Pipernonaline

Piper longum Constituents Induce PANC-1 Human Pancreatic Cancer Cell Death under Nutrition Starvation.[Pubmed:37612242]

Chem Biodivers. 2023 Sep;20(9):e202300280.

Pancreatic cancer is a highly aggressive form of cancer with a poor prognosis, partly due to 'austerity', a phenomenon of tolerance to nutrient deprivation and survival in its hypovascular tumor microenvironment. Anti-austerity agents which preferentially diminish the survival of cancer cells under nutrition starvation is regarded as new generation anti-cancer agents. This study investigated the potential of Piper longum constituents as anti-austerity agents. The ethanolic extract of Piper longum was found to have preferential cytotoxicity towards PANC-1 human pancreatic cancer cells in a nutrient-deprived medium (NDM). Further investigation led to the identification of Pipernonaline (3) as the lead compound with the strongest anti-austerity activity, inducing cell death and inhibiting migration in a normal nutrient medium, as well as strongly inhibiting the Akt/mTOR/autophagy pathway. Therefore, Pipernonaline (3) holds promise as a novel antiausterity agent for the treatment of pancreatic cancer.

Genomic, LC-MS, and FTIR Analysis of Plant Probiotic Potential of Bacillus albus for Managing Xanthomonas oryzae via Different Modes of Application in Rice (Oryza sativa L.).[Pubmed:37462829]

Probiotics Antimicrob Proteins. 2023 Jul 18.

Xanthomonas oryzae causes tremendous damage in rice plants (Oryza sativa L). Therefore, this study is focused on siderophore-producing Bacillus albus (CWTS 10) for managing BLB disease caused by X. oryzae. Both B. albus and its crude siderophore (methanolic and diethyl ether) extracts inhibited X. oryzae (10-12 mm). Fourier transform infrared spectroscopy (FTIR) analysis of the extracts indicated the presence of catecholate siderophore functional groups. Liquid chromatography-mass spectrometry (LC-MS) analysis revealed the presence of antimicrobial compounds such as 2-deoxystreptamine, miserotoxin, fumitremorgin C, pipercide, Pipernonaline, gingerone A, and deoxyvasicinone. Complete genome sequencing revealed the gene clusters for antibiotic, siderophore, antibacterial, antifungal, and secondary metabolite production. An in vivo study revealed that bacteria (CWTS 10) and their siderophore extracts effectively inhibited X. oryzae. The mode of application of bacterial or siderophore extracts in terms of DI and DSI percentage was as follows: soak method > inoculation method > spray method. In addition to providing enhanced antagonistic activity, there was a significant increase in root and shoot length and weight (wet and dry) of treated plants compared to control plants challenged with X. oryzae. Thus, the results clearly indicate that siderophore-producing B. albus and its siderophore extracts strongly inhibited X. oryzae. However, further field experiments are required before being formulated to protect rice crops from X. oryzae.

Complete genome sequencing of Bacillus subtilis (CWTS 5), a siderophore-producing bacterium triggers antagonistic potential against Ralstonia solanacearum.[Pubmed:37002541]

J Appl Microbiol. 2023 Apr 3;134(4):lxad066.

