A new approach to the synthesis of polyunsaturated deuterated isoprostanes: Total synthesis of d4-5-epi-8,12-iso-iPF3α-VI and d4-8,12-iso-iPF3α-VI

The total and stereospecific synthesis of d₄-5-epi-8,12-iso-iPF_3α-VI 55 and d₄-8,12-iso-iPF_3α-VI 64, EPA-derived all-syn-isoprostanes (iPs), has been accomplished. Because of issues related to volatility and yield with some of the primary deuterated synthons an improved synthesis is presented. These two deuterated analogs were used to discover and quantify the presence of the corresponding endogenous isoprostanes in human urine. These assays may serve as a valuable index of oxidative stress in population with omega-3 fatty acid enriched diets containing eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and may also be useful as an index of the severity of inflammatory diseases such as atherosclerosis and Alzheimer’s disease.     

Preparations of 2-epi-fortimicins A from 2-epi-fortimicin B by intramolecular base-catalyzed 2-O-acylation of 1,2′,6′-tri-N-benzyloxycarbonyl-2-epi-fortimicin B

Preparations of 2-epi-fortimicin A (4) from 2-epi-fortimicin B (3) are described. In contrast to the previously reported, selective 4-N-acylation of 1,2′,6′-tri-N-benzyloxycarbonylfortimicin B (8) with N-(N-benzyloxycarbonylglycyloxy)succinimide, 1,2′,6′-tri-N-benzyloxycarbonyl-2-epi-fortimicin B (5) underwent predominant 2-O,4-N-diacylation under similar conditions. Proof of the structure of the diacylated product is presented, with evidence that the diacylated product is formed by initial intramolecular, base-catalyzed 2-O-acylation. The in vitro antibacterial activities of 2-epi-fortimicin A (4), 2-O-glycyl-2-epi-fortimicin A (11), 1-N-glycyl-2-epi-fortimicin A (12), and 5-deoxy-2-epi-fortimicin A (13) are reported.     

Zierane sesquiterpene lactone,cembrane and fusicoccane diterpenoids,from the Tahitian liverwort Chandonanthus hirtellus

Cembrane-type diterpenoids, 13,18,20-epi-iso-chandonanthone (1) and (8E)-4α-acetoxy-12α,13α-epoxycembra-1(15),8-diene (2), two fusicoccane-type diterpenoids, fusicoauritone 6α-methyl ether (3) and 6β,10β-epoxy-5β-hydroxyfusicocc-2-ene (4) and a zierane sesquiterpene γ-lactone, chandolide (5) were isolated from the Tahitian liverwort Chandonanthus hirtellus (Web.) Mitt., together with eight known diterpenoids, chandonanthine (6), fusicogigantone A (7), fusicogigantone B (8), fusicogigantepoxide (9), anadensin (10), fusicoauritone (11), ent-verticillol (12) and ent-epi-verticillol (13). Their structures were established by a combination of extensive NMR spectroscopy and/or X-ray crystallographic analyses. Compounds 1, 5 and 10 showed weak cytotoxic activity against HL-60. Compound 3 also indicated weak cytotoxic activity against KB cell lines.     

Sesquiterpene lactones and other secondary metabolites from Crepis commutata (Spreng.) Greuter – Asteraceae

Sesquiterpene lactones, especially guaianolides, are widespread in the genus Crepis L. We have undertaken the chemical investigation of Crepis commutata (Spreng.) Greuter, an edible plant in Crete. From the non-polar extract of the aerial flowering parts of C. commutata five sesquiterpene lactones: 8-epi-grosheimin (1), 8-epi-isoamberboin (2), 8-epi-isolipidiol (3), 3-acetyl-8-epi-isolipidiol (4), integrifolin 3-O-β-D-glucopyranoside (5), two flavonoids: luteolin (6), luteolin 7-O-β-D-glucuronide (7), and three phenolic acids: p-anisic acid (8), p-hydroxyphenylacetic acid (9) and E-caffeic acid (10) were isolated. The structures of the isolated compounds were elucidated by high-field NMR spectroscopy.     

