Imines and lactones derived from friedelanes and their cytotoxic activity

Abstract

Friedelan-3-one (1) and friedelane-3,16-dione (2) isolated from leaves and branches of Maytenus robusta Reissek were subjected to structural modifications via nucleophilic addition to the carbonyl group and Baeyer-Villiger oxidation in order to synthesize potential cytotoxic compounds. The oximes friedelane-3-hydroxyimino (3) and 3-hydroxyiminofriedelan-16-one (4) together with the lactones friedelane-3,4-lactone (5) and 3,4-lactonefriedelan-16-one (6) were characterized by IR and NMR spectroscopic analyses. Compounds 4 and 6 are reported for the first time. Cytotoxic screening via MTT assay in human leukemia cell lines (THP-1 and K562) demonstrated no significant improvement of compounds 3-6 when compared to the starting materials. Only compounds 3 and 5 demonstrated an improvement against K562 cells. However, the same assay on ovarian and breast cancer cell lines (TOV-21G and MDA-MB-231) showed a reduction in the IC₅₀ for compounds 4-6, indicating that ring A modifications may enhance the biological potential.     

Cytotoxic flavonoids from two Lonchocarpus species

A new isoflavone, 4′-prenyloxyvigvexin A (1) and a new pterocarpan, (6aR,11aR)-3,8-dimethoxybitucarpin B (2) were isolated from the leaves of Lonchocarpus bussei and the stem bark of Lonchocarpus eriocalyx, respectively. The extract of L. bussei also gave four known isoflavones, maximaisoflavone H, 7,2′-dimethoxy-3′,4′-methylenedioxyisoflavone, 6,7,3′-trimethoxy-4′,5′-methylenedioxyisoflavone, durmillone; a chalcone, 4-hydroxylonchocarpin; a geranylated phenylpropanol, colenemol; and two known pterocarpans, (6aR,11aR)-maackiain and (6aR,11aR)-edunol. (6aR,11aR)-Edunol was also isolated from the stem bark of L. eriocalyx. The structures of the isolated compounds were elucidated by spectroscopy. The cytotoxicity of the compounds was tested by resazurin assay using drug-sensitive and multidrug-resistant cancer cell lines. Significant antiproliferative effects with IC₅₀ values below 10 μM were observed for the isoflavones 6,7,3′-trimethoxy-4′,5′-methylenedioxyisoflavone and durmillone against leukemia CCRF-CEM cells; for the chalcone, 4-hydroxylonchocarpin and durmillone against its resistant counterpart CEM/ADR5000 cells; as well as for durmillone against the resistant breast adenocarcinoma MDA-MB231/BCRP cells and resistant gliobastoma U87MG.ΔEGFR cells.     

新型甲氨蝶呤衍生物的合成

设计合成了新的甲氨蝶呤(methotrexate, MTX)衍生物1～4, 在这些新化合物中, 将MTX分子中10-位对氨基苯甲酰谷氨酸砌块移植到4-位, 同时在6-位引入苯环芳香基以及甲基等基团. 生物活性测试结果显示, 化合物1～4具有与MTX相似的抑制iNOS活性的作用; 相对于MTX, 选测的化合物2和4明显地增强了抑制K-562白血病细胞株生长的活性. 本研究为进行MTX的结构修饰开辟了新途径, 2-氨基-4-[N-(对氨基苯甲酰谷氨酸)-基]-6-取代基蝶啶衍生物可成为潜在的抗肿瘤候选药物被进一步研究.     

A new cyclopentanone derivative from <Emphasis Type="Italic">Euphorbia hirta</Emphasis>

A new cyclopentanone derivative, (1'R,5'R)-5-(5'-carboxymethyl-2'-oxocyclopentyl)-3Z-pentenyl acetate (1), was isolated from Euphorbia hirta. Its structure was elucidated on the basis of spectroscopic analysis including 1D and 2D NMR techniques. The EtOAc extract of Euphorbia hirta was evaluated against K562 and A549 cancer cell lines.     

Microbial carbonylation and hydroxylation of 20(R)-panaxadiol by Aspergillus niger

20(R)-panaxadiol (PD) was metabolised by the fungus Aspergillus niger AS 3.3926 to its C-3 carbonylated metabolite and five other hydroxylated metabolites (1–6). Their structures were elucidated as 3-oxo-20(R)-panaxadiol (1), 3-oxo-7β-hydroxyl- 20(R)-panaxadiol (2), 3-oxo-7β,23α-dihydroxyl-20(R)-panaxadiol (3), 3,12-dioxo- 7β,23β-dihydroxyl-20(R)-panaxadiol (4), 3-oxo-1α,7β-dihydroxyl-20(R)-panaxadiol (5) and 3-oxo-7β,15β-dihydroxyl-20(R)-panaxadiol (6) by spectroscopic analysis. Among them, compounds 2–6 were new compounds. Pharmacological studies revealed that compound 6 exhibited significant anti-hepatic fibrosis activity.     

