Terpenoids from Russula lepida and R. amarissima (Basidiomycota,Russulaceae)

Four aristolane sesquiterpenes were isolated from the fruiting bodies of Russula lepida and R. amarissima, namely (1R,2S)-1,2-dihydroxyaristolone (6), (2S,11S)-2,12-dihydroxy-aristolone (7), (1R,2S,11S)-1,2,12-trihydroxyaristolone (8), (1S,2S,11S)-1,2,12-trihydroxy-aristolone (9). In addition, a seco-cucurbitane triterpene, i.e. 3,4-secocucurbita-4,24E-diene-3-hydroxy-26-carboxylic acid (14) was isolated from both species. The configuration at C-2 of the already known rulepidol (2-hydroxyaristolone, 5) was corrected as S instead of R. Several more aristolane and nardosinane sesquiterpenes, as well as cucurbitane triterpenes, already reported both from European and Chinese samples of R. lepida, were also isolated. Compound 14 showed moderate cell growth inhibitory activity.     

Two new isodrimene sesquiterpenes from the fungal culture broth of Polyporus arcularius

Two new isodrimene sesquiterpene derivatives, 2(S)-hydroxyalbicanol (1, =(2S,4aS,8S,8aS)-8-(hydroxymethyl)-4,4,8a-trimethyl-7-methylenedecahydronaphthalen-2-ol) and 2(S)-hydroxyalbicanol 11-acetate (2, =((1S,4aS,7S,8aS)-7-hydroxy-5,5,8a-trimethyl-2-methylenedecahydronaphthalen-1-yl)methyl acetate) were isolated from the culture broth of the fungus Polyporus arcularius, together with two phenylpropanediols, (1S,2S)- and (1R,2S)-1-phenyl-1,2-dihydroxypropane (3, 4). Compound 3 is reported as a naturally occurring compound for the first time. The structures of the compounds were elucidated on the basis of spectroscopic analysis. Compound 1 exhibited growth inhibition of lettuce seedlings with IC₅₀ values of 1.3 mM to hypocotyl and 1.7 mM to radicle.     

Synthesis and antioxidant evaluation of (S,S)- and (R,R)-secoisolariciresinol diglucosides (SDGs)

Secoisolariciresinol diglucosides (SDGs) (S,S)-SDG-1 (major isomer in flaxseed) and (R,R)-SDG-2 (minor isomer in flaxseed) were synthesized from vanillin via secoisolariciresinol (6) and glucosyl donor 7 through a concise route that involved chromatographic separation of diastereomeric diglucoside derivatives (S,S)-8 and (R,R)-9. Synthetic (S,S)-SDG-1 and (R,R)-SDG-2 exhibited potent antioxidant properties (EC₅₀ = 292.17 ± 27.71 μM and 331.94 ± 21.21 μM, respectively), which compared well with that of natural (S,S)-SDG-1 (EC₅₀ = 275.24 ± 13.15 μM). These values are significantly lower than those of ascorbic acid (EC₅₀ = 1129.32 ± 88.79 μM) and α-tocopherol (EC₅₀ = 944.62 ± 148.00 μM). Compounds (S,S)-SDG-1 and (R,R)-SDG-2 also demonstrated powerful scavenging activities against hydroxyl [natural (S,S)-SDG-1: 3.68 ± 0.27; synthetic (S,S)-SDG-1: 2.09 ± 0.16; synthetic (R,R)-SDG-2: 1.96 ± 0.27], peroxyl [natural (S,S)-SDG-1: 2.55 ± 0.11; synthetic (S,S)-SDG-1: 2.20 ± 0.10; synthetic (R,R)-SDG-2: 3.03 ± 0.04] and DPPH [natural (S,S)-SDG-1: EC₅₀ = 83.94 ± 2.80 μM; synthetic (S,S)-SDG-1: EC₅₀ = 157.54 ± 21.30 μM; synthetic (R,R)-SDG-2: EC₅₀ = 123.63 ± 8.67 μM] radicals. These results confirm previous studies with naturally occurring (S,S)-SDG-1 and establish both (S,S)-SDG-1 and (R,R)-SDG-2 as potent antioxidants and free radical scavengers for potential in vivo use.     