Cyclopeptide alkaloids from Scutia buxifolia Reiss

Scutianene E (1), 3,4,28-tris-epi-scutiaene E (2), 28-epi-scutianene E (3) and scutianene L (4), four neutral cyclopeptide alkaloids, were isolated from Scutia buxifolia Reiss, together with four known cyclopeptide alkaloids, scutianines B, C, D and E. Scutianenes 1-3 are diastereoisomeric compounds, with 3-hydroxyleucine as a β-hydroxy amino acid unit, which is connected to the styryl fragment via an ether bridge, β-phenylserine, as a common ring-bonded amino acid residue. Attached to the amino group of β-hydroxyamino acid is a side chain [trans-CH = CH-Ph]. The structures of the peptides were elucidated by means of spectroscopic analysis, including extensive 2D NMR studies. The stereochemistry for the diastereomeric 3,4,28-tris-epi-scutiaene E and 28-epi-scutianene E was confirmed by X-ray diffraction analysis of their O-acetyl derivatives.     

Two cytotoxic stereoisomers of malyngamide C, 8-epi-malyngamide C and 8-O-acetyl-8-epi-malyngamide C,from the marine cyanobacterium Lyngbya majuscula

Two epimers of malyngamide C, 8-O-acetyl-8-epi-malyngamide C (1) and 8-epi-malyngamide C (3) have been isolated along with known compounds 6-O-acetylmalyngamide F (5), H (6), J (7) K (8), and characterized from a Grenada field collection of the marine cyanobacterium Lyngbya majuscula. The structures of these compounds were deduced by 1D and 2D NMR spectroscopic and mass spectral data interpretation. Absolute configurations were determined by a combination of CD-spectroscopy, chemical degradation and the variable temperature Mosher’s method. Compounds 1–5, 7 and 8 displayed moderate cytotoxicity to NCI-H460 human lung tumor and neuro-2a cancer cell lines, with IC₅₀ values ranging between 0.5 and 20 μg/mL.     

Marine bis-γ-pyrone polypropionates of onchidione family and their effects on the XBP1 gene expression

Two additional new members of the onchidione family, 16-epi-onchidione (1) and 4-epi-onchidione (2), co-occurring with six previously reported bis-γ-pyrone polypropionates including onchidione (3), were isolated from the marine pulmonate Onchidium sp. Their structures were determined by extensive spectroscopic analysis and by comparison with 3 and onchidione-related derivatives. The absolute configuration of 1 was established by X-ray diffraction analysis employing graphite monochromated Cu K_α radiation (λ?=?0.71073?Å) with small Flack parameter 0.08. In addition, the absolute stereochemistry of previously reported onchidionol (6) was confirmed by the X-ray diffraction analysis. Some of the isolated compounds showed significant activation effects on the splicing of XBP1 mRNA as ER stress modulators to inhibit the growth of tumors.     

Synthesis of casuarine-related derivatives via 1,3-dipolar cycloaddition between a cyclic nitrone and an unsaturated γ-lactone

The 1,3-dipolar cycloaddition of the cyclic nitrone derived from tartaric acid and (S)-5-hydroxymethyl-2(5H)-furanone leads to the single adduct 7 which can be transformed into the 3-epi-1-homo-casuarine via a reaction sequence involving reduction of the lactone moiety and N-O bond hydrogenolysis, followed by intramolecular alkylation of the nitrogen atom. The adduct 7 can also be used in the synthesis of 1-methyl- or 3-methyl analogues of 3-epi-casuarine.     

