Dihydrofurocoumarin glucosides from Angelica archangelica and Angelica silvestris

A water-soluble root extract of Angelica archangelica subsp. litoralis afforded, in addition to adenosine, coniferin and the two known dihydrofurocoumarin glycosides, apterin and 1′-O-β-d-glycopyranosyl-(S)-marmesin (marmesinin), two new dihydrofuranocoumarin glycosides, 1′-O-β-d-glucopyranosyl-(2S, 3R)-3-hydroxymarmesin, and 2′-β-d-glucopyranosyloxymarmesin. For the latter a 2S-configuration was demonstrated, the stereochemistry at position 1′ remaining undefined. Roots of A. silvestris similarly afforded 1′-O-β-d-glucopyranosyl-(2S, 3R)-3-hydroxymarmesin. By correlation with the aglycone 2S,3R)-3-hydroxymarmesin obtained in this work, the absolute configurations (2S,3R) were established for the known dihydrofurocoumarin diesters smirniorin and smirnioridin.     

Cyanogenic and non-cyanogenic pyridone glucosides from Acalypha indica (Euphorbiaceae)

Seven cyanopyridone derivatives and one corresponding seco compound have been isolated from a methanolic extract of the inflorescences and leaves of Acalypha indica L. (Euphorbiaceae). The absolute configuration of the main cyanogenic glucoside acalyphin, (−)-(5R,6S)-5-cyano-5-β-d-glucopyranosyloxy-6-hydroxy-4-methoxy-1-methyl-2(5,6-dihydro)-pyridone, was deduced from an X-ray crystallographic study. In addition, the 6R-epimer of acalyphin, epiacalyphin, and the corresponding pair of N-demethyl derivatives were isolated. The corresponding amide of acalyphin and a 1′,2′-glucosyl-fused epiacalyphin amide were isolated from air-dried material. Structural elucidation was performed by means of ¹H and ¹³C NMR-spectra, chiroptical methods such as CD-spectroscopy and optical rotation. Two further corresponding derivatives, an aromatized compound and an open-chain structure, were isolated from the aqueous phase.     

Complexes containing the (R,R)-N,N-bis(2-hydroxy-3-functionalised-benzylidene)-1,2-diaminocyclohexane ligand: synthesis and X-ray analyses of titanium chloro and oxo derivatives

Titanium complexes based on the (R,R)-N,N^′-bis(2-hydroxy-3-functionalised-benzylidene)-1,2-diaminocyclohexane ligand and containing either chloro or bridged oxo co-ligands have been prepared, subjected to single crystal X-ray analysis and examined as pre-catalysts for the asymmetric phospho-aldol (PA) reaction. Catalysis does take place although at a much slower rate than with related aluminium complexes and then only to afford racemic products; significant observations that lead to an important design point in PA pre-catalysts.     

Synthesis and structure of dichloropalladium(II) complexes of heteroleptic N,S- and N,Se-donor ligands based on the 2-organochalcogenomethylpyridine motif, and Mizoroki-Heck catalysis mediated by complexes of N,S-donor ligands