Four New Pregnane Steroids from Aglaia abbreviata and Their Cytotoxic Activities

Four new pregnane steroids, aglaiasterols A–D ( 1 – 4 ), have been isolated from the EtOH extract of stems of Aglaia abbreviata. They were identified as (3α,5α,17Z)‐3‐hydroxypregn‐17‐en‐16‐one ( 1 ), (3β,5α,17E)‐3‐hydroxypregn‐17‐en‐16‐one ( 2 ), (3β,5α,17Z)‐3‐hydroxypregn‐17‐en‐16‐one ( 3 ), and (3α,5α,20S*)‐3‐hydroxy‐16‐oxopregnan‐20‐yl acetate ( 4 ) on the basis of spectroscopic methods, including 1D‐ and 2D‐NMR techniques. Compounds 1 – 4 were evaluated for their cytotoxic activities against K562 (human leukemia), MCF‐7 (human breast cancer), and KB (human oral epithelium cancer) cells, and drug‐resistant cells of K562/A02, MCF‐7/ADM, and KB/VCR. These isolates showed weak to moderate inhibitory effects on the growth of the tested cell lines.     

Isolation and structural modifications of ananixanthone from Calophyllum teysmannii and their cytotoxic activities

Two naturally occurring xanthones, ananixanthone (1) and β-mangostin (2), were isolated using column chromatographic method from the n-hexane and methanol extracts of Calophyllum teysmannii, respectively. The major constituent, ananixanthone (1), was subjected to structural modifications via acetylation, methylation and benzylation yielding four new xanthone derivatives, ananixanthone monoacetate (3), ananixanthone diacetate (4), 5-methoxyananixanthone (5) and 5-O-benzylananixanthone (6). Compound 1 together with its four new derivatives were subjected to MTT assay against three cancer cell lines; SNU-1, K562 and LS174T. The results indicated that the parent compound has greater cytotoxicity capabilities against SNU-1 and K562 cell lines with IC₅₀ values of 8.97 ± 0.11 and 2.96 ± 0.06 μg/mL, respectively. Compound 5 on the other hand exhibited better cytotoxicity against LS174T cell line with an IC₅₀ value of 5.76 ± 1.07 μg/mL.     

New Sterol Derivatives from the Marine Sponge Xestospongia sp.

Chemical examination of a marine sponge Xestospongia sp. resulted in the isolation of 20 sterol derivatives ( 1 – 20 ), including eight new sterols namely aragusterols J – L ( 1 – 3 ), (5α,7α,12β,22E)‐7,12,18‐trihydroxystigmast‐22‐en‐3‐one ( 4 ), (5α,7α,12β,24R)‐ and (5α,7α,12β,24S)‐7,12,20‐trihydroxystigmastan‐3‐one ( 5 / 6 ), and (5α,7α,12β,22E,24R)‐ and (5α,7α,12β,22E,24S)‐7,12,20‐trihydroxyergost‐22‐en‐3‐one ( 7 / 8 ). The structures of new compounds were determined through extensive spectroscopic analyses and chemical conversion. The sterol diversity was mainly characterized by the presence of a cyclopropane unit at side chain, while compound 4 with 18‐hydroxymethyl group was found in stigmasterol family for the first time. Cytotoxic test revealed the inhibitory effects of compounds 1 , 4 , and 17 against human leukemia cell line K562 with IC₅₀ values of 18.3, 24.1, and 34.3 μm , respectively.     

Anti-β-amyloid aggregation activity of enantiomeric furolactone-type lignans from Archidendron clypearia (Jack) I.C.N.

Abstract

The phytochemical investigation on the twigs and leaves of Archidendron clypearia (Jack) I.C.N. led to the isolation of three pairs of furolactone-type lignans enantiomers, including a pair of new compounds (1R,5S,6S)-Kachiranol (1a) and (1S,5R,6R)-Kachiranol (1b) and four known compounds (2a/2b and 3a/3b). Separation of the furolactone-type lignans enantiomeric mixtures was achieved using chiral HPLC for the first time. Their structures were determined by spectroscopic analysis and comparison between the experimental and calculated electronic circular dichroism (ECD) spectra. All optical pure compounds were evaluated for their inhibitory effects on β-amyloid aggregation by ThT assay. Among them, the inhibitory activity of the compound 1b (71.1%) was higher than the positive control (61.0%) and other compounds. In addition, molecular dynamics and molecular docking were employed to explore the binding relationship between the ligand and the receptor.     