Dolabellane diterpenoids from Aglaia odorata

Dolabellane diterpenoids, (1R,3E,7E,10S,11S,12R)-dolabella-3,7-dien-10,18-diol (1), (1R,3S,7E,11S,12R)-dolabella-4(16),7-dien-3,18-diol (2), (1R,7E,11S,12R)-18-hydroxydolabella-4(16),7-dien-3-one (3), (1R,3S,4S,7E,11S,12R)-3,4-epoxydolabella-7-en-18-ol (4), and (1R,3R,7E,11S,12R)-dolabella-4(16),7,18-trien-3-ol (5), were obtained from the ornamental plant Aglaia odorata. Their structures were characterized on the basis of spectroscopic analyses and further confirmed by X-ray diffraction. Compounds 1 and 5 showed weak cytotoxicity against the human myeloid leukemia HL-60, hepatocellular carcinoma SMMC-7721, and lung cancer A-549 cells.     

Sesquiterpenoids from the Chinese endangered plant Manglietia aromatica

One new bourbonane-type (1) and one new cadinane-type (2) sesquiterpenoids, along with one known aromodendrane-type (3) and five known megastigmane-type (4–8) compounds, were isolated from the leaves and twigs of Manglietia aromatica, a Chinese endangered plant that has not been previously phytochemically investigated. The structures and absolute configurations of the new isolates, (1R,4S,5S,6S,7S,10S)-4-hydroxy-bourbon-8-one (1) and (1R,6S,7S)-1-hydroxy- cadin-4,9-dien-8-one (2), were established by means of spectroscopic methods and a combination of experimental and calculated electronic circular dichroism (ECD). Among the isolates, compound 2 was found to show a moderate inhibitory effect against the human protein tyrosine phosphatase 1 B (PTP1B) enzyme, a target for the treatment of type-II diabetes and obesity, with an IC₅₀ value of 83.5 μM.     

Synthesis and in vitro antitumor activity of novel iridium(III) complexes with enantiopure C2-symmetrical vicinal diamine ligands

Four novel iridium(III) complexes with enantiopure C₂-symmetrical vicinal diamine ligands were designed, synthesized, and characterized by FT-IR, NMR, and MS. The cytotoxicities of all of the complexes against the human solid tumor cell lines A2780, A549, KB, and MDA-MB-231 were evaluated. Both R,R-configured complexes (R,R)-5a and (R,R)-5b exhibited more potent or similar activity compared with oxaliplatin, whereas their corresponding (S,S)-isomers (S,S)-5a and (S,S)-5b were found to be mostly inactive. As indicated by the activation of caspase-3, the cleavage of PARP, and the upregulation of p53, the preliminary mechanism studies revealed that the mode of cell death initiated by (R,R)-5a in A2780 cells was predominantly p53-mediated apoptosis. In addition, the structure of (R,R)-5a was unambiguously confirmed through single crystal X-ray structure determination.     

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.     

Synthesis of novel benzimidazole functionalized chiral thioureas and evaluation of their antibacterial and anticancer activities

A small library of benzimidazole functionalized chiral thioureas was prepared starting from natural amino acids (S)-alanine, (S)-phenylalanine, (S)-valine and (S)-leucine and also their (R)-isomers and studied their antimicrobial activity against a various Gram-positive and Gram-negative bacterial strains. In this study, compounds 5g and 5j were found to exhibit good antibacterial activity against both Gram-positive and Gram-negative bacterial strains such as Staphylococcus aureus, Bacillus subtilis, Micrococcus luteus, Klebsiella planticola, Escherichia coli and Pseudomonas aeruginosa. In the cytotoxicity study, thioureas derived from non-natural amino acids 5a–l showed good activity against human cancer cell lines A549, MCF7, DU145, HeLa, and no cytotoxicity was observed with their antipodes 6a–l.     