AIM: The aims of this study were to explore the antagonistic potential of siderophore-producing Bacillus subtilis (CWTS 5) for the suppression of Ralstonia solanacearum and to explore the mechanisms of inhibition by FTIR, LC-MS, and whole genome analysis. METHODS AND RESULTS: A siderophore-producing B. subtilis (CWTS 5) possessing several plant growth-promoting properties such as IAA and ACC deaminase production, phosphate solubilization, and nitrogen fixation was assessed for its inhibitory effect against R. solanacearum, and its mechanisms were explored by in vitro and in vivo analyses. The active secondary metabolites in the siderophore extracts were identified as 2-deoxystreptamine, miserotoxin, fumitremorgin C, pipercide, Pipernonaline, gingerone A, and deoxyvasicinone by LC-MS analysis. The Arnow's test and antiSMASH analysis confirmed the presence of catecholate siderophores, and the functional groups determined by FTIR spectroscopy confirmed the presence of secondary metabolites in the siderophore extract possessing antagonistic effect. The complete genome sequence of CWTS 5 revealed the gene clusters responsible for siderophore, antibiotics, secondary metabolite production, and antibacterial and antifungal metabolites. Furthermore, the evaluation of CWTS 5 against R. solanacearum in pot studies demonstrated 40.0% reduced disease severity index (DSI) by CWTS 5, methanolic extract (DSI-26.6%), ethyl acetate extract (DSI-20.0%), and increased plant growth such as root and shoot length, wet weight and dry weight of Solanum lycopersicum L. owing to its antagonistic potential. This genomic insight will support future studies on the application of B. subtilis as a plant growth promoter and biocontrol agent against R. solanacearum for bacterial wilt management. CONCLUSION: The results of this study revealed that B. subtilis (CWTS 5) possesses multiple mechanisms that control R. solanacearum, reduce disease incidence, and improve S. lycopersicum growth.

Design and synthesis of novel pipernonaline derivatives as anti-austerity agents against human pancreatic cancer PANC-1 cells.[Pubmed:35969895]

Bioorg Med Chem. 2022 Oct 1;71:116963.

Pipernonaline (1), one of the components of the spice pepper, preferentially reduced the survival of human pancreatic cancer PANC-1 cells under nutrient-deprived conditions witha PC(50) value of 7.2 muM, suggesting that1couldpotentially lead to the development ofnew anticanceragents basedon theanti-austerity strategy. We have synthesized a total of 31 Pipernonaline derivatives, revealing clear structure-activity relationships. Compound 9, which showed the strongest preferential cytotoxicity among synthesized derivatives, inhibited Akt activation and cancer cell migration, making it an extremely promising candidate compound for new pancreatic cancer agents based on the anti-austerity strategy.

Chemical profile, traditional uses, and biological activities of Piper chaba Hunter: A review.[Pubmed:32283191]

J Ethnopharmacol. 2020 Jul 15;257:112853.

ETHNOPHARMACOLOGICAL RELEVANCE: Piper chaba Hunter, called Chui Jhal or Choi Jhal, is commonly used as a culinary (spice) herb in India and Bangladesh. It exhibits numerous important biological activities and has been widely used in traditional medicine. AIM OF THE STUDY: This review focuses on the chemical and pharmacological activities of a culinary ingredient P. chaba based on information extracted from the literature to highlight its use in traditional medicine. METHODS: A literature search in known databases was conducted (till September 2019) for published articles using the relevant keywords. RESULTS: Findings suggest that, to date, a number of important phytoconstituents such as dimeric alkaloids, and alkamides have been isolated from various parts of P. chaba. Extracts from P. chaba or derived compounds exhibit diverse biological activities, such as anti-microbial, anti-leishmanial, anti-malarial, anti-parasitic, cytotoxic/anticancer, adipogenic, hepato- and gastro-protective, anti-diabetic, analgesic, anti-diarrheal, depressive, anti-inflammatory, diuretic, anti-hypertensive, antipyretic, anti-ulcer, and immunomodulatory effect. Among the isolated compounds, chabamides, piperine, piplartine, retrofractamides A/B, methylenedioxyphenyl)-nona-2E,4E,8E-trienoic acid, n-butyl or n-pentyl amine, piperlonguminine, Pipernonaline, dehydroPipernonaline, N-isobutyl-(2E,4E)-octadecadienamide, and N-isobutyl-(2E,4E,14Z)-eicosatrienamide have documented important biological effects in various test systems. CONCLUSIONS: Taken together, P. chaba may be a potential source of plant-based therapeutic lead compounds, which justify its uses in traditional medicine.

The synthetic antihyperlipidemic drug potassium piperate selectively kills breast cancer cells through inhibiting G1-S-phase transition and inducing apoptosis.[Pubmed:28467790]

Oncotarget. 2017 Jul 18;8(29):47250-47268.

