Determination of absolute configuration and binding efficacy of benzimidazole-based FabI inhibitors through the support of electronic circular dichroism and MM-GBSA techniques

We have previously reported benzimidazole-based compounds to be potent inhibitors of FabI for Francisella tularensis (FtFabI), making them promising antimicrobial hits. Optically active enantiomers exhibit markedly differing affinities toward FtFabI. The IC₅₀ of benzimidazole (?)-1 is ～100× lower than the (+)-enantiomer, with similar results for the 2 enantiomers. Determining the absolute configuration for these optical compounds and elucidating their binding modes is important for further design. Electronic circular dichroism (ECD) quantum calculations have become important in determining absolute configurations of optical compounds. We determined the absolute configuration of (?)/(+)-1 and (?)/(+)-2 by comparing experimental spectra and theoretical density functional theory (DFT) simulations of ECD spectra at the B3LYP/6-311+G(2d, p) level using Gaussian09. Comparison of experimental and calculated ECD spectra indicates that the S configuration corresponds to the (?)-rotation for both compounds 1 and 2, while the R configuration corresponds to the (+)-rotation. Further, molecular dynamics simulations and MM-GBSA binding energy calculations for these two pairs of enantiomers with FtFabI show much tighter binding MM-GBSA free energies for S-1 and S-2 than for their enantiomers, R-1 and R-2, consistent with the S configuration being the more active one, and with the ECD determination of the S configuration corresponding to (?) and the R configuration corresponding to (+). Thus, our computational studies allow us to assign (?) to (S)- and (+) to (R)- for compounds 1 and 2, and to further evaluate structural changes to improve efficacy.     

Oxygenated verticillene derivatives from Bursera suntui

Medium polarity fractions of the hexane extracts of the stems of Bursera suntui afforded six previously known (1-6) and four hitherto unknown verticillane derivatives: (1S,3Z,7S,8S,11S,12S)-(+)-7,8-epoxyverticill-3-en-12,20-diol (7), (1S,3Z,7S,8S,11S,12S)-(+)-7,8-epoxyverticill-3-en-12,20-diol 20-acetate (8), (1S,3Z,7S,11S,12S)-(+)-verticilla-3,8(19)-dien-7,12,20-triol (9), and (1S,3Z,7S,11S,12S)-(+)-verticilla-3,8(19)-dien-7,12,20-triol 20-acetate (10). Acetylation of 9 and 10 yielded (1S,3Z,7S,11S,12S)-(+)-verticilla-3,8(19)-dien-7,12,20-triol 7,20-diacetate (11), while hydrolysis of 8 gave 7. The structures and stereochemistry of 7-11 were established by spectroscopic analyses, particularly by 1D and 2D NMR spectra and HRESIMS. The conformational preferences of 7-11 were studied by molecular mechanics modelling employing the Monte Carlo protocol followed by B3LYP/DGDZVP DFT calculation, thus supporting the observed ¹H NMR NOESY cross peaks.     

An epigenetic modifier enhances the production of anti-diabetic and anti-inflammatory sesquiterpenoids from Aspergillus sydowii

The addition of a DNA methyltransferase inhibitor, 5-azacytidine, to Aspergillus sydowii fungus culture broth changed its secondary metabolites profile. Analysis of the culture broth extract led to the isolation of three new bisabolane-type sesquiterpenoids: (7S)-(+)-7-O-methylsydonol (1), (7S,11S)-(+)-12-hydroxysydonic acid (2) and 7-deoxy-7,14-didehydrosydonol (3), along with eight known compounds. The isolated compounds were evaluated for their anti-diabetic and anti-inflammatory activities. Among the isolates, (S)-(+)-sydonol (4) did not only potentiate insulin-stimulated glucose consumption but also prevented lipid accumulation in 3T3-L1 adipocytes. Additionally, (S)-(+)-sydonol (4) exhibited significant anti-inflammatory activity through inhibiting superoxide anion generation and elastase release by fMLP/CB-induced human neutrophils. This is the first report on isolating a secondary metabolite with anti-diabetic and anti-inflammatory activities from microorganisms.     