Ligands containing the 2-organochalcogenomethylpyridine motif with substituents in the 4- or 6-position of the pyridyl ring, R⁴,R⁶-pyCH₂ER¹ [R⁴ = R⁶ = H, ER¹ = SMe (1), SeMe (2), SPh (6), SePh (7); R⁴ = Me, R⁶ = H, ER¹ = SMe (3), SPh (8), SePh (9); R⁴ = H, R⁶ = Me, ER¹ = SMe (4), SPh (10), SePh (11); R⁴ = H, R⁶ = Ph, ER¹ = SMe (5), SPh (12), SePh (13)] are obtained on the reaction of R⁴,R⁶-pyMe with LiBuⁿ followed by R¹EER¹. On reaction with PdCl₂(NCMe)₂, the ligands with a 6-phenyl substituent form cyclopalladated species PdCl{6-(o-C₆H₄)pyCH₂ER¹-C,N,E} (5a, 12a, 13a) with the structure of 13a (ER¹ = SePh) confirmed by X-ray crystallography; other ligands form complexes of stoichiometry PdCl₂(R⁴,R⁶-pyCH₂ER¹). Complexes with R⁶ = H are monomeric with N,E-bidentate configurations, confirmed by structural analysis for 3a (R⁴ = Me, ER¹ = SMe), 7a (R⁴ = H, ER¹ = SePh) and 9a (R⁴ = Me, ER¹ = SePh). Two of the 6-methyl substituted complexes examined by X-ray crystallography are oligomeric with trans-PdCl₂(N,E) motifs and bridging ligands, trimeric [PdCl₂(μ-6-MepyCH₂SPh-N,S)]₃ (10a) and dimeric [PdCl₂(μ-6-MepyCH₂SePh-N,Se)]₂ (11a). This behaviour is attributed to avoidance of the Me···Cl interaction that would occur in the cis-bidentate configuration if the pyridyl plane had the same orientation with respect to the coordination plane as observed for 3a, 7a and 9a [dihedral angles 8.0(2)-16.8(2)°]. When examined as precatalysts for the Mizoroki-Heck reaction of n-butyl acrylate with aryl halides in N,N-dimethylacetamide at 120 °C, the complexes exhibit the anticipated trends in yield (ArI > ArBr > ArCl, higher yield for electron withdrawing substituents in 4-RC₆H₄Br and 4-RC₆H₄Cl). The most active precatalysts are PdCl₂(R⁴-pyCH₂SMe-N,S) (R = H (1a), Me (3a)); complexes of the selenium containing ligands exhibit very low activity. For closely related ligands, the changes SMe to SPh, 6-H to 6-Me, and 6-H to 6-Ph lead to lower activity, consistent with involvement of both the pyridyl and chalcogen donors in reactions involving aryl bromides. The precatalyst PdCl₂(pyCH₂SMe-N,S) (1a) exhibits higher activity for the reaction of aryl chlorides in Buⁿ₄NCl at 120 °C as a solvent under non-aqueous ionic liquid (NAIL) conditions.     

Preparation, properties and crystal structure of two isomers of R,R,S,S- and R,S,R,S-[chloro(1,3,10,12,16,19-hexaazatetracyclo[17,3,1,1,0]tetracosane)copper(II)]

Two isomers (R,S,R,S- and R,R,S,S-) of five coordinate complex [Cu(L)Cl]⁺ have been separated and characterised. These two isomers have significantly different spectrochemical and electrochemical properties. Absorption maximum of R,S,R,S-[Cu(L)Cl]⁺ shifts to longer wavelength and its reduction potential shifts to more positive direction comparing those of R,R,S,S-[Cu(L)Cl]⁺. R,S,R,S-[Cu(L)Cl]⁺ is significantly distorted to trigonal-bipyramidal structure, whereas R,R,S,S-[Cu(L)Cl]⁺ retains almost square-planar geometry. The average bond distance of Cu-N in basal plane of R,S,R,S-[Cu(L)Cl]⁺ is longer by 0.024 Å than that of R,R,S,S-[Cu(L)Cl]⁺, whereas the bond distance of Cu-Cl in former is shorter by 0.200 Å than that in latter. The isolated square-planar complexes of R,R,S,S- and R,S,R,S-[Cu(L)](ClO₄)₂ are converted to the R,R,S,S- and R,S,R,S-[Cu(L)Cl]⁺ by the addition of Cl⁻ in nitromethane solution with the rate constants, k=1.70 (±0.02) and 8.31 (±0.07) M⁻¹ s⁻¹, respectively.     

Development of selective inhibitors for the treatment of rheumatoid arthritis: (R)-3-(3-(Methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)-3-oxopropanenitrile as a JAK1-selective inhibitor

A series of 3(R)-aminopyrrolidine derivatives were designed and synthesized for JAK1-selective inhibitors through the modification of tofacitinib’s core structure, (3R,4R)-3-amino-4-methylpiperidine. From the new core structures, we selected (R)-N-methyl-N-(pyrrolidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine as a scaffold for further SAR studies. From biochemical enzyme assays and liver microsomal stability tests, (R)-3-(3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)-3-oxopropanenitrile (6) was chosen for further in vivo test through oral administration. Compound 6 showed improved selectivity for JAK1 compared to that of tofacitinib (IC₅₀ 11, 2.4?×?10², 2.8?×?10³, and 1.1?×?10²?nM for JAK1, JAK2, JAK3, and TYK2, respectively). In CIA and AIA model tests, compound 6 exhibited similar efficacy to tofacitinib citrate.     