Piper longum L. is a well-known traditional antihyperlipidemic medicine in China, containing medicinal constituents of piperine, Pipernonaline and piperlonguminine in its fruit. However, the antitumor properties of these constituents have not yet been studied. We found that potassium piperate (GBK), a derivative of piperine, inhibited proliferation of cancer cells. GBK selectively inhibited the G1-S-phase transition in breast cancer cells and the G1 arrest was correlated with induction of p27 expression, which is an inhibitor for cyclin-dependent kinases, and inhibition of cyclin A, cyclin E and cyclin B expression. Moreover, GBK treatment led to a downregulation of the mini-chromosome maintenance protein expression and induction of mitochondrial-dependent cell apoptosis in breast cancer cells. Our results also suggested that GBK might also inhibit cancer cell proliferation through epigenetic signaling pathways. A synergistic effect in inhibition of cancer cell proliferation was found when GBK was combined with chemotherapy medicines etoposide phosphate or cisplatin at middle or low doses in vitro. These results show that GBK is a novel potential anti-breast cancer drug that inhibits cell proliferation and promotes cell apoptosis.

Amides and neolignans from the aerial parts of Piper bonii.[Pubmed:27452451]

Phytochemistry. 2016 Sep;129:36-44.

Six amides, piperbonamides A-F, three neolignans piperbonins A-C, and 11 known compounds were isolated from the aerial parts of Piper bonii (Piperaceae). The structures of piperbonamides A-F and piperbonins A-C were elucidated based on the analysis of 1D and 2D NMR and MS data. Piperbonin A, (+)-trans-acuminatin, (+)-cis-acuminatin, (+)-kadsurenone, and Pipernonaline showed weak activity against platelet aggregation with IC50 values of 118.2, 108.5, 90.02, 107.3, and 116.3 muM, respectively, as compared with the positive control, tirofiban, with an IC50 value of 5.24 muM. Piperbonamides A-F were inactive against five tumor cell lines at concentrations up to 40 muM.

Pipernonaline from Piper longum Linn. induces ROS-mediated apoptosis in human prostate cancer PC-3 cells.[Pubmed:23159637]

Biochem Biophys Res Commun. 2013 Jan 4;430(1):406-12.

The antiproliferation effects of Pipernonaline, a piperine derivative, were investigated on human prostate cancer PC-3 cells. It inhibited growth of androgen independent PC-3 and androgen dependent LNCaP prostate cells in a dose-dependent (30-90 muM) and time-dependent (24-48 h) manner. The growth inhibition of PC-3 cells was associated with sub-G(1) and G(0)/G(1) accumulation, confirmed by the down-regulation of CDK2, CDK4, cyclin D1 and cyclin E, which are correlated with G(1) phase of cell cycle. Pipernonaline up-regulated cleavage of procaspase-3/PARP, but did not change expression of proapoptotic bax and antiapoptotic bcl-2 proteins. Its caspase-3 activation was confirmed by the caspase-3 assay kit. In addition, Pipernonaline caused the production of reactive oxygen species (ROS), increase of intracellular Ca(2+), and mitochondrial membrane depolarization, which these phenomena were reversed by N-acetylcysteine, a ROS scavenger. The results suggest that Pipernonaline exhibits apoptotic properties through ROS production, which causes disruption of mitochondrial function and Ca(2+) homeostasis and leads to its downstream events including activation of caspase-3 and cleavage of PARP in PC-3 cells. This is the first report of Pipernonaline toward the anticancer activity of prostate cancer cells, which provides a role for candidate agent as well as the molecular basis for human prostate cancer.

Piperidine alkaloids from Piper retrofractum Vahl. protect against high-fat diet-induced obesity by regulating lipid metabolism and activating AMP-activated protein kinase.[Pubmed:21741367]

Biochem Biophys Res Commun. 2011 Jul 22;411(1):219-25.