Enantiomeric trans β-aryl-δ-iodo-γ-lactones derived from 2,5-dimethylbenzaldehyde induce apoptosis in canine lymphoma cell lines by downregulation of anti-apoptotic Bcl-2 family members Bcl-xL and Bcl-2

For many years, studies focused on developing new natural or synthetic compounds with antineoplastic activity have attracted the attention of researchers. An interesting group of such compounds seem to be those with both lactone moiety and an aromatic ring which, in addition to antimicrobial or antiviral activity, also exhibit antitumor properties. The study shows antitumor activity of two enantiomeric trans isomers of 5-(1-iodoethyl)-4-(2′,5′-dimethylphenyl)dihydrofuran-2-one. Our aim was to determine their antitumor activity manifested as an ability to induce apoptosis in selected canine cancer cell lines as well as to evaluate differences in their strength depending on the configuration of their stereogenic centers. The enantiomers (+)-(4R,5S,6R)-1 and (?)-(4S,5R,6S)-2 were found to induce classical caspase-dependent apoptosis through downregulation of the expression of anti-apoptotic proteins Bcl-xL and Bcl-2. Although the mechanism of apoptosis induction was the same for both enantiomers, they differed in their strength, as stronger antineoplastic activity in vitro was exhibited by isomer (+)-(4R,5S,6R)-1.     

Synthesis and characterization of pyridoxine,nicotine and nicotinamide salts of dithiophosphoric acids as antibacterial agents against resistant wound infection

The pyridine-derived biomolecules are of considerable interest in developing medicinal compounds with various specific activities. Novel ammonium salts of pyridoxine, (S)-(–)-nicotine and nicotinamide with O,O-diorganyl dithiophosphoric acids (DTPA) were synthesized and characterized. The complexation of chiral monoterpenyl DTPA, including (S)-(–)-menthyl, (R)-(+)-menthyl, (1R)-endo-(+)-fenchyl, (1S,2S,3S,5R)-(+)-isopinocampheolyl derivatives, with pyridoxine and nicotine provided effective antibacterial compounds 3a,b,e,f, and 5a,b,d,f with MIC values against Gram-positive bacteria as low as 10?µM (6?µg/mL). Two selected pyridoxine and nicotine salts based on menthyl DTPA 3a and 5a were similarly active against antibiotic-resistant bacteria from burn wounds including MRSA. The compounds had enhanced amphiphilic and hemolytic properties and effectively altered surface characteristics and matrix-secreting ability of P. aeroginosa and S. aureus. MBC/MIC ratios of 3a and 5a suggested the bactericidal mode of their action. Furthermore, the compounds exhibited moderate cytotoxicity towards human skin fibroblasts (IC₅₀?=?48.6 and 57.6?µM, respectively, 72?h), encouraging their further investigation as potential antimicrobials against skin and wound infections.     

Ulmosides A and B: Flavonoid 6-C-glycosides from Ulmus wallichiana,stimulating osteoblast differentiation assessed by alkaline phosphatase

Chemical investigation of Ulmus wallichiana stem bark resulted in isolation and identification of three new compounds (2S,3S)-(+)-3′,4′,5,7-tetrahydroxydihydroflavonol-6-C-β-d-glucopyranoside (1), (2S,3S)-(+)-4′,5,7-trihydroxydihydroflavonol-6-C-β-d-glucopyranoside (3) and 3-C-β-d-glucopyranoside-2,4,6-trihydroxymethylbenzoate (8), together with five known flavonoid-6-C-glucosides (2, 4–7). Their structures were elucidated using 1D and 2D NMR spectroscopic analysis. The absolute stereochemistry in compounds 1 and 3 were established with the help of CD data analysis and comparison with the literature data analysis. All the isolated compounds (1–8) were assessed for promoting the osteoblast differentiation using primary culture of rat osteoblast as an in vitro system. Compounds 1–3 and 5 significantly increased osteoblast differentiation as assessed by alkaline phosphatase activity.     

Aporphine alkaloids and cytotoxic lignans from the roots of Illigera luzonensis

Six aporphine alkaloids, (+)-(S)-N-butyrylcaaverine (1), (+)-(S)-N-propionylcaaverine (2), (+)-(S)-N-acetylcaaverine (3), (+)-(6aR,7R)-N-butyrylnorushinsunine (4), (+)-(6aR,7R,E)-N-(but-2-enoyl)norushinsunine (5), and N-formyldehydrocaaverine (6) were isolated from the roots of Illigera luzonensis, together with 16 known compounds. Their structures were determined through spectroscopic and MS analyses. Among the isolates, (−)-deoxypodophyllotoxin (13) was the most cytotoxic, with IC₅₀ values of 0.0057, 0.0067, 0.00004, and 0.0035 μg/mL, respectively, against DLD-1, CCRF-CEM, HL-60, and IMR-32 cell lines. In addition, (−)-yatein (12) exhibited cytotoxic effects, with IC₅₀ values of 0.81, 0.20, and 0.59 μg/mL, respectively, against DLD-1, CCRF-CEM, and HL-60 cell lines.     