Cytotoxic quinazoline alkaloids from the seeds of Peganum harmala

Seventeen quinazoline alkaloids and derivatives, containing two pairs of new epimers, named as (S)- and (R)-1-(2-aminobenzyl)-3-hydroxypyrrolidin-2-one β-d-glucopyranosyl-(1?→?6)-β-d-glucopyranoside (1, 2), (S)- and (R)-vasicinone β-d-glucopyranosyl-(1?→?6)-β-d-glucopyranoside (3, 4), and a new enantiomer (12b), together with six known ones (5–8, 10, and 12a), and three pairs of known enantiomers (9, 11, and 13), were isolated from the ethanol extracts of the seeds of Peganum harmala L.. Their structures including the absolute configuration were elucidated by using 1D and 2D NMR, and ECD calculation approaches. The cytotoxic activities of all isolated compounds were evaluated. 11 showed moderate cytotoxicity against PC-3 cells with an IC₅₀ value of 15.41?μM.     

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.     

Structural elucidation and partial synthesis of 3-hydroxyheterodendrin,a cyanogenic glucoside from Acacia sieberiana var. woodii

A new cyanogenic glucoside, isolated from pods of Acacia sieberiana var. woodii, was shown to be (2R)-2- (β-d-glucopyranosyloxy)-3-hydroxy-3-methylbutanenitrile by spectroscopic and chemical methods. The absolute configuration of this glucoside was correlated with that of proacacipetalin by oxymercuration of the latter, followed by borohydride reduction of the product.     

Antimalarial sesquiterpene lactones from Distephanus angulifolius

Combined use of bioassay-guided fractionation based on in vitro antiplasmodial assay and dereplication based on HPLC-PDA-MS-SPE-NMR led to isolation of (6S,7R,8S)-14-acetoxy-8-[2-hydroxymethylacrylat]-15-helianga-1(10),4,11(13)-trien-15-al-6,12-olid and (5R,6R,7R,8S,10S)-14-acetoxy-8-[2-hydroxymethylacrylat]-elema-1,3,11(13)-trien-15-al-6,12-olid, along with vernodalol, vernodalin, and 11,13β-dihydroxyvernodalin from extract of Distephanus angulifolius. All compounds were identified by spectroscopic methods, including 1D and 2D homo- and heteronuclear NMR experiments. The isolated compounds showed IC₅₀ values in the range 1.6-3.8 μM and 2.1-4.9 μM against chloroquine sensitive D10 and chloroquine resistant W2 Plasmodium falciparum strains, respectively.     

Stereochemical and structural effects of (2R,6R)-hydroxynorketamine on the mitochondrial metabolome in PC-12 cells

Background

Impairment in mitochondrial biogenesis and function plays a key role in depression and anxiety, both of which being associated with changes in fatty acid and phospholipid metabolism. The antidepressant effects of (R,S)-ketamine have been linked to its conversion into (2S,6S;2R,6R)-hydroxynorketamine (HNK); however, the connection between structure and stereochemistry of ketamine and HNK in the mitochondrial homeostatic response has not yet been fully elucidated at a metabolic level.

(8R,14S)-8-angeloyloxythapsan-14-ol,a sesquiterpene with a novel carbon skeleton,from Thapsia villosa

The roots of Thapsia villosa afforded in addition to other terpenoids, a sesquiterpene, with a new carbon skeleton. The structure, including the relative configuration, was elucidated by spectroscopic methods, a few chemical transformations and by X-ray analysis. The absolute configuration was determined by means of the method of Horeau. The trivial name thapsan is suggested for the parent structure [2aR,2bR,6aS,7aS]-2b,3,3,6a-tetramethylperhydroindeno[2,3-c]-furan.     