α-Tetralone glycosides from the green walnut husks of Juglans mandshurica Maxim. and their cytotoxic activities

Abstract

Five new α-tetralone glycosides, juglanbiosides A-E (1–5), together with an α-tetralone derivative (15) and nine known 1,4-naphthoquinones (6–14) were isolated from the 95% EtOH extract of green walnut husks of Juglans mandshurica Maxim. Their structures were elucidated by comprehensive spectroscopic methods (¹H, ¹³C NMR, DEPT, HSQC, HMBC, CD, HR-ESI-MS). In vitro cytotoxicities of all the isolated compounds were evaluated against BGC-823, HCT-15 and K562 cancer cell lines.

     

利用工业废弃物中获得的(R)-5-甲基-δ-戊酸内酯为原料合成(2R,6R)-2,6,10-三甲基十一醇

(2R,6R)-2,6,10-三甲基十一醇(1)是维生素E、维生素K和植醇的基本结构单元. 利用从甾体皂甙元氧化降解产生的工业废弃物中所获得的手性化合物(R)-5-甲基-δ-戊酸内酯(6), 先将其转化成为化学性质稳定的(4R)-甲基-5-甲氧甲氧基戊酸甲酯(7), 再经十二步反应, 以14.1%的总收率合成得到了目标化合物(2R,6R)-2,6,10-三甲基十一醇(1).     

Isolation and antiproliferative activity of chemical constituents from Asystasia buettneri Lindau

N-hexane and methanol extracts of Asystasia buettneri Lindau aerial parts exhibited antiproliferative activity on leukaemia blood carcinoma, K-562. Hexadecane (1), 1,3-propan-2-ol (9Z,12′Z,15″Z)-bis(doeicos-9,12,15-trienoate) (2), hydrocarbon, 2,3,3,10,23-pentamethyl tetraeicos-10,13,16-trien-1-ol (3), hexadecanoic acid (4) and taraxerol (5) were isolated from n-hexane extract; stigmasterol (6) and (Z)-9-octadecenoic acid (7) were isolated from ethyl acetate extract; while unsaturated hydrocarbons, octadecene (8), 8-methyl tetradec-6-ene (9) and 19-methyl eicos-1-ene (10), fatty acids, (Z)-5-hexadecenoic acid (11), 11,22-dimethyl ethyltrieicos-11-enoate (12) and taraxasterol (13) were isolated from methanol extract of the plant. Compounds 4, 5, 7, 11, 12 and 13 exhibited antiproliferative activity against K-562, while compounds 5, 6, 7 and 9 revealed antiproliferative activity by inhibiting hepatic liver (WRL68) cell lines.     

Secondary metabolites from Antarctic marine-derived fungus Penicillium crustosum HDN153086

A new polyene compound (1) and a new diketopiperazine (2), as well as three known compounds (3–5), were isolated from the Antarctic marine-derived fungus Penicillium crustosum HDN153086. The structures of 1–5 were deduced based on MS, NMR and TD-DFT calculations of specific ECD spectra. These compounds were evaluated for their cytotoxic activities against K562 cell line and only compound 2 exhibited cytotoxicity against K562 cell, with IC₅₀ value of 12.7 μM.     

A new dihydrobenzofuran lignan and potential α-glucosidase inhibitory activity of isolated compounds from Mitrephora teysmannii

A new dihydrobenzofuran lignan, (2R,3S)-2-(3′,4′-dimethoxyphenyl)-5-(3-hydroxypropyl)-7-methoxy-2,3-dihydrobenzofuran-3-methyl acetate, named as mitredrusin (1), was isolated from the leaves of Mitrephora teysmannii (Annonaceae) together with 12 known compounds including a related dihydrobenzofuran lignan: (?)-3′,4-di-O-methylcedrusin (2), four polyacetylenic acids: 13(E)-octadecene-9,11-diynoic acid (3), 13(E),17-octadecadiene-9,11-diynoic acid (4), octadeca-9,11,13-triynoic acid (5) and octadeca-17-en-9,11,13-triynoic acid (6), five lignans: (?)-eudesmin (7), (?)-epieudesmin (8), (?)-phillygenin (9), magnone A (10) and forsythialan B (11) and two megastigmans: (3S,5R,6S,7E,9R)-7-megastigmene-3,6,9-triol (12) and annoionol A (13). The chemical structures of these compounds were established on the basis of their 1-D and 2-D NMR spectroscopic data. All compounds were evaluated for their α-glucosidase inhibitory activity. Among these isolates, polyacetylenic acids 3 and 4 showed more than 20-fold much higher activity compared with that of the antidiabetic drug acarbose.     