Oxirapentyns B–D produced by a marine sediment-derived fungus Isaria felina (DC.) Fr

Three new highly oxygenated chromene derivatives, oxirapentyns B–D (1–3) and one known oxirapentyn A (4) were isolated from the lipophilic extract of the marine-derived fungus Isaria felina KMM 4639. The structures of compounds 1–3 were determined based on spectroscopic methods. The absolute configuration of oxirapentyn B (1) as 2R, 4S, 5S, 6S, 7R, 8S, 9S was established by a combination of modified Mosher's method, X-ray analysis, and NOESY data. Oxirapentyn A (4) showed weak cytotoxicity against SK-Mel-5, SK-Mel-28 human malignant melanoma, and T-47D human breast cancer cell lines.     

Design,synthesis and evaluation of novel oxazaphosphorine prodrugs of 9-(2-phosphonomethoxyethyl)adenine (PMEA,adefovir) as potent HBV inhibitors

A series of novel oxazaphosphorine prodrugs of 9-(2-phosphonomethoxyethyl)adenine (PMEA, adefovir) were synthesized and their anti-hepatitis B virus (HBV) activity was evaluated in HepG2 2.2.15 cells, with adefovir dipivoxil as a reference drug. In the cell assays, compounds 7b and 7d exhibited anti-HBV activity comparable to that of adefovir dipivoxil, while compound 7c, with an IC₅₀ value of 0.12 μM, was found to be three times more potent than the reference compound. In vitro stability studies showed that (S_P,S)-7c, the diastereomer of compound 7c, was stable in human blood plasma but underwent rapid metabolism to release the parent drug PMEA in liver microsomes. The possible metabolic pathway of (S_P,S)-7c in human liver microsomes was described. These findings suggest that compound (S_P,S)-7c is a promising anti-HBV drug candidate for further development.     

Microbial transformation of 20(S)-protopanaxatriol by Absidia corymbifera and their cytotoxic activities against two human prostate cancer cell lines

Seven hydroxylates of 20(S)-protopanaxatriol (1) transformed by Absidia corymbifera AS 3.3387 were isolated and identified by spectral methods including 2D-NMR. Among them, 7β-hydroxyl-20(S)-protopanaxatriol (2), 7α-hydroxyl-20(S)-protopanaxatriol (3), and 7β, 15α-dihydroxyl-20(S)-protopanaxatriol (7) are new compounds. The metabolites 2, 6, 7, and 8 showed the more potent inhibitory effects against DU-145 and PC-3 cell lines than the substrate.     

(2S)-Prenylflavanones and taraxerane triterpenoids from Mallotus mollissimus

Three prenylflavanones, (2S)-5,7-dihydroxy-4′-methoxy-8-(3″,3″-dimethylallyl)flavanone (3), (2S)-5,4′-dihydroxy-7-methoxy-6-(3″,3″-dimethylallyl)flavanone (6), 8-prenylnaringenin (11), and a new epimeric pair (2″S/2″R)-(2S)-5,7-dihydroxy-4′-methoxy-6-(2″-hydroxy-3″-methylbut-3″-enyl)flavanones (4a/4b) were isolated together with taraxerone, taraxerol, epitaraxerol, β-sitosterol, oleanolic acid, 1-O-docosanoyl glycerol, apigenin, and apigenin 7-O-β-D-glucopyranoside from the MeOH extract of the leaves of Mallotus mollissimus. The structures of the isolated compounds were determined on the basis of 1D/2D NMR and HR-MS spectroscopic data; the 2S configuration of the prenylflavanones 3, 4, and 6 was deduced from CD spectroscopic data. The presence of three taraxerane triterpenoids reinforces the inclusion of M. mollissimus (syn. Croton mollissimus) in Mallotus genus. Among species of Mallotus the occurrence of the (2S)-prenylflavanones 3, 4, and 6 is confined to M. mollissimus.     