Synthesis and antioxidant activity of thymol and carvacrol based Schiff bases

Thymol and carvacrol are well known antioxidants found in the extract of the plants of thyme species. The Schiff bases of 2-iso-propyl-5-methyl-phenol (thymol/1a), 2-tert-butyl-5-methyl-phenol (1b) and 5-iso-propyl-2-methyl-phenol (carvacrol/1c) exhibited much better antioxidant activity than thymol and carvacrol in DPPH assay. Ten compounds (4k, 4l, 4r, 5k, 5l, 5q, 5r, 6k, 6l and 6r) showed better or similar activity as compared to the reference compound ascorbic acid. Twenty-four most active compounds were also screened by ABTS method and showed 60–90% inhibition at 5 μg/mL concentration.     

Cytotoxic monoterpenoid indole alkaloids from the leaves and twigs of Tabernaemontana bovina

Phytochemical investigation of the leaves and twigs of Tabernaemontana bovina led to the isolation of 10 monoterpenoid indole alkaloids, including two new taberbovinines A (1) and B (2) along with eight known analogs: mehranine (3), 14α,15β-dihydroxy-N-methylaspidospermidine (4), (16S*)− 15-epi-E-isositsirikine (5), (16R*)− 15-epi-E-isositsirikine (6), 16 R*-19,20-E-isositsirikine acetate (7), hecubine (8), voafinidine (9), and voacangarine (10). Taberbovinine B (2) represents the first case of an unusual ring C/D cleavage among the natural Corynanthe-type alkaloids. Compounds 2 and 8 exhibited weak cytotoxicity against five human cancer cell lines, including SK-LU-1, HepG2, MCF-7, SK-Mel-2, and LNCaP, with IC₅₀ values ranging from 42.9 to 66.3 μM, whereas compounds 4 − 6 and 9 were cytotoxic toward MCF-7, SK-LU-1 and LNCaP cells, with IC₅₀ values in a range of 51.6–93.3 μM.     

The synthesis of new deoxynitroinositols by cyclization of 6-deoxy-3-O-methyl-6-nitro-d-allose and -l-talose

6-Deoxy-3-O-methyl-6-nitro-d-allose (5) and -l-talose (6) were synthesized from 1,2-O-isopropylidene-3O-methyl-α-d-allofuranose (1) by the nitromethane method via their furanoid, 1,2-O-isopropylidene derivatives (2 and 3). The barium hydroxide-catalyzed cyclization of the free nitrohexoses (5 and 6) was investigated. Under conditions favoring kinetic control (pH ～8, 0°), 5 gave mainly 1d-5-deoxy-2-O-methyl-5-nitro-allo-inositol (7), with the 1l-epi-1 (8) and epi-6 (9) stereoisomers as minor products. Compound 6 afforded a high yield of the myo-5-isomer (11); the 1l-allo-5 (13) and 1d-epi-1 (14) isomers were formed in small proportions but not isolated. The thermodynamically controlled, mutual interconversion of the stereoisomeric products was studied, as was the formation of nitronate salts and the regeneration of free nitroinositols. Upon immediate acidification, the nitronate obtained from 11 gave 11 and the neo-2 epimer (12) in a ratio of 2:3. The nitronate produced by 7 underwent rapid β-epimerization. The five isolated deoxynitroinositol monomethyl ethers were further characterized as tetra-acetates (7a, 9a, 11a, and 12a) and isopropylidene derivatives (7b, 8b, and 9b).     

Sesquiterpenes and diterpenes from Ambrosia arborescens

Six compounds, eudesm-11(13)-en-4β,9β-diol, 15R,16-dihydroxy-3-oxoisopimar-9(11)-ene, 15S,16-dihydroxy-3-oxoisopimar-9(11)-ene, 1α-hydroxy-7-oxo-iso-anhydrooplopanone, 10α-hydroxy-11,13-dihydro-5-epi-psilostachyin, and 4β-hydroxypseudoguaian-12,6-olide 4-O-β-d-glucopyranoside, together with 12 known sesquiterpenes, were isolated from the leaves of Ambrosia arborescens. Structures were elucidated by 1D and 2D NMR spectroscopy including 1D-TOCSY, DQF-COSY, 2D-ROESY, HSQC, and HMBC experiments, as well as by ESI mass spectrometry. The absolute configuration of the 15,16-diol moiety in 15R,16-dihydroxy-3-oxoisopimar-9(11)-ene and 15S,16-dihydroxy-3-oxoisopimar-9(11)-ene was determined using Snatzke’s method. All compounds were evaluated for antiproliferative activity.     

