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.

Chemoselective one-pot cleavage and oxidation of silyl ethers to corresponding carbonyl compounds using IBX and acid catalysts.

Herein, we describe the chemoselective one-pot cleavage and oxidation of silyl ethers using catalytic amount of TsOH·H2O and IBX in DMSO. The oxidation of primary alkyl TBS ethers afforded the corresponding aldehydes in 51-94% yields, in the presence of aryl TBS, MOM, and PMB ethers, as well as N-Boc and acetonide groups. Secondary benzyl TBS ethers bearing aryl TBS ethers were also oxidized to ketones in moderate yields. A possible reaction pathway was also proposed.

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%.

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.

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.

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.

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.

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.

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.

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).

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.

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.

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.

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.

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.

Potent and selective inhibition of hepatitis C virus replication by novel phenanthridinone derivatives.

A number of novel phenanthridinone derivatives were examined for their inhibitory effect on hepatitis C virus (HCV) replication in Huh-7 cells harboring self-replicating subgenomic viral RNA replicons with a luciferase reporter (LucNeo#2). The activity of compounds was further confirmed by inhibition of viral RNA copy number in different subgenomic and full-genomic replicon cells using real-time reverse transcription polymerase chain reaction. Among the compounds, 4-butyl-11-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-7-methoxy-[1,3]dioxolo[4,5-c]phenanthridin-5(4H)-one (HA-719) was found to be the most active with a 50% effective concentration of 0.063 ± 0.010 µM in LucNeo#2 cells. The compound did not show apparent cytotoxicity to the host cells at concentrations up to 40 µM. Western blot analysis demonstrated that HA-719 reduced the levels of NS3 and NS5A proteins in a dose-dependent fashion in the replicon cells. Interestingly, the phenanthridinone derivatives including HA-719 were less potent inhibitors of JFH1 strain (genobtype 2a HCV) in cell-free virus infection assay. Although biochemical assays revealed that HA-719 proved not to inhibit NS3 protease or NS5B RNA polymerase activity at the concentrations capable of inhibiting viral replication, their molecular target (mechanism of inhibition) remains unknown. Considering the fact that most of the anti-HCV agents currently approved or under clinical trials are protease and polymerase inhibitors, the phenanthridinone derivatives are worth pursuing for their mechanism of action and potential as novel anti-HCV agents.

Non-competitive and selective dipeptidyl peptidase IV inhibitors with phenethylphenylphthalimide skeleton derived from thalidomide-related α-glucosidase inhibitors and liver X receptor antagonists.

Novel dipeptidyl peptidase IV (DPP-IV) inhibitors with a phenethylphenylphthalimide skeleton were prepared based on α-glucosidase inhibitors and liver X receptor (LXR) antagonists derived from thalidomide. Representative compounds showed non-competitive inhibition of DPP-IV and 28a exhibited 10-fold selectivity for DPP-IV over DPP-8. Compound 28a is the first non-competitive, selective DPP-IV inhibitor.

Peroxisome proliferator-activated receptor agonists with phenethylphenylphthalimide skeleton derived from thalidomide-related liver X receptor antagonists: relationship between absolute configuration and subtype selectivity.

Introduction of an alkylcarboxylic acid unit, which is a partial structure of endogenous peroxisome proliferator-activated receptor (PPAR) ligands, into a phenethylphenylphthalimide skeleton, which possesses liver X receptor (LXR) antagonistic activity, afforded novel PPAR ligands. The results of structure-activity relationship analysis and docking studies led us to the potent PPAR agonists 13c-e. The absolute configuration of 13c-e affects the PPAR subtype selectivity.

Discovery of a new 2-aminobenzhydrol template for highly potent squalene synthase inhibitors.

To obtain small and efficient squalene synthase inhibitors, a flexible 2-aminobenzhydrol open form structure was designed and showed potent inhibitory activity comparable to 4,1-benzoxazepin compounds. Further chemical modification led to the discovery of a novel template with a strong squalene synthase inhibitory activity, and its basic structure-activity relationship was revealed. The X-ray crystallographic data of compound 12 bound to the active site of squalene synthase provided an important insight into the binding mode of this alternative template that formed 11-membered ring conformations with an intramolecular hydrogen bond.

Fused heterocyclic amido compounds as anti-hepatitis C virus agents.

We identified a fused heteroaromatic amido structure based on the phenanthridine skeleton as a superior scaffold for candidate drugs with potent anti-HCV activity. Among the compounds synthesized, a phenanthridine analogue with a 1,3-dioxolyl group (24) possessed the most potent anti-HCV activity (EC(50) value: 50 nM), with acceptable cytotoxicity. The structural development and structure-activity relationships of these compounds are described.