Synthesis of 2- (and 6-) -dithian-2-yluracil nucleosides and their conversion into nucleoside derivatives

Addition of 2,2′-anhydro-[1-(3-O-acetyl-5-O-trityl-β-D-arabinofuranosyl)uracil] (1) to excess 2-litho-1,3-dithiane (2)in oxolane at ?78° gave 2-(1,3-dithian-2-yl)-1-(5-O-trityl-β-D-arabinofuranosyl)-4(1H)pyrimidinone (3), O²,2′-anhydro-5,6-di-hydro-6-(S)-(1,3-dithian-2-yl)-5′-O-trityluridine (4), and 2-(1,4-dihydroxybutyl)-1,3-dithiane (5) in yields of 15, 30, and 10% respectively. The structure of 3 was proved by its hydrolysis in acid to give 2-(1,3-dithian-2-yl)-4-pyrimidinone (6) and arabinose, and by desulfurization with Raney nickel to yield the known 2-methyl-1-(5-O-trityl-β-D-arabinofuranosyl)-4(1H)-pyrimidinone (7). Detritylation of 3 without glycosidic cleavage could only be effected by prior acetylation to 1-(2,3-di-O-acetyl-5-O-trityl-β-D-arabinofuranosyl)-2-(1,3-dithian-2-yl)-4(1H)-pyrimidinone (8) which, after treatment with acetic acid at room temperature for 65 h followed by the action of sodium methoxide gave 2-(1,3-dithian-2-yl)-1-β-D-arabinofuranosyl-4(1H)-pyrimidinone (10) in 45% yield. Detritylation of 4 in boiling acetic acid gave 5,6-dihydro-6-(S)-(1,3-dithian-2-yl)-1-β-D-arabinofuranosyluracil (12) and 3-[(S)-1-(1,3-dithian-2-yl)]propionamido-(1,2-dideoxy-β-D-arabinofurano)-[1,2-d]-2-oxazolidinone (13) in 10 and 90% yields, respectively. When 12 was kept in water or methanol for 7 days, quantitative conversion into 13 occurred. Acid hydrolysis of 12 afforded arabinose and 5,6-di-hydro-6-(1,3-dithian-2-yl)uracil (14), which was desulfurized with Raney nickel to the known 5,6-dihydro-6-methyluracil (15). Treatment of 13 with trifluoroacetic anhydride-pyridine yielded 77% of the cyano derivative 17. Similar dehydration of 3-(R)-1-methylpropionamido-(1,2-dideoxy-β-D-arabinofurano)-[1,2-d]-2-oxalidinone (18), obtained by desulfurization of 13, gave 60% of the nitrile 19. Hydrogenation of 19 over platinum oxide in acetic anhydride gave the acetamide derivative 20 in 95% yield. Nitrobenzoylation of 13 gave 3-[(S)-1-(1,3-dithian-2-yl)]cyanomethyl-3,5-di-O-p-nitrobenzoyl-(1,2-dideoxy-β-D-arabinofurano)-[1,2-d]-2-oxazolidinone (22), which was converted in 37% yield by treatment with methyl iodide in dimethyl sulfoxide into the aldehyde 24, characterized as the semicarbazone 25. The purification of 5 and its characterization as 2-(1,4-di-O-p-nitrobenzoylbutyl)-1,3-dithiane (27) is described.     

Novel fluorinated pyrrolo[1,2-a]pyrazine-2,6-dione derivatives: Synthesis and anticonvulsant evaluation in animal models of epilepsy

A series of fluorinated analogs of the potent investigative anticonvulsant agent (4S,8aS)-4-phenylperhydropyrrolo[1,2-a]pyrazine-2,6-dione 1 was prepared and characterized by IR, ¹H, ¹³C NMR and mass spectral data. The compounds have been evaluated in the in vivo rodent models of epilepsy. They displayed high activity in the ‘classical’ maximal electroshock seizure (MES) and subcutaneous Metrazol (scMET) tests as well as in the 6 Hz model of pharmacoresistant limbic seizures. The results showed that incorporating fluorine atoms into the phenyl ring of 1 can be beneficial for the anticonvulsant potency. The most promising meta-trifluoromethyl and meta-trifluoromethoxy derivatives (4S,8aS)-5h and (4S,8aS)-5l, respectively, displayed very broad spectra of activity across the preclinical seizure models.     