The fruits of Piper retrofractum Vahl. have been used for their anti-flatulent, expectorant, antitussive, antifungal, and appetizing properties in traditional medicine, and they are reported to possess gastroprotective and cholesterol-lowering properties. However, their anti-obesity activity remains unexplored. The present study was conducted to isolate the anti-obesity constituents from P. retrofractum Vahl. and evaluate their effects in high-fat diet (HFD)-induced obese mice. Piperidine alkaloids from P. retrofractum Vahl. (PRPAs), including piperine, Pipernonaline, and dehydroPipernonaline, were isolated as the anti-obesity constituents through a peroxisome proliferator-activated receptor delta (PPARdelta) transactivation assay. The molecular mechanism was investigated in 3T3-L1 adipocytes and L6 myocytes. PRPA treatment activated AMP-activated protein kinase (AMPK) signaling and PPARdelta protein and also regulated the expression of lipid metabolism-related proteins. In the animal model, oral PRPA administration (50, 100, or 300mg/kg/day for 8weeks) significantly reduced HFD-induced body weight gain without altering the amount of food intake. Fat pad mass was reduced in the PRPA treatment groups, as evidenced by reduced adipocyte size. In addition, elevated serum levels of total cholesterol, low-density lipoprotein cholesterol, total lipid, leptin, and lipase were suppressed by PRPA treatment. PRPA also protected against the development of nonalcoholic fatty liver by decreasing hepatic triglyceride accumulation. Consistent with the in vitro results, PRPA activated AMPK signaling and altered the expression of lipid metabolism-related proteins in liver and skeletal muscle. Taken together, these findings demonstrate that PRPAs attenuate HFD-induced obesity by activating AMPK and PPARdelta, and regulate lipid metabolism, suggesting their potential anti-obesity effects.

Activation of TRPV1 and TRPA1 by black pepper components.[Pubmed:20460725]

Biosci Biotechnol Biochem. 2010;74(5):1068-72.

We searched in this study for novel agonists of transient receptor potential cation channel, subfamily V, member 1 (TRPV1) and transient receptor potential cation channel, subfamily A, member 1 (TRPA1) in pepper, focusing attention on 19 compounds contained in black pepper. Almost all the compounds in HEK cells heterogeneously expressed TRPV1 or TRPA1, increased the intracellular Ca(2+) concentration ([Ca(2+)](i)) in a concentration-dependent manner. Among these, piperine, isopiperine, isochavicine, piperanine, Pipernonaline, dehydroPipernonaline, retrofractamide C, piperolein A, and piperolein B relatively strongly activated TRPV1. The EC(50) values of these compounds for TRPV1 were 0.6-128 microM. Piperine, isopiperine, isochavicine, piperanine, piperolein A, piperolein B, and N-isobutyl-(2E,4E)-tetradeca-2,4-diamide also relatively strongly activated TRPA1, the EC(50) values of these compounds for TRPA1 were 7.8-148 microM. The Ca(2+) responses of these compounds for TRPV1 and TRPA1 were significantly suppressed by co-applying each antagonist. We identified in this study new transient receptor potential (TRP) agonists present in black pepper and found that piperine, isopiperine, isochavicine, piperanine, piperolein A, and piperolein B activated both TRPV1 and TRPA1.

Antihyperlipidemic compounds from the fruit of Piper longum L.[Pubmed:19172581]

Phytother Res. 2009 Aug;23(8):1194-6.

A bioassay-guided isolation of an ethanol extract of the fruit of Piper longum L. yielded piperlonguminine, piperine and Pipernonaline, as the main antihyperlipidemic constituents. They exhibit appreciable antihyperlipidemic activity in vivo, which is comparable to that of the commercial antihyperlipidemic drug, simvastatin.

Alkamides from the fruits of Piper longum and Piper nigrum displaying potent cell adhesion inhibition.[Pubmed:18672369]

Bioorg Med Chem Lett. 2008 Aug 15;18(16):4544-6.

Eight alkamides 1-8 were isolated by bioassay-guided isolation of EtOH extracts of the fruits of Piper longum and Piper nigum (Piperaceae). Their structures were elucidated by spectroscopic analysis ((1)H, (13)C NMR, and ESI-MS) as follows: guineensine (1), retrofracamide C (2), (2E,4Z,8E)-N-[9-(3,4-methylenedioxyphenyl)-2,4,8-nonatrienoyl]piperidine (3), Pipernonaline (4), piperrolein B (5), piperchabamide D (6), pellitorin (7), and dehydroPipernonaline (8). Their compounds 3-5, 7, and 8 inhibited potently the direct binding between sICAM-1 and LFA-1 of THP-1 cells in a dose-dependent manner, with IC(50) values of 10.7, 8.8, 13.4, 13.5, and 6.0 microg/mL, respectively.

