Angelic acid

The roots of Angelica sinensis

Two new eudesman-4alpha-ol epoxides from the stem essential oil of Laggera pterodonta from Cote d'Ivoire.[Pubmed:30908078]

Nat Prod Res. 2019 Mar 25:1-7.

The investigation of the stem essential oil of Laggera pterodonta (DC.) Sch. Bip. ex Oliv. (Asteraceae) from Cote d'Ivoire was carried out, using a combination of chromatographic (GC-RI, CC, pc-GC) and spectroscopic (GC-MS, (13)C NMR) techniques. This study led to the identification of fifty constituents of which two new natural compounds 7beta,11beta-epoxy-eudesman-4alpha-ol and 7alpha,11alpha-epoxy-eudesman-4alpha-ol. Their structures were elucidated by 1 D and 2 D NMR spectroscopy after pc-GC purifying. Finally, 98.9% of the whole composition of the oil was identified with a high amount of 2,5-dimethoxy-p-cymene (78.9%). The other significant components were alpha-humulene (6.2%), (E)-beta-caryophyllene (1.7%), thymyl methyl oxide (1.7%), alpha-phellandrene (1.5%), p-cymene (1.2%), (3alphaH,4betaH,6alphaH,1alphaMe)-1,6-epoxy-3-hydroxycarvotanacetone Angelic acid ester (1.1%) and 10-epi-gamma-eudesmol (1.0%).

Biosynthesis of angelyl-CoA in Saccharomyces cerevisiae.[Pubmed:29753326]

Microb Cell Fact. 2018 May 12;17(1):72.

BACKGROUND: The Angelic acid moiety represents an essential modification in many biologically active products. These products are commonly known as angelates and several studies have demonstrated their therapeutic benefits, including anti-inflammatory and anti-cancer effects. However, their availability for use in the development of therapeutics is limited due to poor extraction yields. Chemical synthesis has been achieved but its complexity prevents application, therefore microbial production may offer a promising alternative. Here, we engineered the budding yeast Saccharomyces cerevisiae to produce angelyl-CoA, the CoA-activated form of Angelic acid. RESULTS: For yeast-based production of angelyl-CoA we first expressed genes recently identified in the biosynthetic cluster ssf of Streptomyces sp. SF2575 in S. cerevisiae. Exogenous feeding of propionate and heterologous expression of a propionyl-CoA synthase from Streptomyces sp. were initially employed to increase the intracellular propionyl-CoA level, resulting in production of angelyl-CoA in the order of 5 mg/L. Substituting the Streptomyces sp. propionyl-CoA carboxylase with a carboxylase derived from Streptomyces coelicolor resulted in angelyl-CoA levels up to 6.4 mg/L. In vivo analysis allowed identification of important intermediates in the pathway, including methyl-malonyl-CoA and 3-hydroxyl-2-methyl-butyryl-CoA. Furthermore, methyl-malonate supplementation and expression of matB CoA ligase from S. coelicolor allowed for methyl-malonyl-CoA synthesis and supported, together with parts of the ssf pathway, angelyl-CoA titres of approximately 1.5 mg/L. Finally, feeding of Angelic acid to yeasts expressing acyl-CoA ligases from plant species led to angelyl-CoA production rates of approximately 40 mg/L. CONCLUSIONS: Our results demonstrate the biosynthesis of angelyl-CoA in yeast from exogenously supplied carboxylic acid precursors. This is the first report on the activity of the ssf genes. We envision that our approach will provide a platform for a more sustainable production of the pharmaceutically important compound class of angelates.

Trehangelins A, B and C, novel photo-oxidative hemolysis inhibitors produced by an endophytic actinomycete, Polymorphospora rubra K07-0510.[Pubmed:23591606]

J Antibiot (Tokyo). 2013 Jun;66(6):311-7.

Three new natural products, designated trehangelins A, B and C, were isolated by solvent extraction, silica gel and octadecylsilyl silica gel column chromatographies and subsequent preparative HPLC from the cultured broth of an endophytic actinomycete strain, Polymorphospora rubra K07-0510. The trehangelins consisted of a trehalose moiety and two Angelic acid moieties. Trehangelins A (IC50 value, 0.1 mg ml(-1)) and C (IC50 value, 0.4 mg ml(-1)), with symmetric structures, showed potent inhibitory activity against hemolysis of red blood cells induced by light-activated pheophorbide a. However, trehangelin B, with an asymmetric structure, displayed only a slight inhibition (IC50 value, 1.0 mg ml(-1)).