Structure-activity relationship study towards non-peptidic positron emission tomography (PET) radiotracer for gastrin releasing peptide receptors: Development of [18F] (S)-3-(1H-indol-3-yl)-N-[1-[5-(2-fluoroethoxy)pyridin-2-yl]cyclohexylmethyl]-2-methyl-2-[3-(4-nitrophenyl)ureido]propionamide

Gastrin-releasing peptide receptors (GRP-Rs, also known as bombesin 2 receptors) are overexpressed in a variety of human cancers, including prostate cancer, and therefore they represent a promising target for in vivo imaging of tumors using positron emission tomography (PET). Structural modifications of the non-peptidic GRP-R antagonist PD-176252 ((S)-1a) led to the identification of the fluorinated analog (S)-3-(1H-indol-3-yl)-N-[1-[5-(2-fluoroethoxy)pyridin-2-yl]cyclohexylmethyl]-2-methyl-2-[3-(4-nitrophenyl)ureido]propionamide ((S)-1m) that showed high affinity and antagonistic properties for GRP-R. This antagonist was stable in rat plasma and towards microsomal oxidative metabolism in vitro. (S)-1m was successfully radiolabeled with fluorine-18 through a conventional radiochemistry procedure. [¹⁸F](S)-1m showed high affinity and displaceable interaction for GRP-Rs in PC3 cells in vitro.     

Synthesis of 6-substituted uridines. synthesis of (R or S)-6-(3-amino-2-carboxypropyl)uridine

Addition of 5-bromo-2′,3′-O-isopropylidene-5′-O-trityluridine (2) in pyridine to an excess of 2-lithio-1,3-dithiane (3) in oxolane at 78° gave (6R)-5,6-dihydro-(1,3-dithian-2-yl)-2′,3′-O-isopropylidene -5′-O-trityluridine (4), (5S,6S)-5-bromo-5,6-dihydro-(1,3-dithian-2-yl)-2′,3′-O-isopropylidene-5′-O-trityluridine (5), and its (5R) isomer 6 in yields of 37, 35, and 10%, respectively. The structure of 4 was proved by Raney nickel desulphurization to (6S)-5,6-dihydro-2′,3′-O-isopropylidene-6-methyl-5′-O-trityluridine (7) and by acid hydrolysis to give D-ribose and (6R)-5,6-dihydro-6-(1,3-dithian-2-yl)uracil (9). Treatment of 4 with methyl iodide in aqueous acetone gave a 30&%; yield of (R,S)-5,6-dihydro-6-formyl-2′,3′-O-isopropylidene-5′-O-trityl-uridine (10), characterized as its semicarbazone 11. Both 5 and 6 gave 4 upon brief treatment with Raney nickel. Both 5 and 6 also gave 6-formyl-2′,3′-O-isopropylidene-5′- O-trityluridine (12) in ～41%; yield when treated with methyl iodide in aqueous acetone containin- 10%; dimethyl sulfoxide. A by-product, identified as the N-methyl derivative (13) of 12 was also formed in yields which varied with the amount of dimethyl sulfoxide used. Reduction of 12 with sodium borohydride, followed by deprotection, afforded 6-(hydroxymethyl)uridine (17), characterized by hydrolysis to the known 6-(hydroxymethyl)uracil (18). Knoevenagel condensation of a mixture of the aldehydes 12 and 13 with ethyl cyanoacetate yielded 38%; of E- (or Z-)6-[(2-cyano-2-ethoxycarbonyl)ethylidene]-2′,3′-O-isopropylidene-5′-O-trityluridine (19) and 10%; of its N-methyl derivative 20. Hydrogenation of 19 over platinum oxide in acetic anhydride followed by deprotection gave R (or S)-6-(3-amino-2-carboxypropyl)uridine (23).     

