Itadaki Yamaguchi

Bio: Itadaki Yamaguchi is an academic researcher from Kyoto Pharmaceutical University. The author has contributed to research in topics: Piper chaba & Piperine. The author has an hindex of 5, co-authored 6 publications receiving 276 citations.

New amides and gastroprotective constituents from the fruit of Piper chaba.

Abstract: The 80 % aqueous acetone extract from the fruit of Piper chaba was found to show protective effects on ethanol- and indomethacin-induced gastric lesions in rats. From the aqueous acetone extract, four new amides named piperchabamides A ( 1), B ( 2), C ( 3), and D ( 4) were isolated, and their structures were determined on the basis of chemical and physicochemical evidence. In addition, the gastroprotective effects of the principal constituents, piperine ( 5), piperanine ( 6), pipernonaline ( 7), dehydropipernonaline ( 8), piperlonguminine ( 9), retrofractamide B ( 10), guineensine ( 11), N-isobutyl-(2 E,4 E)-octadecadienamide ( 12), N-isobutyl-(2 E,4 E,14 Z)-eicosatrienamide ( 13), and methyl piperate ( 14), were examined. As a result, compounds 5 - 10 and 12 - 14 significantly inhibited ethanol-induced gastric lesions at a dose of 25 mg/kg, p. o., while 5, 7, 8, 10, 12, and 13 also significantly inhibited indomethacin-induced gastric lesions at the same dose.

A new amide, piperchabamide F, and two new phenylpropanoid glycosides, piperchabaosides A and B, from the fruit of Piper chaba.

Abstract: A new amide, piperchabamide F (1), and two new phenylpropanoid glycosides, piperchabaosides A (2) and B (3), were isolated from 80% aqueous acetone extract from fruit of Piper chaba. Their stereostructures were elucidated on the basis of chemical and physicochemical evidence.

Adipogenic effects of piperlonguminine in 3T3-L1 cells and plasma concentrations of several amide constituents from Piper chaba extracts after treatment of mice

Abstract: In our previous study, piperlonguminine from the fruit of Piper chaba was reported to promote adipogenesis in 3T3-L1 cells like the peroxisome proliferator-activated receptor-γ (PPARγ) agonist, troglitazone. In the present study, the mode of action of piperlonguminine in cells was examined. Piperlonguminine increased mRNA levels of adiponectin, glucose transporter 4, and fatty acid-binding protein (aP2). It also increased mRNA levels of PPARγ2 but, unlike troglitazone, piperlonguminine did not activate PPARγ directly in a nuclear receptor cofactor assay. Analyses of plasma from mice treated with piperlonguminine, piperine, and retrofractamide A, and an extract of the fruit, showed that concentrations of piperlonguminine were higher than those of piperine and retrofractamide A, and that the "area-under-the-curve" of piperine increased following in vivo administration of the extract.

Biological role of Piper nigrum L. (Black pepper): A review

Abstract: Piper nigrum L. is considered the king of spices throughout the world due to its pungent principle piperine. Peppercorn of Piper nigrum as a whole or its active components are used in most of the food items. Different parts of Piper nigrum including secondary metabolites are also used as drug, preservative, insecticidal and larvicidal control agents. Biologically Piper nigrum is very important specie. The biological role of this specie is explained in different experiments that peppercorn and secondary metabolites of Piper nigrum can be used as Antiapoptotic, Antibacterial, Anti-Colon toxin, Antidepressant, Antifungal, Antidiarrhoeal, Anti-inflammatory, Antimutagenic, Anti-metastatic activity, Antioxidative, Antiriyretic, Antispasmodic, Antispermatogenic, Antitumor, Antithyroid, Ciprofloxacin potentiator, Cold extremities, Gastric ailments, Hepatoprotective, Insecticidal activity, Intermittent fever and Larvisidal activity. Other roles of this specie includes protection against diabetes induced oxidative stress; Piperine protect oxidation of various chemicals, decreased mitochondrial lipid peroxidation, inhibition of aryl hydroxylation, increased bioavailability of vaccine and sparteine, increase the bioavailability of active compounds, delayed elimination of antiepileptic drug, increased orocecal transit time, piperine influenced and activate the biomembrane to absorb variety of active agents, increased serum concentration, reducing mutational events, tumour inhibitory activity, Piperine inhibite mitochondrial oxidative phosphorylation, growth stimulatory activity and chemopreventive effect. This review based on the biological role of Piper nigrum can provide that the peppercorn or other parts can be used as crude drug for various diseases while the secondary metabolites such as piperine can be used for specific diseases.