Seven new triterpenoids from the aerial parts of Ilex cornuta and protective effects against H2O2-induced myocardial cell injury

Seven new triterpenoids (1–7), together with two known ones (8–9), were isolated from the aerial parts ofIlex cornuta. The leaves of I. cornuta are the major source of “Kudingcha”, a popular herbal tea consumed in China and other countries. The structures of compounds 1–7 were determined as 20-epi-urs-12,18-dien-28-oic acid 3β-O-α-l-arabinopyranoside (1), 20-epi-urs-12,18-dien-28-oic acid 2′-O-acetyl-3β-O-α-l-arabinopyranoside (2), 20-epi-urs-12,18-dien-28-oic acid 3β-O-β-d-glucuronopyranoside-6-O-methyl ester (3), 3β,23-dihydroxy-20-epi-urs-12,18-dien-28-oic acid (4), 23-hydroxy-20-epi-urs-12,18-dien-28-oic acid 3β-O-α-l-arabinopyranoside (5), 23-hydroxy-20-epi-urs-12,18-dien-28-oic acid 3β-O-β-d-glucuronic acid (6), 23-hydroxy-20-epi-urs-12,18-dien-28-oic acid 3β-O-β-d-glucuronopyranoside-6-O-methyl ester (7), on the basis of spectroscopic analyses (IR, ESI–MS, HR-ESI–MS, 1D and 2D NMR) and chemical reactions. Protective effects against H₂O₂-induced H9c2 cardiomyocyte injury were tested in vitro for compounds 1–9, and the data showed that compound 4 had significant cell-protective effect. Compounds 1-9 did not show significant DPPH radical scavenging activity.     

Synthesis and evaluation of 2,3-dinorprostaglandins: Dinor-PGD1 and 13-epi-dinor-PGD1 are peroxisome proliferator-activated receptor α/γ dual agonists

2,3-Dinorprostaglandins (dinor-PGs) have been regarded as β-oxidation products of arachidonic-acid-derived prostaglandins, but their biological activities in mammalian cells remain unclear. On the other hand, C18 polyunsaturated fatty acids (PUFAs), such as γ-linolenic acid (GLA), have various biological activities, and dinor-PGs are speculated to be biosynthesized from GLA. Here, we synthesized dinor-PGs that may possibly be derived from GLA and examined their activities towards peroxisome proliferator-activated receptors (PPARs). Dinor-PGD₁ (1) and its epimer 13-epi-dinor-PGD₁ (epi-1) were found to be dual agonists for PPARα/γ, whereas PGD₂ derived from arachidonic acid is selective for PPARγ. Thus, GLA-derived dinor-PGs may have unique biological roles.     

Heteroannelated and 7-deoxygenated goniofufurone mimics with antitumour activity: Design,synthesis and preliminary SAR studies

Cytotoxic (+)-goniofufurone mimic such as benzoxepane 2 was preferentially formed after the treatment of 7-O-benzoyl-5-O-benzyl (+)-goniofufurone derivative 6 with titanium(IV) fluoride. However, the corresponding 7-epimer 5 (derivative of 7-epi-goniofufurone) under the similar reaction conditions gave mainly 7-deoxy derivative 7 as a result of an unexpected 1,5-hydride shift. Extension of this methodology to the enantiomer ent-6 provided cytotoxic (?)-goniofufurone mimics ent-2 and ent-7. Synthesized compounds showed diverse growth inhibitory effects against selected tumour cell lines, but were devoid of any significant toxicity towards the normal foetal lung fibroblasts (MRC-5). A SAR study reveals the structural features of these lactones that are beneficial for their antiproliferative activity, such as presence of an additional oxepane ring, the absolute stereochemistry and the presence of a deoxy function at the C-7 position.     