Dehydropyrrolizidine alkaloids in two Cryptantha species: including two new open chain diesters one of which is amphoteric.[Pubmed:23070903]

Phytochem Anal. 2013 May-Jun;24(3):201-12.

INTRODUCTION: A livestock poisoning outbreak near Kingman, Arizona, USA, potentially linked to dehydropyrrolizidine alkaloids, prompted an evaluation of some local plants for the presence of these hepatotoxic alkaloids. OBJECTIVE: To qualitatively and quantitatively examine two species of Cryptantha, a Boraginaceous genus previously shown to produce potentially toxic pyrrolizidine alkaloids, collected from the vicinity of Kingman, Arizona. METHOD: Plant extracts were analysed using HPLC-electrospray ionisation (+)-MS and MS/MS to determine the presence of dehydropyrrolizidine alkaloid esters. Identities were confirmed by comparison of chromatographic and MS data with authenticated standards and, in the case of the previously undescribed alkaloids, using one- and two-dimensional NMR spectroscopy and high-resolution mass measurement. RESULTS: Cryptantha inequata and C. utahensis were shown to produce retronecine-based dehydropyrrolizidine alkaloids at approximately 0.05% and 0.09% w/w respectively. Cryptantha inequata produced mainly echimidine, acetylechimidine and echiuplatine; dehydropyrrolizidine alkaloids that were previously associated with Echium plantagineum. The previously undescribed structure of echiuplatine was elucidated as an amphoteric, open chain diester with Angelic acid and 3-hydroxy-3-methylglutaric acid. Along with lycopsamine, intermedine and dihydroxyechiumine, C. utahensis produced cryptanthine, a previously undescribed open chain diester alkaloid esterified with Angelic acid and 2,3-dihydroxy-2-methylbutanoic acid. All pyrrolizidine alkaloids detected were present in the plants mainly as their N-oxides. CONCLUSION: The retronecine-based alkaloids detected in both Cryptantha species herein investigated aligns them within the Krynitzkia subgenus. The dehydropyrrolizidine alkaloids detected are expected to be toxic but the low levels in the plants potentially mitigate the risk. The identification of the amphoteric echiuplatine provides a cautionary note with respect to the analysis of total dehydropyrrolizidine alkaloid content.

Biochemical analysis of the biosynthetic pathway of an anticancer tetracycline SF2575.[Pubmed:19908837]

J Am Chem Soc. 2009 Dec 9;131(48):17677-89.

SF2575 1 is a tetracycline polyketide produced by Streptomyces sp. SF2575 and displays exceptionally potent anticancer activity toward a broad range of cancer cell lines. The structure of SF2575 is characterized by a highly substituted tetracycline aglycon. The modifications include methylation of the C-6 and C-12a hydroxyl groups, acylation of the 4-(S)-hydroxyl with salicylic acid, C-glycosylation of the C-9 of the D-ring with D-olivose and further acylation of the C4'-hydroxyl of D-olivose with the unusual Angelic acid. Understanding the biosynthesis of SF2575 can therefore expand the repertoire of enzymes that can modify tetracyclines, and facilitate engineered biosynthesis of SF2575 analogues. In this study, we identified, sequenced, and functionally analyzed the ssf biosynthetic gene cluster which contains 40 putative open reading frames. Genes encoding enzymes that can assemble the tetracycline aglycon, as well as installing these unique structural features, are found in the gene cluster. Biosynthetic intermediates were isolated from the SF2575 culture extract to suggest the order of pendant-group addition is C-9 glycosylation, C-4 salicylation, and O-4' angelylcylation. Using in vitro assays, two enzymes that are responsible for C-4 acylation of salicylic acid were identified. These enzymes include an ATP-dependent salicylyl-CoA ligase SsfL1 and a putative GDSL family acyltransferase SsfX3, both of which were shown to have relaxed substrate specificity toward substituted benzoic acids. Since the salicylic acid moiety is critically important for the anticancer properties of SF2575, verification of the activities of SsfL1 and SsfX3 sets the stage for biosynthetic modification of the C-4 group toward structure-activity relationship studies of SF2575. Using heterologous biosynthesis in Streptomyces lividans, we also determined that biosynthesis of the SF2575 tetracycline aglycon 8 parallels that of oxytetracycline 4 and diverges after the assembly of 4-keto-anhydrotetracycline 51. The minimal ssf polyketide synthase together with the amidotransferase SsfD produced the amidated decaketide backbone that is required for the formation of 2-naphthacenecarboxamide skeleton. Additional enzymes, such as cyclases C-6 methyltransferase and C-4/C-12a dihydroxylase, were functionally reconstituted.