Evaluation of enantioselectivity in lipase-catalyzed acylation of hydroxyalkylphosphine oxides

The lipase-catalyzed optical resolution of 2-, 3-, and 5-hydroxyalkyl phosphorus compounds 1 provided the corresponding optically pure diastereomers in good yields. (S_P, R)- and (R_P, S)-1 were acylated faster than (S_P, S)- and (R_P, R)-1. The stereoselectivity at the phosphorus atom changed with the flexibility of the active sites in the lipases. The stereoselectivity at the phosphorus atom was higher in the reaction of 1a than in the reaction of 1b,c. The reaction rate of ɛ-hydroxyalkylphosphine oxide 1c was faster than that of 1a, although less enantioselectivity was observed at the phosphorus atom.     

Abietane diterpenoids from Isodon inflexus

Four abietane diterpenoids, inflexanin C, inflexanin D, inflexuside A and inflexuside B, were isolated from the aerial parts of Isodon inflexus. Their respective structures were established by NMR, mass spectrometry and CD as (+)-(1S,4R,5S,7S,8S,10S,13S)-1,7,18-trihydroxy-abieta-9(11)-ene-12-one 1-monoacetate, (+)-(1S,4R,5S,10S,13S)-1,18-dihydroxy-abieta-7,9(11)-diene-12-one 1-monoacetate, (−)-(1S,5S,10S,11R,13R)-1,11,13-trihydroxy-abieta-8-ene-7-one 1-O-β-d-glucopyranoside and (−)-(1S,5S,10S,11R,13R)-1,11,13-trihydroxy-abieta-8-ene-7-one 1-O-(2-O-coumaroyl)-β-d-glucopyranoside. All compounds showed strong inhibitory activity against nitric oxide (NO) production in RAW264.7 lipopolysaccaride (LPS)-activated macrophages.     

N-Acetyldopamine derivatives from Periostracum Cicadae

Five new N-acetyldopamine (NADA) derivatives (1–5) and one known NADA quinone methide (6) were isolated from Periostracum Cicadae (the cast-off shell of the cicada Cryptotympana pustulata Fabricius), which is known as chantui in China and is used in traditional Chinese medicine to treat soreness of the throat, hoarseness, itching, and spasms. By combined analysis of one-dimensional and two-dimensional nuclear magnetic resonance (NMR) spectroscopy, mass spectrometry, CD spectra, and chemical evidence, the structures of the isolated compounds were established as (R)-N-(2-(3,4-dihydroxyphenyl)-1-ethoxy-2-oxoethyl)acetamide (1), (1R,2R)-N-(1,2-diethoxy-2-(3,4-dihydroxyphenyl)-ethyl)acetamide (2), (R)-N-(1-acetamido-2-ethoxy-2-(3,4-dihydroxyphenyl)-ethyl)acetamide (3), (1R,2R)-N-(2-(3,4-dihydroxyphenyl)-2-ethoxy-1-methoxyethyl)acetamide (4), (1S,2S)-N-(2-(3,4-dihydroxyphenyl)-2-ethoxy-1-methoxyethyl)acetamide (5), and (R)-N-(2-(3,4-dihydroxyphenyl)-2-methoxyethyl)acetamide (6).     

Polyhydroxylated azetidine iminosugars: Synthesis,glycosidase inhibitory activity and molecular docking studies

An efficient and practical strategy for the synthesis of unknown azetidine iminosugars (2S,3R,4S)-2-((R)-1,2-dihydroxyethyl)-3-hydroxy-4-(hydroxymethyl)azetidine 2, (2S,3r,4R)-3-hydroxy-2,4-bis(hydroxymethyl)azetidine 3 and (2S,3R,4S)-3-hydroxy-4-(hydroxymethyl)-N-methylazetidine-2-carboxylic acid 4, starting from the d-glucose has been reported. The methodology involves preparation of the 3-amino-N-benzyloxycarbonyl-3-deoxy-6-O-tert-butyldimethylsillyl-1,2-O-isopropylidene-α-d-glucofuranose 9, which was converted to the C-5-OMs derivative 11. Intramolecular nucleophilic displacement of the C-5-OMs group with in situ generated 3-amino functionality provided the required key azetidine ring skeletons 10 with additional hydroxymethyl group. Removal of 1,2-acetonide protection, followed by reduction and hydrogenolysis afforded azetidine iminosugar 2. Alternatively, removal of 1,2-acetonide group and chopping of C1-anomeric carbon gave C2-aldehyde that on reduction or oxidation followed by hydrogenolysis gave 2,4-bis(hydroxymethyl) azetidine iminosugars 3 and N-methylazetidine-2-carboxylic acid 4 respectively. The glycosidase inhibitory activity of 2–4 iminosugars was screened against various glycosidase enzymes and compared with a standard miglitol. Amongst synthesized targets, the compound 2 was found to be more potent amyloglucosidase inhibitor than miglitol. These results were supported by molecular docking studies.     