Flavan-3-ols from the leaves of Malaysian Uncaria longiflora var. pteropoda (Miq.) Ridsd

A novel flavonoid, (?)-2R,3R-3,5,4′-trihydoxyflavan-[6,7:5″,6″]-2″-pyranone, named uncariechin (1), was isolated from the methanolic extract of the leaves of Uncaria longiflora var. pteropoda (Miq.) Ridsd. along with the known (?)-epiafzelechin (2) and (?)-epicatechin (3), methyl 4-hydroxybenzoate and 4-hydroxybenzaldehyde, four pentacyclic oxindole alkaloids, isopteropodine, pteropodine, uncarine F and isopteropodic acid, previously found in the stems, and two coumarins, scopoletin and 3,4-dihydroxy-7-methoxycoumarin. Structures of the compounds were elucidated by 1D and 2D NMR, FTIR, UV, MS, and experimental as well as calculated electronic circular dichroism (ECD) data. Compounds 2 and 3 were evaluated for their neurotoxic and neuroprotective properties against differentiated SH-SY5Y neuroblastoma cell lines using the MTS assay. Compounds 2 and 3 did not show any neurotoxic effects but showed strong protective potential against hydrogen peroxide-induced neurotoxicity with maximum cell viability at a concentration of 1 μM.     

The synthesis of evernitrose and 3-epi-evernitrose

Evernitrose (2,3,6-trideoxy-3-C-methyl-4-O-methyl-3-nitro-L-arabino-hexopyranose) was synthesized from methyl 2,6-dideoxy-4-O-methyl-α-L-erythro-hexopyranosid-3-ulose (2) through introduction of an amino group attached to the tertiary branching carbon by the method of Bourgeois, and subsequent oxidation of the amino group by m-chloroperoxybenzoic acid to a nitro group. 3-Cyano-3-O-mesylation of 2 by Bourgeois's method gave exclusively the desired product having the L-ribo configuration; furthermore, the β anomer of 2 gave the L-ribo and L-arabino products in the ratio of 1:2. The latter compound was converted into 3-epi-evernitrose by a similar sequence of reactions.     

Further chemical constituents from Sinningia canescens and S. leucotricha (Gesneriaceae)

Four new compounds were isolated from the tubers of Sinningia canescens and S. leucotricha: one naphthoquinone, 7-methoxy-8-hydroxy-α-dunnione (1); two arylbenzofurans, sinningial A (2) and B (3); and one sesquiterpene, 11-epi-subergorgiol (4). Seventeen additional known compounds were isolated and identified. The structures of all compounds were determined by spectroscopic and MS analysis.     

2-Substituted fortimicins by ring opening of 2-deoxy-1,2-epimino-2-epi-fortimicin B and by nucleophilic displacements of 2-O-(methylsulfonyl)fortimicin derivatives

Opening of the aziridine ring of 2-deoxy-1,2-epimino-2-epi-fortimicin B (10) has been effected with both chloride and azide. The reactions are both stereo- and regiospecific and give 2-chloro-2-deoxyfortimicin B (2c) and 2-azido-2-deoxy-fortimicin B (2d). The nucleophilic displacements of the methanesulfonate groups of some 1-N-benzyloxycarbonyl-2-O-(methylsulfonyl)fortimicin derivatives with chloride, azide, and cyanide in N,N-dimethylformamide are dependent both on the nature of the nucleophile and the specific 1-N-benzyloxycarbonyl-2-methanesulfonate employed as the substrate. Striking differences in the stereochemistry of the azide displacements with different 2-methanesulfonates are believed to have a conformational basis. 2-Amino-2-deoxyfortimicin A (1c) and both of the 2-epimeric 2-chloro-2-deoxyfortimicins A (1b) and (5) were prepared for antibacterial assay and the in vitro results are reported.