Two sesquiterpene lactones from Trichogonia gardneri

The structures and stereochemistries of two sesquiterpene lactones from Trichogonia gardneri were established as (6R,7S,8S,9S,IOR)-4E-9,10-dihydroxy-8-tigloxygermacr-4-en-6,12-olide) and (5R*,6R*,7S*,8S*,9R*)-14-acetoxy-3-chloro-9-hydroxy-2-oxo-8-tigloxyguia-1(10),3-dien-6,12-of olide by a combination of NMR spectrometry and X-ray diffraction. The results show that the structures of several sesquiterpene lactones which were isolated previously from related species require revision.     

Lignans from Piper cubeba

From the hot petrol extract of Piper cubeba ftuits, six lignans were isolated. Two of these, which have been obtained from a natural source for the first time, have been characterized as (2R,3R)-2-(3″,4″,5″-trimethoxybenzyl)-3-(3′,4′-methylenedioxybenzyl)-1,4-butanediol [(?)-dihydroclusin] and (3R,4R)-3,4-bis-(3,4,5-trimethoxybenzyl)tetra-hydro-2-furanol [(?)-cubebinin]. (?)Cubebin, (?)-hinokinin, (?)-clusin and (?)-dihydrocubebin were also found in this plant. Only (?)-cubebin has been reported so far from this source.     

Absolute configuration of ceriporic acids, the iron redox-silencing metabolites produced by a selective lignin-degrading fungus, Ceriporiopsis subvermispora

Ceriporic acids are a class of alk(en)ylitaconic acids produced by a selective lignin-degrading fungus, Ceriporiopsis subvermispora. The unique function of alkylitaconic acid is the redox silencing of the Fenton reaction system by inhibiting reduction of Fe³⁺. Ceriporic acids have an asymmetric centre at carbon-3, but absolute configuration has not been determined. We have isolated a series of ceriporic acids from the cultures of C. subvermispora, and measured their NMR spectra using a chiral shift reagent. In comparison with NMR spectra of (R)-(−)- and (S)-(+)-methylsuccinic acid and those of natural and chemically synthesized racemic mixtures of ceriporic acids, we have determined the absolute configuration of ceriporic acids as (R)-3-tetradecylitaconic acid (ceriporic acid A), (R)-3-hexadecylitaconic acid (ceriporic acid B) and (R,Z)-2-(hexadec-7-enyl)-3-itaconic acid (ceriporic acid C). We herein discuss their stereoselective biosynthetic pathway and the structural diversity of fungal secondary metabolites.     

Cytotoxic lignans from Podophyllum, and the nomenclature of aryltetralin lignans

Roots of Podophyllum hexandrum and P. peltatum both contain (1R,2R,3R)-desoxypodophyllotoxin [(1α,2α,3β)- desoxypodophyllotoxin] and the previously unreported (1R,2R,3R)-podophyllotoxone [(1α,2α,3α)-podophyllotoxone]. Thermal isomerization of (loc,2ct,3fl)-podophyllotoxone readily occurs to yield (1α,2α,3α)-podophyllotoxone (isopicropodophyllone) with traces of (1α,2β,3β)-podophyllotoxone (picropodophyllone). Small amounts of (1α,2α,3α)-podophyllotoxone were also present in dried roots of P. hexandrum and P. peltatum. A more systematic nomenclature for podophyllotoxin derivatives and other aryltetralin lignans using α,β conventions is proposed.     

Flavonoids from Millettia pulchra

Chemical examination of Millettia pulchra yielded (?)-maackiain, (?)-pterocarpin, (?)-sophoranone and the new compounds (6S, 6aS, 11aR)-6α-methoxypterocarpin, (6S, 6aS,11aR)-6α-methoxyhomopterocarpin, (2S)5,7,4′-trihydroxy-8,3′,5′-triprenylflavanone, (2R,3R)7,4′-dihydroxy-8,3′,5′-triprenyldihydroflavanol, 5,7,2′,4′-tetrahydroxy-6,3′-diprenylisoflavone and 5,7,4′-trihydroxy-2′-methoxy-6,3′-diprenylisoflavone.     