Synthesis, structure, and catalytic activity of chiral Cu(II) and Ag(I) complexes with (S,S)-1,2-diaminocyclohexane-based N4-donor ligands

Condensation of (S,S)-1,2-cyclohexanediamine with 2 equiv. of 2-pyridine carboxaldehyde in toluene in the presence of molecular sieves at 70 °C gives N,N′-bis(pyridin-2-ylmethylene)-(S,S)-1,2-cyclohexanediamine (S,S-1) in 95% yield. Reduction of 1 with an excess of NaBH₄ in MeOH at 50 °C gives N,N′-bis(pyridin-2-ylmethyl)-(S,S)-1,2-cyclohexanediamine (S,S-2) in 90% yield. Reaction of 1 or 2 with 1 equiv. of CuCl₂ · 2H₂O in methanol gives complexes [N-(pyridin-2-ylmethylene)-(S,S)-1,2-cyclohexanediamine]CuCl₂ (3) and [Cu(S,S-2)(H₂O)]Cl₂ · H₂O (4), respectively, in good yields. Complex 4 can further react with 1 equiv. of CuCl₂ · 2H₂O in methanol to give [Cu(S,S-2)][CuCl₄] (5) in 75% yield. The rigidity of the ligand coupled with the steric effect of the free anion plays an important role in the formation of the helicates. Treatment of ligand S,S-1 with AgNO₃ induces a polymer helicate {[Ag(S,S-1)][NO₃]}_n (6), while reaction of ligand 2 with AgPF₆ or AgNO₃ in methanol affords a mononuclear single helicate [Ag(S,S-2)][PF₆] (7) or a dinuclear double helicate [Ag₂(S,S-2)₂][NO₃]₂ · 2CH₃OH (8) in good yields, respectively. All compounds have been characterized by various spectroscopic data and elemental analyses. Compounds 1, 3-5, 7 and 8 have been further subjected to single-crystal X-ray diffraction analyses. The Cu(II) complexes do not show catalytic activity for allylation reaction, in contrast to Ag(I) complexes, but they do show catalytic activity for Henry reaction (nitroaldol reaction) that Ag(I) complexes do not.     

Two novel hydroperoxylated products of 20(S)-protopanaxadiol produced by Mucor racemosus and their cytotoxic activities against human prostate cancer cells

Microbial transformation of 20(S)-protopanaxadiol (1) by Mucor racemosus AS 3.205 yielded two novel hydroperoxylated metabolites and three known hydroxylated metabolites. The structures of the metabolites were identified as 26-hydroxyl-20(S)-protopanaxadiol (2), 23,24-en-25-hydroxyl-20(S)-protopanaxadiol (3), 25,26-en-24(R)-hydroperoxyl-20(S)-protopanaxadiol (4), 23,24-en-25-hydroperoxyl-20(S)-protopanaxadiol (5), and 25-hydroxyl-20(S)-protopanaxadiol (6). 4 and 5 are new compounds. Metabolites 2, 4, and 5 showed the more potent inhibitory effects against DU-145 and PC-3 cell lines than the substrate.     

Diterpenoids from the needles and twigs of the cultivated endangered pine Pinus kwangtungensis and their PTP1B inhibitory effects

Pinus kwangtungensis is an endangered pine species native to China. In the present study, 15 diterpenoids including three new labdane-type analogs were isolated and characterized during a pioneer phytochemical investigation on a mass-limited sample of the needles and twigs of this plant, which is growing in a Cantonese garden. The new structures, (4S,5R,9S,10R)-6-oxo-labd-7,13-dien-16,15- olid-19-oic acid (1), 15(S)-n-butoxypinusolidic acid (2), and β-d-glucopyranosyl- (4S,5R,9S,10R)-labda-8(17),13-dien-15,16-olid-19-oate (3), were established by extensive spectroscopic methods and some chemical transformations. Among the isolates, lambertianic acid (10) and cassipourol (15) showed inhibitory activities against human protein tyrosine phosphatase 1 B (PTP1B), a target for the treatment of type-II diabetes and obesity, with IC₅₀ values of 25.5 and 11.2 μM, respectively.     