Pyrrolizidine alkaloids of the endemic Mexican genus Pittocaulon and assignment of stereoisomeric 1,2-saturated necine bases.[Pubmed:17719067]

Phytochemistry. 2008 Jan;69(1):154-67.

The endemic Mexican genus Pittocaulon (subtribe Tussilagininae, tribe Senecioneae, Asteraceae) belongs to a monophyletic group of genera distributed in Mexico and North America. The five Pittocaulon species represent shrubs with broom-like succulent branches. All species were found to contain pyrrolizidine alkaloids (PAs). With one exception (i.e., stems of Pittocaulon velatum are devoid of PAs) PAs were found in all plant organs with the highest levels (up to 0.3% of dry weight) in the flower heads. Three structural types of PAs were found: (1) macrocyclic otonecine esters, e.g. senkirkine and acetylpetasitenine; (2) macrocyclic retronecine esters, e.g. senecionine, only found in roots, and (3) monoesters of 1,2-saturated necines with Angelic acid. For an unambiguous assignment of the different stereoisomeric 1,2-saturated necine bases a GC-MS method was established that allows the separation and identification of the four stereoisomers as their diacetyl or trimethylsilyl derivatives. All otonecine esters that generally do not form N-oxides and the 1,2-saturated PAs were exclusively found as free bases, while the 1,2-unsaturated 7-angeloylheliotridine occurring in P. velatum was found only as its N-oxide. In a comparative study the 1H and 13C NMR spectra of the four stereoisomeric necine bases were completely assigned by the use of DEPT-135, H,H-COSY, H,C-HSQC and H,H-NOESY experiments and by iterative analysis of the 1H NMR spectra. Based on these methods the PA monoesters occurring in Pittocaulon praecox and P. velatum were assigned as 7-O-angeloyl ester respectively 9-O-angeloyl ester of dihydroxyheliotridane which could be identified for the first time as naturally occurring necine base. Unexpectedly, in the monoesters isolated from the three other Pittocaulon species dihydroxyheliotridane is replaced by the necine base turneforcidine with opposite configuration at C-1 and C-7. The species-specific and organ-typical PA profiles of the five Pittocaulon species are discussed in a biogenetic context.

Phytogrowth-inhibitory and antifungal constituents of Helianthella quinquenervis.[Pubmed:8882437]

J Nat Prod. 1996 Mar;59(3):323-6.

Investigation on the roots of Helianthella quinquenervis (Hook.) A. Gray (Asteraceae), led to the isolation of one new benzofuran (6-methoxy-tremetone (1)) and a new prenylacetophenone (4-beta-D-(glucopyranosyloxy)-3-[3-methoxy-trans-isopenten-1 -yl] acetophenone (3)). In addition, 6-hydroxy-3-methoxytremetone (2), encecalin (6), euparin (5), demethylencecalin (4), and Angelic acid were obtained. Structural assignments of the isolated compounds were based on spectroscopic and spectrometric analysis. Natural products 1-4 showed marginal cytotoxicity against three human tumor cell lines [MCF-7, A-549, and HT-29]. Compounds 4 and 6 inhibited the radicle growth of Amaranthus hypochondriacus and Echinochloa crusgalli. Furthermore, substances 4-6 exhibited antifungal activity against Trichophyton mentagrophytes.

