Pisiferic Acid Research Articles

Marine-Derived Cytosine Arabinoside (Ara-C) Inhibits Biofilm Formation by Inhibiting PEL Operon Proteins (Pel A and Pel B) of Pseudomonas aeruginosa: An In Silico Approach.

Pseudomonas aeruginosa (P. aeruginosa) is a gram-negative biofilm-forming opportunistic human pathogen whose vital mechanism is biofilm formation for better survival. PelA and PelB proteins of the PEL operon are essential for bacterial-synthesized pellicle polysaccharide (PEL), which is a vital structural component of the biofilm. It helps in adherence of biofilm on the surface and maintenance of cell-to-cell interactions and with other matrix components. Here, in-silico molecular docking and simulation studies were performed against PelA and PelB using ten natural bioactive compounds, individually [podocarpic acids, ferruginol, scopadulcic acid B, pisiferic acid, metachromin A, Cytarabine (cytosine arabinoside; Ara-C), ursolic acid, oleanolic acid, maslinic acid, and betulinic acid], those have already been established as anti-infectious compounds. The results obtained from AutoDock and Glide-Schordinger stated that a marine-derived cytosine arabinoside(Ara-C) among the ten compounds binds active sites of PelA and PelB, exhibiting strong binding affinity [Trp224 (hydrogen), Ser219 (polar), Val234 (hydrophobic) for PelA; Leu365 and Glu389 (hydrogen), Gln366 (polar) for PelB] with high negative binding energy -5.518kcal/mol and -6.056kcal/mol, respectively. The molecular dynamic and simulation studies for 100ns showed the MMGBSA binding energy scores are -16.4kcal/mol (Ara-C with PelA), and -22.25kcal/mol (Ara-C with PelB). Further, ADME/T studies indicate the IC50 values of AraC are 6.10mM for PelA and 18.78mM for PelB, which is a comparatively very low dose. The zero violation of Lipinski's Rule of Five further established that Ara-C is a good candidate for drug development. Thus, Ara-C could be considered a potent anti-biofilm compound against PEL operon-dependent biofilm formation of P. aeruginosa.

Cytotoxic diterpenoids from Salvia glutinosa and comparison with the tanshinone profile of danshen (Salvia miltiorrhiza).

The roots of Salvia miltiorrhiza are the source of the traditional Chinese medicine danshen and the class of tanshinones, particular quinoid nor-diterpenoids of the abietane type. Of these compounds, cryptotanshinone, dihydrotanshinone I, tanshinone I, and tanshinone IIA, have been extensively studied for their anticancer potential, not only but as well because of their high abundance in S. miltiorrhiza and their thus easy availability. However, also additional Salvia species are known to contain tanshinones, mainly such of the subgenus Glutinaria, of which S. glutinosa is the only species widely occurring in Europe. Using UHPLC-DAD-MS, the tanshinone profile of S. glutinosa roots collected from two different locations was compared to the profile in S. miltiorrhiza roots. In addition, tanshinone IIA and another six diterpenoids from S. glutinosa were investigated for their antiproliferative and cytotoxic potential against MDA-MB-231 and HL-60 cells. Apart from dihydrotanshinone I, which has been previously characterized due to its anticancer properties, we determined danshenol A as a highly antiproliferative and cytotoxic agent, significantly surpassing the effects of dihydrotanshinone I. With regard to the diterpenoid profile, S. miltiorrhiza showed a higher concentration for most of the tanshinones, except for (+)-danshexinkun A, which was present in comparable amounts in both species. Danshenol A, in contrast, was only present in S. glutinosa as were dehydroabietic acid and (+)-pisiferic acid. The results of our study underlines the long traditional use of danshen due to its high amount on tanshinones, but also demonstrates the potential value of investigating closely related species for the discovery of new biologically active lead compounds.

New Labdanes with Antimicrobial and Acaricidal Activity: Terpenes of Callitris and Widdringtonia (Cupressaceae).

