and short-duration action of the G protein-biased µ-ligand oliceridine.

TRV130 (oliceridine), a G protein-biased ligand for µ-opioid receptor, has recently been synthesized. It is considered to have strong antinociceptive effects and only minor adverse effects. However, whether or not oliceridine actually exhibits an ideal pharmacological profile as an analgesic has not yet been fully clarified in animal studies. This study examined the pharmacological profile of oliceridine in cells and animals. Oliceridine (10 µM) did not produce any µ-opioid receptor internalization in cells even though it increased impedance, which reflects the activation of Gi protein using the CellKey™ system, and inhibited the formation of cAMP. In mice, oliceridine (0.3-10 mg/kg) produced a dose-dependent antinociceptive effect with a rapid-onset and short-duration action in the hot-plate test, as well as antihyperalgesia after sciatic nerve ligation without the development of antinociceptive tolerance using the thermal hyperalgesia test. On the other hand, oliceridine inhibited gastrointestinal transit. Furthermore, oliceridine produced rapid-onset hyperlocomotion at antinociceptive doses; sensitization developed in mice and an emetic effect was observed in ferrets. These results indicate that, although oliceridine may produce dopamine-related behaviors even through selective stimulation of the G-protein-biased µ-opioid receptor pathway, it still offers advantages for breakthrough pain without antinociceptive tolerance with adequate doses.

Diastereoselective Total Syntheses of (±)-Caseabalansin A and (±)-18-Epicaseabalansin A via Intramolecular Robinson-type Annulation.

Highly diastereoselective total syntheses of (±)-caseabalansin A (1) and (±)-18-epicaseabalansin A (2) are described in this paper. We revealed that the intramolecular Robinson-type annulation of an alkynone was effective in the stereocontrolled construction of the bicyclic skeleton of 1 and 2. Further transformation of the resulting enone, including diastereoselective reduction by LiAlH(OtBu)3 , hydroxy-group-directed hydrogenation, cyclization to form the cyclic acetal moiety, and introduction of a side chain by a C(sp3 )-C(sp3 ) Stille coupling reaction, resulted in the total syntheses of (±)-1 and (±)-2.

Facile Total Synthesis of (+)-Spinoxazine B.

Herein we describe a short total synthesis of (+)-spinoxazine B, which inhibits nitric oxide (NO) production in BV-2 microgrial cells. Spinoxazine B is the first example of a natural alkaloid containing an oxazinone-pyrrolidone nucleus, and it is expected to serve as a novel drug lead compound as well as a drug discovery scaffold.

Enantioselective, Protecting-Group-Free Total Synthesis of Boscartin F.

In this work, the protecting-group-free total synthesis and stereochemical assignment of (-)-boscartin F have been reported. The key steps, including Sharpless asymmetric epoxidation, I2-mediated iodoetherification, aldol reaction, and ring-closing metathesis, allowed for rapid and highly stereoselective access to boscartin F. In addition, single-crystal X-ray crystallographic analysis of the semicarbazone derivative 22 confirmed the stereochemistry of boscartin F.

Usefulness for the combination of G-protein- and ß-arrestin-biased ligands of µ-opioid receptors: Prevention of antinociceptive tolerance.