Sequential C sp 3H Arylation and Olefination: Total Synthesis of the Proposed Structure of Pipercyclobutanamide A

Abstract: Our laboratory recently reported the synthesis of the pseudodimeric cyclobutane natural products piperarborenine B (1, Figure 1A) and piperarborenine D (proposed structure, 2) through a sequential cyclobutane C–H arylation strategy.[1,2] This led to both the concise preparation of these molecules (6–7 steps) and the structural reassignment of piperarborenine D (revised structure, 3). While the piperarborenines are the simplest examples of heterodimeric cyclobutane natural products isolated from pepper plants, a number of other heterodimers have been isolated, which all arise from a formal [2+2] cycloaddition of piperine-like monomers (4) with varying oxidation states and chain lengths.[3] Looking to extend our C–H functionalization strategy to more complex members of the family, our attention turned to the pipercyclobutanamides (5 and 6). Figure 1 Selected heterodimeric cyclobutane natural products and retrosynthesis of pipercyclobutanamide A (5) The pipercyclobutanamides were first isolated by Fujiwara and coworkers in 2001 from the fruits of the black pepper plant, Piper nigrum, though no biological activity was reported at that time.[3a] In 2006, Tezuka and coworkers reisolated pipercyclobutanamide A (5) and demonstrated a selective inhibition of cytochrome P450 2D6 (CYP2D6).[3c] These heterodimers represent a greater synthetic challenge than the piperarborenines (1,3) due to the presence of four different substituents on the cyclobutane ring. Both of these natural products contain an unusual cis unsaturated amide, and pipercyclobutanamide A (5) and B (6) contain styrene and styryl diene motifs, respectively. Viewing these molecules as an opportunity to develop cyclobutane C–H olefination chemistry, a synthetic strategy was devised and the retrosynthetic analysis of pipercyclobutanamide A (5) is shown in Figure 1B. First, the cis-alkene is transformed into an aldehyde through a stereocontrolled olefination reaction. The aldehyde could then be deconstructed to a directing group (DG) and the amide into a methyl ester using standard functional group manipulations to provide intermediate 7. Applying the strategy developed for the piperarborenines, this intermediate could be prepared through a series of epimerizations and sp3 C–H functionalizations on a desymmetrized cyclobutane dicarboxylate 8. The direct olefination of sp2 C–H bonds has been known since the seminal work of Fujiwara and Moritani in the late 1960’s,[4] but few examples exist for the direct olefination of unactivated sp3 C–H bonds.[5] During a study towards the teleocidin natural products, Sames coupled an unactivated methyl group with a vinyl boronic acid, though the sequence proceeded through a discretely isolated palladacycle.[5e] The first catalytic example was reported in 2010 by Yu and coworkers.[5a] A highly electron-deficient anilide directing group was employed to couple acrylate derivatives directly to unactivated methyl and cyclopropyl C–H bonds. Chen and coworkers later reported the coupling of cyclic vinyl iodides with methylene C–H bonds using Daugulis’ picolinamide directing group under palladium catalysis.[5d] Encouraged by this result in particular, a styrenyl iodide was chosen as the first coupling partner to examine for the synthesis of pipercyclobutanamide A (5).[6] Investigations started with the preparation of the requisite cyclobutane starting material 12 (Scheme 1). Applying the methodology developed previously for the piperarborenine natural products, methyl coumalate (9) underwent photochemical 4π electrocyclization at reduced temperature to give photopyrone 10.[7] This unstable intermediate was immediately hydrogenated and coupled to 8-aminoquinoline[8] in a single operation to give the desired C–H olefination precursor (12) in 54% overall yield. The olefination reaction was initially studied with (2-iodovinyl)benzene as a model coupling partner. The use of conditions originally developed for monoarylation (hexafluoroisopropanol (HFIP) as solvent and pivalic acid) resulted in low conversion and significant amounts of decomposition. Switching the solvent to toluene improved the reaction considerably to give bis-olefinated cyclobutane 13 as the major product in 50% isolated yield. This is in contrast to our previous work on the piperarborenines in which an epimerization event was required to allow for an efficient second C–H functionalization on the cyclobutane ring. The reason for this direct bis-olefination is unclear, but it may simply be that the vinyl iodide is smaller than the aryl iodide, leading to a more facile second reaction. Furthermore, 13 is an all-cis-cyclobutane that is quite strained and, to our knowledge, there are no other general methods for the controlled construction of this stereochemical array on a cyclobutane. Scheme 1 Total synthesis of the proposed structure of pipercyclobutanamide A (5). Reagents and conditions: a) 450-W Hanovia lamp, Pyrex filter, DCM, 15 °C, 96 h; then H2, Pt/C, 4 h; then 8-aminoquinoline (1.2 equiv), EDC (1.2 equiv), 0 to 23 °C, ... Given the modularity of this sequential C–H functionalization strategy, a monoarylation reaction could take place, followed by an olefination reaction to reach the end goal. When the standard