In spite of the evidence for antimicrobial and acaricidal effects in ethnobotanical reports of Callitris and Widdringtonia, the diterpene acids from Widdringtonia have never been described and no comparison to the Australian clade sister genus Callitris has been made. The critically endangered South African Clanwilliam cedar, Widdringtonia wallichii (syn. W. cedarbergensis), of the Cederberg Mountains was once prized for its enduring fragrant timbers and an essential oil that gives an aroma comparable to better known Mediterranean cedars, predominantly comprised by widdrol, cedrol, and thujopsene. In South Africa, two other ‘cedars’ are known, which are called W. nodiflora and W. schwarzii, but, until now, their chemical similarity to W. wallichii has not been investigated. Much like Widdringtonia, Callitris was once prized for its termite resistant timbers and an ‘earthy’ essential oil, but predominantly guaiol. The current study demonstrates that the essential oils were similar across all three species of Widdringtonia and two known non-volatile diterpene acids were identified in leaves: the pimaradiene sandaracopimaric acid (1) and the labdane Z-communic acid (2) with a lower yield of the E-isomer (3). Additionally, in the leaves of the three species, the structures of five new antimicrobial labdanes were assigned: 12-hydroxy-8R,17-epoxy-isocommunic acid (4), 8S-formyl-isocommunic acid (5), 8R,17-epoxy-isocommunic acid (6), 8R-17R-epoxy-E-communic acid (7), and 8R-17-epoxy-E-communic acid (8). Australian Callitris columellaris (syn. C. glaucophylla) also produced 1 and its isomer isopimaric acid, pisiferal (9), and pisiferic acid (10) from its leaves. Callitris endlicheri (Parl.) F.M.Bailey yielded isoozic acid (11) as the only major diterpene. Diterpenes 4–6, pisiferic acid (10), spathulenol, and guaiol (12) demonstrated antimicrobial and acaricidal activity.

Overcoming the plasticity of plant specialized metabolism for selective diterpene production in yeast

Plants synthesize numerous specialized metabolites (also termed natural products) to mediate dynamic interactions with their surroundings. The complexity of plant specialized metabolism is the result of an inherent biosynthetic plasticity rooted in the substrate and product promiscuity of the enzymes involved. The pathway of carnosic acid-related diterpenes in rosemary and sage involves promiscuous cytochrome P450s whose combined activity results in a multitude of structurally related compounds. Some of these minor products, such as pisiferic acid and salviol, have established bioactivity, but their limited availability prevents further evaluation. Reconstructing carnosic acid biosynthesis in yeast achieved significant titers of the main compound but could not specifically yield the minor products. Specific production of pisiferic acid and salviol was achieved by restricting the promiscuity of a key enzyme, CYP76AH24, through a single-residue substitution (F112L). Coupled with additional metabolic engineering interventions, overall improvements of 24 and 14-fold for pisiferic acid and salviol, respectively, were obtained. These results provide an example of how synthetic biology can help navigating the complex landscape of plant natural product biosynthesis to achieve heterologous production of useful minor metabolites. In the context of plant adaptation, these findings also suggest a molecular basis for the rapid evolution of terpene biosynthetic pathways.

Inhibitory Effects of Pisiferic Acid on Angiogenesis and Lymphangiogenesis

Pisiferic acid, a diterpene isolated from Chamaecyparis pisifera, has a chemical structure similar to carnosic acid, which has antioxidant activity and exerts various biological effects such as antibiotic and antiangiogenic activity. However, the effect of pisiferic acid on angiogenesis, which is involved in various diseases including cancer and diabetic retinopathy, has not been elucidated. We found that pisiferic acid inhibited angiogenesis and suppressed human umbilical vein endothelial cell tube formation and proliferation but had no effect on human umbilical vein endothelial cell chemotaxis. Furthermore, in lymphangiogenesis assays, pisiferic acid inhibited lymphangiogenesis and lymphatic endothelial cell tube formation and proliferation. Together, these results suggest pisiferic acid to be a useful natural compound, such as carnosic acid, with beneficial effects on angiogenesis- and lymphangiogenesis-related diseases.

Semisynthesis of (−)-Barbatusol, (+)-Demethylsalvicanol, and (+)-Rosmaridiphenol from (+)-Pisiferic Acid

(+)-Pisiferic acid (1) was converted into (+)-12-O-methoxymethylpisiferol (5c) in 3 steps. The rearrangement of 5c with trifluoromethanesulfonic anhydride in pyridine provided (−)-12-O-methoxymethylpisiferin (6c), which was converted into icetexane phenols 6a, 11, and 14. The ortho-selective oxygenation of 6a and 14 with stabilized 2-iodoxybenzoic acid (SIBX), followed by the reduction of intermediary quinones afforded (−)-barbatusol (2) and (+)-rosmaridiphenol (4) in 49% and 35%, respectively. The oxygenation of 11 using potassium 5-methyl-2-iodobenzenesulfonate (pre-MIBS) with Oxone® followed by reduction gave (+)-demethylsalvicanol (3) in 59% yield.