Two new guaiane sesquiterpenes from Datura metel L. with anti-inflammatory activity

Chemical investigation of an acidic methanol extract of the whole plants of Datura metel resulted in the isolation of two new guainane sesquiterpenes, 1β,5α,7β-guaiane-4β,10α,11-triol (1) and 1α,5α,7α-11-guaiene-2α,3β,4α,10α,13-pentaol (2), along with eight known compounds: pterodontriol B (3), disciferitriol (4), scopolamine (5), kaempferol 3-O-β-d-glucosyl(1 → 2)-β-d-galactoside 7-O-β-d-glucoside (6), kaempferol 3-O-β-glucopyranosyl(1 → 2)-β-glucopyranoside-7-O-α-rhamnopyranoside (7), pinoresinol 4′′-O-β-d-glucopyranoside (8), (7R,8S,7′S,8′R)-4,9,4′,7′-tetrahydroxy-3,3′-dimethoxy-7,9′-epoxy-lignan-4-O-β-d-glucopyranoside (9), and (7S,8R,7′S,8′S)-4,9,4′,7′-tetrahydroxy-3,3′-dimethoxy-7,9′-epoxylignan-4-O-β-d-glucopyranoside (10). Their structures were elucidated by extensive spectroscopic methods, including 1D and 2D NMR and MS spectra. Compounds 2-4 and 6-10 were shown to have modest anti-inflammatory effects through inhibition of NO production in LPS-stimulated BV cells.     

Two new dihydrobenzofuran-type neolignans from Breynia fruticosa

(7S,8R,7′S)-9,7′,9′-Trihydroxy-3,4-methylenedioxy-3′-methoxy [7-O-4′,8-5′] neolignan (1) and (7S,8R,7′S)-9,9′-dihydroxy-3,4-methylenedioxy-3′,7′-dimethoxy [7-O-4′,8-5′] neolignan (2), two new natural dihydrobenzofuran-type neolignans, along with 9,9′-dihydroxy-3,4-methylenedioxy-3′-methoxy [7-O-4′,8-5′] neolignan (3) and (-)-machicendiol (4), were isolated from the whole plants of Breynia fruticosa. The structures of 1 and 2, including the absolute configurations, were determined by spectroscopic methods and circular dichroism (CD) techniques. The absolute configuration of 4 was confirmed by calculations of the OR spectrum, together with OR and ECD spectra of its p-bromobenzoate ester (4a).     

New cytotoxic dihydrochalcone and steroidal saponins from the aerial parts of Sansevieria cylindrica Bojer ex Hook

A new dihydrochalcone, 2‘,4‘-dihydroxy-3‘-methoxy-3,4-methylenedioxy-8-hydroxymethylene dihydrochalcone 1 and two new steroidal saponins, (25S)-ruscogenin-1-O-α-l-rhamnopyranosyl-(1 → 2)-β-d-glucopyranoside 2, (25S)-ruscogenin-3-O-α-l-rhamnopyranosyl-(1 → 4)-β-d-glucopyranoside 3, together with three known steroidal saponins (25S)-ruscogenin-3-O-β-d-glucopyranoside 4, (25S)-ruscogenin-1-O-α-l-rhamnopyranosyl-(1 → 2)-[β-d-xylopyranosyl-(1 → 3)]-α-l-arabinopyranoside 5 and (25R)-26-O-β-d-glucopyranosyl-furost-5-ene-1β,3β,22α,26-tetrol-1-O-α-L-rhamnopyranosyl-(1 → 2)-[β-d-xylopyranosyl-(1 → 3)]-α-l-arabinopyranoside 6 were isolated from the aerial parts of Sansevieria cylindrica. The structures of the new compounds were established by UV, IR, EI-MS, HR-ESI–MS as well as 1D (¹H,¹³C and DEPT-135) and 2D (HSQC, HMBC and TOCSY) NMR spectral analysis. The isolated compounds 1-6 were assayed for in vitro cytotoxicities against the three human tumor cell lines HT116, MCF7 and HepG2. Compound 1 showed a moderate cytotoxicity against MCF7. Compounds 2, 3 and 6 exhibited moderate cytotoxicities against the three used cell lines and compound 5 showed marked cytotoxicities against all used cell lines.     