Analysis, isolation and insecticidal activity of linear furanocoumarins and other coumarin derivatives fromPeucedanum (Apiaceae: Apioideae).[Pubmed:24242727]

J Chem Ecol. 1994 Aug;20(8):2035-54.

Peucedanum arenarium Waldst. & Kit.,P. austriacum (Jacq.) Koch,P. coriaceum Reichenb.,P. longifolium Waldst. & Kit,P. officinale L.,P. oreoselinum (L.) Moench,P. ostruthium L., andP. palustre (L.) Moench accumulate different structural types of coumarins including simple coumarins, linear furanocoumarins, linear dihydropyranocoumarins, angular dihydrofuranocoumarins and angular dihydropyranocoumarins. Linear furanocoumarins, known for various biological activities, include some well-known antifeedants, such as bergapten, isopimpinellin, and xanthotoxin. The aim of this investigation was to screen the diverse coumarins fromPeucedanum for insecticidal activity. LC was used to analyze and isolate coumarins for the bioassays. A growth inhibition bioassay with 17 derivatives, comprising all structural types fromPeucedanum, carried out withSpodoptera littoralis (Boisduval) (Lepidoptera: Noctuidae) as test organism, indicated the majority of the linear furanocoumarins and the angular dihydrofuranocoumarin athamantin as active compounds. Oxygenation of the prenyl residue of linear furanocoumarins decreased activity. Further formation of an ester with Angelic acid even resulted in complete inactivity. Five active linear furanocoumarins, bergapten, isopimpinellin, xanthotoxin, isoimperatorin, and imperatorin, and two linear furanocoumarins with a substituted furan ring, peucedanin and 8-methoxypeucedanin, were compared in a dietary utilization bioassay. Relative growth rate (RGR) and relative consumption rate (RCR) divided the tested coumarins in three groups of similar activity. Isopimpinellin and peucedanin slightly decreased RGR and RCR of the treated larvae, and xanthotoxin, isoimperatorin, and 8-methoxypeucedanin heavily decreased RGR and RCR. Bergapten and imperatorin differed by the lowest RGR values and rather high RCR values. The effects caused by these two coumarins indicate specific postingestive toxicity. The results obtained in this study add to the reputation of coumarins to be an effective chemical defense, postulating that chemical diversity is a necessary trait for well-defended plants.

Identification and characterization of inhibitors of peptido-leukotriene-synthesis from Petasites hybridus.[Pubmed:7938265]

Planta Med. 1994 Aug;60(4):318-22.

Extracts from Petasites hybridus were found to inhibit peptido-leukotriene biosynthesis in isolated peritoneal macrophages. Chemical analysis by gas chromatography coupled with mass and infrared spectroscopy facilitated the identification of three isomeric oxopetasan esters, petasin, and isopetasin as the main compounds of these extracts. Fractionations obtained by column chromatography of the most effective extract indicated a correlation between peptido-leukotriene biosynthesis inhibition and the content of isopetasin, a sesquiterpene ester of isopetasol and Angelic acid, as well as the isomeric oxopetasan esters. Petasin, a structural isomer of isopetasin, however, was found to be inactive. It may even reduce the peptido-leukotrine inhibitory effect of isopetasin. It is concluded that isopetasin and the oxopetasan esters in Petasites hybridus inhibit the biosynthesis of the vasoconstrictive peptido-leukotrienes. This effect may contribute to some of the medicinal properties of Petasites hybridus extracts such as, e.g., gastroprotection and spasmolytic activity.

A new tetracycline antibiotic with antitumor activity. II. The structural elucidation of SF2575.[Pubmed:1577661]

J Antibiot (Tokyo). 1992 Mar;45(3):325-30.

The structure of a new antitumor antibiotic SF2575, has been determined by spectroscopic analyses of the antibiotic and its alkaline degradation products. The relative stereochemistry has been confirmed by X-ray crystallographic analysis. The antibiotic has a 2-naphthacenecarboxamide carbon skelton which is structurally related to the tetracycline antibiotics and it is unique by bearing C-glycoside, salicyclic acid and Angelic acid moieties.

Angelic Acid is a substance found in the essential oil of Anthemis nobilis, and it exists in an ester form. Angelic acid aids in wound healing and exhibits sedative and psychotropic properties.

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