Antiplatelet effects of acidamides isolated from the fruits of Piper longum L.[Pubmed:17689230]

Phytomedicine. 2007 Dec;14(12):853-5.

The inhibitory effects of four acidamides, piperine, Pipernonaline, piperoctadecalidine, and piperlongumine, isolated from the fruits of Piper longum L. on washed rabbit platelet aggregation were examined. All of the four tested acidamides showed dose-dependent inhibitory activities on washed rabbit platelet aggregation induced by collagen, arachidonic acid (AA), and platelet-activating factor (PAF), except for that induced by thrombin. Piperlongumine, in particular, showed stronger inhibitory effects than other acidamides to rabbit platelet aggregation induced by collagen, AA and PAF.

Inhibition of diacylglycerol acyltransferase by alkamides isolated from the fruits of Piper longum and Piper nigrum.[Pubmed:17177498]

J Agric Food Chem. 2006 Dec 27;54(26):9759-63.

Pharmacological inhibition of acyl CoA:diacylglycerol acyltransferase (DGAT, EC 2.3.1.20) has emerged as a potential therapy for the treatment of obesity and type 2 diabetes. Bioassay-guided isolation of CHCl3 extracts of the fruits of Piper longum and Piper nigum (Piperaceae), using an in vitro DGAT inhibitory assay, lead to isolation of a new alkamide named (2E,4Z,8E)-N-[9-(3,4-methylenedioxyphenyl)-2,4,8-nonatrienoyl]piperidine (2), together with four known alkamides: retrofractamide C (1), Pipernonaline (3), piperrolein B (4), and dehydroPipernonaline (5). Compounds 2-5 inhibited DGAT with IC50 values of 29.8 (2), 37.2 (3), 20.1 (4), and 21.2 (5) microM, respectively, but the IC50 value for 1 was more than 900 microM. This finding indicates that compounds possessing piperidine groups (2-5) can be potential DGAT inhibitors.

Preparative isolation and purification of amides from the fruits of Piper longum L. by upright counter-current chromatography and reversed-phase liquid chromatography.[Pubmed:15230526]

J Chromatogr A. 2004 Jun 25;1040(2):193-204.

A versatile counter-current chromatography (CCC) with upright type-J multilayer coil planet centrifuge, named upright CCC, was applied to the isolation and purification of amides from Piper longum L., which is widely used as an anodyne and a treatment for stomach disease in China. After the saponification by KOH of the ethanol extracts solution of 15 kg of crude drug "Piper Longi Fructus", the fruits of P. longum L., the solution was extracted with light petroleum and 500 g of red crude oil was obtained. Using 2.5 g of red crude oil as sample, the preparative upright CCC with a two-phase system composed of light petroleum (bp 60-90 degrees C)-ethyl acetate-tetrachloromethane-methanol-water (1:1:8:6:1, v/v) was successfully performed, which yielded nine fractions. Then these fractions were further purified by use of reversed-phase liquid chromatography (RPLC) with a glass column of 500 x 10 mm i.d. packed with reversed-phase silica gel. As a result, nine target amides with over 95% purity, i.e., 50 mg of (2E,4E)-N-isobutyl-eicosa-2,4-dienamide, 150 mg of (2E,4E,14Z)-N-isobutyl-eicosa-2,4,14-trienamide, 110 mg of (2E,4E,12Z)-N-isobutyl-ocatadeca-2,4,12-trienamide, 50 mg of guineensine, 60 mg of Pipernonaline, 75 mg of pellitorine, 63 mg of piperine, 45 mg of piperanine, and 40 mg of piperlonguminine were isolated, respectively. Structures of all compounds were identified by electrospray ionization MS, electron impact ionization MS, one- and two-dimensional NMR spectra.