Fatty acid derivatives and dammarane triterpenes from the glandular trichome exudates of Ibicella lutea and Proboscidea louisiana

Ibicella lutea and Proboscidea louisiana, both of the Martyniaceae family, are known for rich glandular trichomes on their leaves and stems. Chemical investigations of the glandular trichome exudates on leaves of the two plants furnished three types of secondary metabolites, glycosylated fatty acids, glycerides (2-O-(3,6-diacetyloxyfattyacyl)glycerols and 2-O-(3-acetyloxyfattyacyl)glycerols) and dammarane triterpenes. The glycosylated fatty acids from I. lutea were determined to be 6(S)-(6-O-acetyl-β-d-glucopyranosyloxy)-octadecanoic acid (1A), -eicosanoic acid (1B) and -docosanoic acid (1C), as well as their respective deacetyl congeners (2A, 2B and 2C), whereas P. louisiana furnished 8(S)-(6-O-acetyl-β-d-glucopyranosyloxy)-eicosanoic acid (3A) and -docosanoic acid (3B) and their respective deacetyl congeners (4A and 4B), together with 2B. Both plants contained 12 identical 2-O-[(3R,6S)-3,6-diacetyloxyfattyacyl]glycerols (5A-L), in which the fatty acyl moieties contained between 17 and 21 carbon atoms. The corresponding mono-acetyloxy compounds, 2-O-[(3R)-3-acetyloxyfattyacyl]glycerols (6A–L) were detected in both plants. Among these glycerides, ten compounds (5A, 5C, 5F, 5H, 5K, 6A, 6C, 6F, 6H and 6K) had iso-fattyacyl structures and four (5E, 5J, 6E and 6J) had anteiso-fattyacyl structures. A previously unknown dammarane triterpene, betulatriterpene C 3-acetate (7), was isolated together with three known dammarane triterpenes, 24-epi-polacandrin 1,3-diacetate (8), betulatriterpene C (9) and 24-epi-polacandrin 3-acetate (10) from I. lutea, whereas 12 dammarane triterpenes, named probosciderols A–L (12–23), and the known compound betulafolienetriol (11) were isolated from P. louisiana. The structures of these compounds were elucidated by spectroscopic analysis including 2D-NMR techniques and chemical transformations. The 6-O-acetylglucosyloxy-fatty acids 1A–C (42%) and the dammarane triterpenes 7–10 (31%) were the two most abundant constituents in the glandular trichome exudate of I. lutea, whereas the dammarane triterpenes 11–23 (47%) and the glucosyloxy-fatty acids (4A, 4B and 2B) (38%) were the most abundant constituents in the glandular trichome exudate of P. louisiana.     

Microbial alcohol dehydrogenase screening for enantiopure lactone synthesis: Down-stream process from microtiter plate to bench bioreactor

One-pot conversion with whole cells of bacteria was performed for biooxidation of meso monocyclic (3a–b) and bicyclic diols (3c–e) into corresponding chiral lactones of bicyclo[4.3.0]nonane structure (2a–b) as well as exo- and endo-bridged lactones with the structure of [2.2.1] (3c–d) and [2.2.2] (3e). Micrococcus sp. DSM 30771 was selected as biocatalyst with significant alcohol dehydrogenase activity. Among tested strains, microbial oxidation of meso diols 3a–e catalyzed by Micrococcus sp. afforded enantiomerically pure ((+)-(2S,3R)-2c (ee = 99%), (+)-(2S,3R)-2e (ee = 99%)) or enriched ((+)-(1S,5R)-2a (ee = 90%), (−)-(1S,5R)-2b (ee = 86%), (+)-(2S,3R)-2d (ee = 80%)) lactone moieties. Comparative study with respect to microbial cultivation as well as biooxidation was undertaken to verify agreement of secondary metabolite biosynthesis in different scales: from MTP (4 mL), across shake flask (100 mL) till bioreactor (4 L). The results from biotransformations showed quite similar dependence in oxidation of all substrates 3a–e in MTP and flasks as well, thereby confirmed the validity and reasonable approach of using MTP for preliminary studies.