monoarylation conditions were applied to reaction of cyclobutane 12 with 1-iodo-3,4-methylenedioxybenzene, poor conversion was observed due to methylenedioxy ring (3,4-dimethoxyiodobenzene as a coupling partner performed well). Pivalic acid proved to be an effective additive, and when the reaction was performed in tBuOH at high concentration, an acceptable monoarylation yield was obtained (54%, 1.00g scale). Due to the facile double olefination observed in the preparation of 13, monoarylated 14 was directly subjected to the C–H olefination reaction with styrenyl iodide 15. Optimizing the reaction was straightforward, employing catalytic Pd(OAc)2 in the presence of 1.5 equivalents of AgOAc with toluene as the solvent gave all-cis-cyclobutane 16 in 59% yield (480 mg scale). Pivalic acid as an additive retarded the reaction rate, and protic solvents such as t-BuOH or HFIP were inferior, giving low conversion or substantial decomposition, respectively. With the sequential functionalization product (16) in hand, the relative stereochemistry needed to be altered to the all-trans configuration found in the natural product. This was anticipated to be a facile process given the strained nature of the all-cis stereochemistry and the thermodynamically downhill path to the desired all-trans product. Experimentally, this was verified through the use of two equivalents of sodium methoxide with C-1 epimerization occurring rapidly at room temperature (< 1 min). Upon warming the reaction mixture to 45 °C, the methyl ester (C-3) epimerizes over two hours and fully hydrolyzes after the addition of aqueous sodium hydroxide to give acid 18. Without further purification, 18 was treated with excess DIBAL to transform the aminoquinoline directing group directly into an aldehyde. By employing the free carboxylic acid in this reaction, the correct oxidation state found in the natural product is maintained with the carboxylate anion acting as an innate protecting group.[9] Additionally, the direct reduction of secondary amides with DIBAL has limited precedent, and the success of this reaction is likely the result of the chelating nature of the aminoquinoline motif.[10] Furthermore, this presents a new method for the cleavage of this amide directing group that avoids the extremes of pH and heat, expanding the synthetic utility of the Daugulis methodology if found to be general. Moving forward with the crude reaction product 19, piperidine was used as both a base and a coupling partner in the reaction with T3P® (propylphosphonic anhydride) to provide amide 20 in 40–45% isolated yield over 3 steps (114 – 386 mg scale). To complete the synthesis of pipercyclobutanamide A (5), only an olefination reaction remained. This was accomplished through the use of Ando’s methodology for cis-selective unsaturated amide synthesis.[11] Treatment of aldehyde 20 with the Ando phosphonate (21) in the presence of tBuOK resulted in a ca. 5:1 cis:trans mixture of easily separable olefin isomers, giving the desired pipercyclobutanamide A (5) in 80% isolated yield (100 mg scale). Unfortunately, the 1H and 13C NMR data did not match the spectrum reported for the natural product.[12] The concise synthesis of the proposed structure of pipercyclobutanamide A (5) further demonstrates the power of C–H functionalization logic in synthesis to provide substantial amounts of complex cyclobutanes (7 steps, 5 chromatographic purifications, 5% overall yield, >100 mg prepared). The sequence features mostly skeleton-forming transforms, is protecting-group-free,[13] and has only one concession step (DIBAL reduction) leading to an ideality of 85%.[14] Salient features of the synthesis include: (1) the first example of C–H olefination on an unactivated cyclobutane ring; (2) stereocontrolled access to highly strained all-cis cyclobutanes; (3) direct conversion of aminoquinoline amides directly to aldehydes; and (4) the use of a carboxylate anion as an “innate protecting group” in an amide reduction.

A Comprehensive Review on Pharmacotherapeutics of Herbal Bioenhancers

Abstract: In India, Ayurveda has made a major contribution to the drug discovery process with new means of identifying active compounds. Recent advancement in bioavailability enhancement of drugs by compounds of herbal origin has produced a revolutionary shift in the way of therapeutics. Thus, bibliographic investigation was carried out by analyzing classical text books and peer-reviewed papers, consulting worldwide-accepted scientific databases from last 30 years. Herbal bioenhancers have been shown to enhance bioavailability and bioefficacy of different classes of drugs, such as antibiotics, antituberculosis, antiviral, antifungal, and anticancerous drugs at low doses. They have also improved oral absorption of nutraceuticals like vitamins, minerals, amino acids, and certain herbal compounds. Their mechanism of action is mainly through absorption process, drug metabolism, and action on drug target. This paper clearly indicates that scientific researchers and pharmaceutical industries have to give emphasis on experimental studies to find out novel active principles from such a vast array of unexploited plants having a role as a bioavailability and bioefficacy enhancer. Also, the mechanisms of action by which bioenhancer compounds exert bioenhancing effects remain to be explored.