Iodocyclization: Past and Present Examples

Many reagents have been utilized to accomplish the cyclization of organic compounds to utilize the resulting product in the synthesis of natural products and bioactive compounds. The commercially available iodine has been frequently utilized in the cyclization of several compounds such as olefinic benzyl ethers, dimethylalkenyl malonates, allylic fluorides, propargylic esters, enamides, allylated β-hydroxyketones,4,5-alkadienols, CF3-allylmorpholinones, lithium 2-(vinyl)-dithiobenzoate derivatives, 2,4-dialkenyl-1,3-dicarbonyl compounds, allylic fluorides, 1-(methylthio)-3-tosylhexa-1,3-diene-5-ynes, etc. Some of these cyclic compounds have been utilized in the synthesis of sesquiterpenes: davanone, artemone, junenol, glutinosone; diterpene pisiferic acid, iodoalkyl, dihydrofurans, β-fluorinated-γ- lactones, substituted 2-iodoindolizinones, iodinated arenes etc. The present review concentrates mainly on the recent progress of cyclization mediated by iodine. Some past examples have also been included for a comparative study. Keywords: Iodine, cyclization, propargylic ester, CF3-allylmorpholine, βfluorinatedγlactones, iodinated arenes, lactonization reaction, halogenation, hydrolysis, condensation, NMR spectroscopy, alkylmalonates, nucleophile, enantioselectivity, hypoiodides

ChemInform Abstract: Conversion of 2-Oxomanoyl Oxide into an Analogue of Pisiferic Acid.

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Pisiferdiol and pisiferic acid isolated from Chamaecyparis pisifera activate protein phosphatase 2C in vitro and induce caspase-3/7-dependent apoptosis via dephosphorylation of Bad in HL60 cells

Protein phosphatase 2C (PP2C) dephosphorylates a broad range of substrates and regulates apoptosis, stress response and growth-related pathways. In the course of screening for PP2C activators from natural sources, we isolated abietane-type diterpenes, pisiferdiol and pisiferic acid from Chamaecyparis pisifera. Pisiferdiol having a unique seven-membered ring showed more specific PP2C activation activity (1.3-fold at 100 microM) than pisiferic acid having a normal six-membered ring and oleic acid, which is known to activate PP2C. Pisiferdiol and pisiferic acid showed mixed-type activation with respect to alpha-casein, and this differed from the non-competitive activation of oleic acid in vitro. In vivo, the cytotoxicity of pisiferdiol toward human promyelocytic leukemia cell line HL60 with an IC(50) value of 18.3 microM was 2-fold and 7-fold stronger than those of pisiferic acid and oleic acid, and pisiferdiol induced apoptosis through a caspase 3/7-dependent mechanism involving the dephosphorylation of Bad(1), which is a PP2C substrate. We thus conclude that pisiferdiol and pisiferic acid are novel PP2C activators, and the more specific activator, pisiferdiol, may be a useful chemical probe to study PP2C-mediated signaling pathways, and a lead compound for pharmaceutical agents.

Syntheses of Carnosic Acid and Carnosol, Anti-oxidants in Rosemary, from Pisiferic Acid, the Major Constituent of Sawara

Carnosic acid (2), a major anti-oxidant in rosemary (Rosmarinus officinalis), was synthesized from pisiferic acid (1), the major constituent of Sawara (Chamaecyparis pisifera), via ortho-oxidation of the phenol using meta-chlorobenzoyl peroxide (mCBPO), chloroacetyl meta-chlorobenzoyl peroxide (CAMCBPO) or 2-iodoxybenzoic acid (IBX). Carnosol (3), another anti-oxidant in rosemary, was synthesized from carnosic acid by oxidation with silver oxide. Potent antibacterial activities against Propionibacterium acnes (ATCC 6919) (minimum inhibitory concentration (MIC) mug/ml) and Staphylococcus aureus ME/GM/TC Resistant (ATCC 33592) (MIC mug/ml) of carnosic acid and carnosol were reported.

Chitin Synthase 2 Inhibitory Activity of O-Methyl Pisiferic Acid and 8,20-Dihydroxy-9(11),13-abietadien-12-one, Isolated from Chamaecyparis pisifera

In the course of search for potent chitin synthase inhibitors from plant extracts, the chitin synthase 2 inhibitors, O-methyl pisiferic acid and 8,20-dihydroxy-9(11),13-abietadien-12-one which have diterpene skeleton, were isolated from the leaves of Chamaecyparis pisifera. These compounds inhibited chitin synthase 2 of Saccharomyces cerevisiae with the IC50 values of 5.8 and 226.4 microM, respectively. Especially, O-methyl pisiferic acid showed 15.3-fold stronger inhibitory activity than polyoxin D (IC50=88.6 microM), a well-known chitin synthase inhibitor. These compounds exhibited weaker inhibitory activities against chitin synthase 1 than chitin synthase 2, whereas it showed no inhibitory activity for chitin synthase 3. The compound exhibited mixed competitive inhibition with respect to UDP-N-acetyl-D-glucosamine as substrate (Ki=5 microM). These results indicated that O-methyl pisiferic acid is a specific inhibitor of chitin synthase 2. The compound also inhibited chitin synthase 1 of Candida albicans, which represents analogues to chitin synthase 2 of S. cerevisiae, with an IC50 of 75.6 microM, which represents 1.8-fold weaker activity than that of polyoxin D. Although O-methyl pisiferic acid has been reported for antibacterial and insecticidal activities, the present study is the first report on its inhibitory activity against chitin synthase 2.