Withanolides from Withania aristata and their cytotoxic activity

Seven new withanolides (1-7), along with three known ones (8-10), were isolated from the leaves of Withania aristata. Their structures were elucidated on the basis of spectroscopic analysis, including 2D NMR experiments and spectrometric techniques, and the absolute configuration of 1 and 2 was established by CD analysis. In the search for new cytotoxic compounds from Withania species, the isolated compounds 1-9, along with two derivatives, were assayed for their cytotoxicity against HeLa, MCF-7 and A-549 human tumor cell lines. Derivative (4S,20R,22R)-27-acetoxy-4-p-bromobenzoyloxy-1-oxo-witha-2,5,16,24-tetraenolide (13) showed cytotoxicity against all the cell lines assayed with IC₅₀ values ranging from 2.8 to 3.6 μM, and (4S,20R,22R)-4,27-diacetoxy-4-hydroxy-1-oxo-witha-2,5,16,24-tetraenolide (12) exhibited an IC₅₀ value of 5.4 μM on the MCF-7 cell line.     

Cycloartanes from Lindheimera texana

The following new cycloartanes were isolated from the aerial parts of Lindheimera texana: (16S,23S)- and (16S,23R)-16,23-epoxycycloart-24-en-3-one, (3S,16S,23S)- and (3S,16S,23R)-16,23-epoxycycloart-24-en-3ol, (16S,23R)-16,23-epoxy-23,25-epidioxycycloartan-3-one, (16S)-23,24,25,26,27-pentanorcycloartan-3-one-16,22-olide, (16S,23S,24R)- or (16S,23R,24S)-23,24-epoxycycloartan-3-one-16,25-diol and (16S,23ζ,24ζ)-cycloartan-3-one-16,23,24,25-tetrol. Structures were established by chemical transformations and spectroscopic methods and, in the case of (16S,23R)-16,23-epoxy-23,25-epidioxycycloartan-3-one, by X-ray crystallography. Norambreinolide, several known labdanes and oleanolic acid were also isolated.     

Five-coordinate zinc(II) complexes with optically active Schiff bases derived from (1R,2R)-(−)cyclohexanediamine: X-ray structure and CP MAS NMR characterization of [cyclohexylenebis(5-chlorosalicylideneiminato)zinc(II)pyridine] and [cyclohexylenebis(5-bromosalicylideneiminato)zinc(II)pyridine]

Schiff bases obtained from (1R,2R)-(−)-cyclohexanediamine and 5-chloro- (1) or 5-bromosalicylaldehyde (2) are used as ligands for Zn(II) resulting in [(1R,2R)-cyclohexylenebis(5-chlorosalicylideneiminato)]zinc(II) (1a) and (1R,2R)-[cyclohexylenebis-(5-bromosalicylideneiminato)]zinc(II) (2a). In the presence of pyridine, 1a and 2a turned out into (1R,2R)-[cyclohexylenebis(5-chlorosalicylideneiminato)pyridine]zinc(II) (1b) and (1R,2R)-[cyclohexylenebis(5-bromosalicylideneiminato)pyridine]zinc(II) (2b). Coordination sphere of Zn(II) atoms in both pyridine adducts is a slightly distorted square pyramid, with N₂O₂ chromophore units and axially bonded pyridine as it is evident from single crystal X-ray analyzes of 1b and 2b. The asymmetric unit of 1b and 2b contains two molecules of complexes. The observed distances of Zn-O in both molecules indicate the rigidity of the tetradentate ligand as a main factor influencing the geometry of coordination sphere. Obtained complexes were characterized by ¹H NMR in solution and ¹³C CP MAS NMR. NOE differential experiments revealed significant steric interactions between C(6)-H in the phenyl ring, cyclohexyl C(1)-H and imine hydrogen. Significant coordination shifts of carbons in the closest proximity to the coordination center were noted as well.