Synthesis and biological evaluation of enantiomerically pure glyceric acid derivatives as LpxC inhibitors

Inhibitors of the UDP-3-O-[(R)-3-hydroxymyristoyl]-N-acetylglucosamine deacetylase (LpxC) represent a promising class of novel antibiotics, selectively combating Gram-negative bacteria. In order to elucidate the impact of the hydroxymethyl groups of diol (S,S)-4 on the inhibitory activity against LpxC, glyceric acid ethers (R)-7a, (S)-7a, (R)-7b, and (S)-7b, lacking the hydroxymethyl group in benzylic position, were synthesized. The compounds were obtained in enantiomerically pure form by a chiral pool synthesis and a lipase-catalyzed enantioselective desymmetrization, respectively. The enantiomeric hydroxamic acids (R)-7b (K_i = 230 nM) and (S)-7b (K_i = 390 nM) show promising enzyme inhibition. However, their inhibitory activities do not substantially differ from each other leading to a low eudismic ratio. Generally, the synthesized glyceric acid derivatives 7 show antibacterial activities against two Escherichia coli strains exceeding the ones of their respective regioisomes 6.     

Enantiomeric lignans with anti-β-amyloid aggregation activity from the twigs and leaves of Pithecellobium clypearia Benth

To develop potential agents for slowing the progression of Alzheimer′s disease, two pairs of new enantiomeric lignans, including a couple of rarely 8′,9′-dinor-3′,7-epoxy-8,4′-oxyneolignanes named (7S, 8S)- and (7R, 8R)-pithecellobiumin A (1a/1b) and a pair of 2′,9′-epoxy-arylnaphthalenes named (7R, 8R, 8′R)- and (7S, 8S, 8′S)-pithecellobiumin B (2a/2b) were separated by chiral high performance liquid chromatography (HPLC). Their planar structures were elucidated by spectroscopic data analyses. The absolute configurations were determined by comparing of experimental and calculated electronic circular dichroism (ECD). The inhibitory activity on Aβ aggregation of all optical pure compounds was tested by ThT assay. Interestingly, enantiomeric inhibitors 1a (62.1%) and 1b (81.6%) exhibited different degrees of anti-Aβ aggregation activity. However, 2a (65.4%) and 2b (68.4%) showed similar inhibition rate. The different inhibition profiles were explained by molecular dynamics and docking simulation studies.     

Trinorsesquiterpenoids from Inula racemosa

Four trinorsesquiterpenoids (1–4) were isolated from the roots of Inula racemosa and the structures of two new compounds, (4R,5S,10S)-5-hydroxy-11,12,13-trinoreudesm-6-en-8-one (1) and (4R,5R,10R)-4,15-epoxy-11,12,13-trinoreudesman-8-one (3), were elucidated by extensive spectroscopic analysis. Furthermore, the structure of compound 2a should be revised as (4R,5R,10S)-5-hydroxy-11,12,13-trinoreudesm-6-en-8-one (2) and compound 2 showed antiproliferative activity against A549, HepG2, and HT1080 cell lines with IC50 values of 3.71, 5.94, and 3.95 μg/mL, respectively.     

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).     

Enantiopure dihalocyclopropyl alcohols and esters by lipase catalyzed kinetic resolution

Four halogenated cyclopropane derivatives with a side chain containing a primary (1 and 2) or secondary (3 and 4) alcohol moiety were subject to kinetic resolution catalyzed by lipases. Two of them containing secondary alcohol groups gave excellent results with Candida antarctica lipase B with E-values around 1000. Two enantiopure alcohols and two enantiopure butanoates are described: (1S,1′S)-1-(2′,2′-dichloro-3′,3′-dimethylcyclopropyl) ethanol (3), the corresponding (1R,1′R)-butanoate (3b) and (1S,1′S)-1-(1′-methyl-2′,2′-dibromocyclopropyl) ethanol (4) and the corresponding (1R,1′R)-butanoate (4b).