A Convenient Strategy for the Total Synthesis of Pisiferic Acid Type Diterpenes.

AbstractFor Abstract see ChemInform Abstract in Full Text.

A Convenient Strategy for the Total Synthesis of Pisiferic Acid Type Diterpenes

A practical method for the total synthesis of pisiferic acid type diterpenoids is described. This involves Robinson annulation of the keto ester for the key intermediate.

Synthesis of Bioactive Diterpenes

AbstractFor Abstract see ChemInform Abstract in Full Text.

Stereocontrolled total syntheses of (±)-pisiferic acid and (±)- O-methylpisiferic acid

A stereocontrolled approach to the construction of the angularly ester substituted trans-octahydrophenanthrene ring system related to diterpenes involving an aryl participated diazoketone cyclisation strategy is delineated. The tetrahydrophenanthrenone 7 was prepared from the tetralone 6 through the intermediates 13 , 14 , 16 and 17 . The formyl derivative of 7 was treated with alkaline H 2O 2 to give the diacid 18 which was converted into the diazomethyl ketone 9 . Aryl participated cyclisation of 9 afforded the enedione 10 which was stereoselectively converted into the keto-ester 11 . The transformation of 11 into the diterpenes 1 and 4 has been efficiently accomplished.

Stereoselective Partial Synthesis of (+)‐Pisiferic Acid

Abstract(+)‐Pisiferic acid (1), an antibiotic active against Gram‐negative and Gram‐positive bacteria, was synthesized starting from dehydroabietic acid (2) or abietic acid (26). The terpene ring system was functionalized and a Barton reaction used to oxidize Me(20). The intermediates of this photochemical reaction were isolated and characterized.

Conversion of 2-Oxomanoyl Oxide Into an Analog of Pisiferic Acid

An analogue (3) of pisiferic acid (1), a known antibiotic, has been prepared from 2-oxomanoyl oxide (9) through a lead tetraacetate induced long-range oxidation.

ChemInform Abstract: Synthesis of (.+‐.)‐Pisiferin, (.+‐.)‐Pisiferol, and Related Compounds by Intramolecular (4 + 2) Cycloaddition.

AbstractThe preparation of the methyl ether (VIIa) constitutes a formal synthesis of pisiferol (VIIIa), pisiferic acid (VIIIb) and methyl pisiferate (VIIIc).

Synthesis of (±)-pisiferin, (±)-pisiferol, and related compounds by intramolecular [4 + 2]cycloaddition

Thermolysis of the olefinic benzocyclobutene (17) afforded the tricyclic compounds (18a) and (18b), whose sequential reduction, via the aldehyde (19), gave rise to the pisiferol derivatives (20a) and (20b). Since (20a) was transformed into pisiferol (2), pisiferic acid (3), and methyl pisiferate (4), this synthesis constitutes their formal synthesis. Wolff–Kishner reduction of the hydrazone of (19b) yielded the known tricyclic compound (21), which has previously been transformed into xanthoperyl methyl ether (22). Furthermore, the predominantly cis used mixture of compound (18)(a/b= 1 : 4) was converted into the predominantly trans-fused mixture (a/b= 3 : 1) using catalytic hydrogenation of the enone (24) as a key reaction. Finally, a skeletal rearrangement of an abietane-type into a 9(10→20)abeo-abietane-type compound was demonstrated. Dehydration of the alcohol (20a) afforded the methyl ether (26) and its isomer (27) in the ratio of 3 : 1 as an inseparable mixture. Demethylation of the mixture (26) and (27) provided pisiferin (1) and compound (28). Interestingly, rearrangement of the cis-fused compound (20b) formed the methyl ether (27) as a sole product, which was converted into isopisiferin (29).

Effect of pisiferic acid and its derivatives on cytotoxicity macromolecular synthesis and dna polymerase α of hela cells

1. 1. Seventy-seven derivatives of pisiferic acid (2), an antimicrobial diterpenoid, were tested for cytotoxicity against HeLa cells and 9 derivatives were found to show cytotoxicity at < 2 μg/ml dose (IC 50). 2. 2. Hydrophobicity was revealed to be an important factor for cytotoxicity of the derivatives. 3. 3. Compound 2 inhibited predominantly DNA synthesis in HeLa cells as compared with RNA and protein synthesis. 4. 4. No direct interaction between 2 and nucleic acid bases was indicated by a u.v. spectral method. 5. 5. Several of the pisiferie acid species showed inhibitory action on HeLa DNA polymerase α, and the inhibitory activity was about 1 20 of aphidicolin.