Background: µ-Opioid receptor internalization is considered to be critically linked to antinociceptive tolerance. Although µ-opioid receptor agonists have been administered simultaneously with other drugs to control pain, little information is available regarding opioid­opioid interactions. Therefore, the present study was designed to further investigate the utility of a new G protein-biased ligand for µ-opioid receptors, TRV130, which has an antinociceptive effect without ß-arrestin-dependent µ-opioid receptor internalization, and its combination with fentanyl using µ-opioid receptor-expressing cells and mice. Results: In the present study, we confirmed that fentanyl produced a profound increase in ß-arrestin-2 recruitment accompanied by µ-opioid receptor internalization, whereas TRV130 did not induce either the recruitment of ß-arrestin-2 or µ-opioid receptor internalization in µ-opioid receptor-expressing cells. Under these conditions, ß-arrestin-2 recruitment accompanied by µ-opioid receptor internalization induced by fentanyl was abolished by TRV130, whereas TRV130 did not alter the reduction of cyclic adenosine monophosphate formation by fentanyl in µ-opioid receptor-expressing cells. In a behavioral assay, TRV130 exerted an antinociceptive effect in a hot-plate test in mice. In a combination test, the antinociceptive effect of TRV130 was synergistically increased by fentanyl. Fentanyl induced antihyperalgesia and development of its tolerance under a neuropathic pain-like state following sciatic nerve ligation. However, treatment of mice with an antinociceptive dose of TRV130 did not induce the rapid development of tolerance to its antihyperalgesic effect under a neuropathic pain-like state. Furthermore, the rapid development of tolerance to the antihyperalgesic effect induced by fentanyl plus TRV130 in mice with sciatic nerve ligation was not observed, unlike in the case of fentanyl alone. Conclusions: These findings provide evidence that activation of the G protein-biased pathway through µ-opioid receptors can alter signaling in the ß-arrestin-2 pathway linked to the stimulation of µ-opioid receptors. Furthermore, the combination of G protein-biased and ß-arrestin-biased ligands of µ-opioid receptors exerts an ideal antinociceptive effect without the rapid development of antinociceptive tolerance.

Iodoalkyne-Based Catalyst-Mediated Activation of Thioamides through Halogen Bonding.

Halogen bonding catalysis has recently gained increasing attention as a powerful tool to activate organic molecules. However, the variety of the catalyst structure has been quite limited so far. Herein, we report the first example of the use of an iodoalkyne as a halogen bond donor catalyst. By using an iodoalkyne bearing a pentafluorophenyl group as a catalyst, thioamides were efficiently activated and reacted with 2-aminophenol to generate benzoxazoles in good yield. Mechanistic studies, including 13 C NMR spectroscopic analysis and several control experiments, provided concrete evidence that this catalytic activation is based on halogen bonding. Thus, the results obtained in this study demonstrate that iodoalkynes can serve as a new scaffold for future development of halogen bonding catalysis.

Design, synthesis and structure-activity relationship studies of novel sirtuin 2 (SIRT2) inhibitors with a benzamide skeleton.

Human sirtuin 2 (SIRT2) is an attractive target molecule for development of drugs to treat neurodegenerative diseases and cancer, because SIRT2 inhibitors have a protective effect against neurodegeneration and an anti-proliferative effect on cancer stem cells. We designed and synthesized a series of benzamide derivatives as SIRT2 inhibitor candidates. Among them, compound 17k showed the most potent SIRT2-inhibitory activity (IC50=0.60µM), with more than 150-fold selectivity over SIRT1 and SIRT3 isoforms (IC50 >100µM).

Rheinanthrone, a metabolite of sennoside A, triggers macrophage activation to decrease aquaporin-3 expression in the colon, causing the laxative effect of rhubarb extract.

ETHNOPHARMACOLOGICAL RELEVANCE: Aquaporin-3 (AQP3) is expressed in mucosal epithelial cells in the colon and is important for regulating fecal water content. We examined the role of AQP3 in the laxative effect of rhubarb extract. METHODS: After orally administering rhubarb extract or its major component (sennoside A) to rats, the fecal water content, AQP3 expression and prostaglandin E2 (PGE2) concentrations in the colon were examined. The mechanism by which sennoside A decreases the expression of AQP3 was examined using the human colon cancer HT-29 cells and macrophage-derived Raw264.7 cells. RESULTS: During diarrhea by rhubarb extract administration, the PGE2 levels in the colon increased while the AQP3 expression significantly decreased. Similar changes were also observed when sennoside A was administered. When sennoside A or its metabolites, rheinanthrone and rhein were added to Raw264.7 cells, a significant increase in the PGE2 concentration was observed only in cells treated with rheinanthrone. Fifteen minutes after adding PGE2 to the HT-29 cells, the AQP3 expression decreased to approximately 40% of the control. When pretreated with indomethacin, sennoside A neither decreased the AQP3 expression nor induced diarrhea. CONCLUSIONS: Sennoside A may decrease AQP3 expression in the colon to inhibit water transport from the luminal to the vascular side, leading to a laxative effect. The decreases in the levels of AQP3 are caused by rheinanthrone, which is a metabolite of sennoside A, this metabolite activates the macrophages in the colon and increases the secretion of PGE2; PGE2 acts as a paracrine factor and decreases AQP3 expression in colon mucosal epithelial cells.

7-Dehydrocholesterol metabolites produced by sterol 27-hydroxylase (CYP27A1) modulate liver X receptor activity.

7-Dehydrocholesterol (7-DHC) is a common precursor of vitamin D3 and cholesterol. Although various oxysterols, oxygenated cholesterol derivatives, have been implicated in cellular signaling pathways, 7-DHC metabolism and potential functions of its metabolites remain poorly understood. We examined 7-DHC metabolism by various P450 enzymes and detected three metabolites produced by sterol 27-hydroxylase (CYP27A1) using high-performance liquid chromatography. Two were further identified as 25-hydroxy-7-DHC and 26/27-hydroxy-7-DHC. These 7-DHC metabolites were detected in serum of a patient with Smith-Lemli-Opitz syndrome. Luciferase reporter assays showed that 25-hydroxy-7-DHC activates liver X receptor (LXR) α, LXRß and vitamin D receptor and that 26/27-hydroxy-7-DHC induces activation of LXRα and LXRß, although the activities of both compounds on LXRs were weak. In a mammalian two-hybrid assay, 25-hydroxy-7-DHC and 26/27-hydroxy-7-DHC induced interaction between LXRα and a coactivator fragment less efficiently than a natural LXR agonist, 22(R)-hydroxycholesterol. These 7-DHC metabolites did not oppose agonist-induced LXR activation and interacted directly to LXRα in a manner distinct from a potent agonist. These findings indicate that the 7-DHC metabolites are partial LXR activators. Interestingly, 25-hydroxy-7-DHC and 26/27-hydroxy-7-DHC suppressed mRNA expression of sterol regulatory element-binding protein 1c, an LXR target gene, in HepG2 cells and HaCaT cells, while they weakly increased mRNA levels of ATP-binding cassette transporter A1, another LXR target, in HaCaT cells. Thus, 7-DHC is catabolized by CYP27A1 to metabolites that act as selective LXR modulators.

Structure-activity relationships of bisphenol A analogs at estrogen receptors (ERs): discovery of an ERα-selective antagonist.

Our multi-template approach for drug discovery, focusing on protein targets with similar fold structures, has yielded lead compounds for various targets. We have also shown that a diphenylmethane skeleton can serve as a surrogate for a steroid skeleton. Here, on the basis of those ideas, we hypothesized that the diphenylmethane derivative bisphenol A (BPA) would bind to the ligand-binding domain of estrogen receptors (ERs) in a similar manner to estradiol and act as a steroid surrogate. To test this idea, we synthesized a series of BPA analogs and evaluated their structure-activity relationships, focusing on agonistic/antagonistic activities at ERs and ERα/ERß subtype selectivity. Among the compounds examined, 18 was found to be a potent ERα-antagonist with high selectivity over ERß and androgen receptor under our assay conditions. A computational docking study suggested that 18 would bind to the antagonistic conformation of ERα. ERα-selective antagonists, such as 18, are candidate agents for treatment of breast cancer.

Discovery of DF-461, a Potent Squalene Synthase Inhibitor.

We report the development of a new trifluoromethyltriazolobenzoxazepine series of squalene synthase inhibitors. Structure-activity studies and pharmacokinetics optimization on this series led to the identification of compound 23 (DF-461), which exhibited potent squalene synthase inhibitory activity, high hepatic selectivity, excellent rat hepatic cholesterol synthesis inhibitory activity, and plasma lipid lowering efficacy in nonrodent repeated dose studies.

Discovery of novel tricyclic compounds as squalene synthase inhibitors.

In the present article, we have reported the design, synthesis, and identification of highly potent benzhydrol derivatives as squalene synthase inhibitors (compound 1). Unfortunately, the in vivo efficacies of the compounds were not enough for acquiring the clinical candidate. We continued our investigation to obtain a more in vivo efficacious template than the benzhydrol template. In our effort, we focused on a benzoxazepine ring and designed a new tricyclic scaffold by the incorporation of heterocycle into it. Prepared pyrrolobenzoxazepine derivatives showed further efficient in vitro and in vivo activities.