New Route to N‐Alkylated trans‐Pyrrolidine Diols from 2,2,3,3‐Tetramethoxybutane‐Protected Dimethyl Tartrate

A short synthesis of some trans‐pyrrolidine diols is described starting from (2R,3R,5R,6R)‐5,6‐dimethoxy‐5,6‐dimethyl[1,4]dioxane‐2,3‐dicarboxylic acid dimethyl ester 3. The key step was the occurrence of a tandem azide reduction/cyclization sequence on mono‐azide intermediate 6 upon catalytic hydrogenation. This method afforded both (3R,4R)‐(+)‐1‐benzyl‐3,4‐pyrrolidinediol 9a and (3R,4R)‐(+)‐1‐allyl‐3,4‐pyrrolidinediol 9b starting from 3. Cytotoxicity tests were performed on compounds 9a and 9b using the brine shrimp bioassay, but each showed no activity, as were anti‐oxidant tests using the stable free radical diphenylpicrylhydrazyl (DPPH).     

Non‐iterative Asymmetric Synthesis of C15 Polyketide Spiroketals

The 2,2′‐methylenebis[furan] ( 1 ) was converted to 1‐{(4R,6S))‐6‐[(2R)‐2,4‐dihydroxybutyl]‐2,2‐dimethyl‐1,3‐dioxan‐4‐yl}‐3‐[(2R,4R)‐tetrahydro‐4,6‐dihydroxy‐2H‐pyran‐2‐yl)propan‐2‐one ((+)‐ 18 ) and its (4S)‐epimer (?)‐ 19 with high stereo‐ and enantioselectivity (Schemes 1–3). Under acidic methanolysis, (+)‐ 18 yielded a single spiroketal, (3R)‐4‐{(1R,3S,4′R,5R,6′S,7R)‐3′,4′,5′,6′‐tetrahydro‐4′‐hydroxy‐7‐methoxyspiro[2,6‐dioxabicyclo[3.3.1]nonane‐3,2′‐[2H]pyran]‐6′‐yl}butane‐1,3‐diol ((?)‐ 20 ), in which both O‐atoms at the spiro center reside in equatorial positions, this being due to the tricyclic nature of (?)‐ 20 (methyl pyranoside formation). Compound (?)‐ 19 was converted similarly into the (4′S)‐epimeric tricyclic spiroketal (?)‐ 21 that also adopts a similar (3S)‐configuration and conformation. Spiroketals (?)‐ 20 , (?)‐ 21 and analog (?)‐ 23 , i.e., (1R,3S,4′R,5R,6′R)‐3′,4′,5′,6′‐tetrahydro‐6′‐[(2S)‐2‐hydroxybut‐3‐enyl]‐7‐methoxyspiro[2,6‐dioxabicyclo[3.3.1]nonane‐3,2′‐[2H]pyran]‐4′‐ol, derived from (?)‐ 20 , were assayed for their cytotoxicity toward murine P388 lymphocytic leukemia and six human cancer cell lines. Only racemic (±)‐ 21 showed evidence of cancer‐cell‐growth inhibition (P388, ED₅₀: 6.9 μg/ml).     

Pestalotiopisorin B,a new isocoumarin derivative from the mangrove endophytic fungus Pestalotiopsis sp. HHL101

Abstract

A new isocoumarin derivative pestalotiopisorin B (1), along with six known compounds, (R)-(-)- mellein methyl ether (2), pestalotiopyrone G (3), (R)-mevalonolactone (4), pestalotiollides A–B (5–6) and pestalotiopsol A(7) were isolated from Pestalotiopsis sp., an endophytic fungus obtained from Chinese mangrove plant Rhizophora stylosa. Their structures were elucidated unambiguously by the comprehensive analysis of extensive spectroscopic data. Compound 1 exhibited modest antibacterial activity against Escherichia coli and Pseudomonas aeruginosa with 12.5?μg/ml, 50?μg/ml, respectively. Compound 4 showed moderate calcineurin inhibitory activity towards p-nitrophenyl phosphate (IC₅₀ =134.29?±?5.377?μM).     

Acetylcholinesterase inhibitory active metabolites from the endophytic fungus Colletotrichum sp. YMF432

An endophytic fungus, Chaetomium sp. YMF432, was isolated from Huperzia serrata (Thunb. ex Murray) Trev. and subjected to phytochemical investigation based on its special environment. From the extracts of fermentation solid of strain YMF 432, eight compounds including 1-O-methylemodin (1), 5-methoxy-2-methyl-3-tricosyl-1,4-benzoquinone (2), 4,8-dihydroxy-1-tetralone (3), (3β,5α,6α, 22E)-3-hydroxy-5,6-epoxy-7-one-8(14),22-dien-ergosta (4), ergosta-4,6,8(14),22-tetraen-3-one (5), β-sitostenone (6), β-sitosterol (7) and (22E,24R)-ergosta-5,7,22 -trien-3β-ol (8) were obtained. Their structures were elucidated on the basis of their spectroscopic data. These compounds were evaluated for acetylcholinesterase inhibitory activities in vitro. Compounds 1, 2, and 4 showed moderate acetylcholinesterase inhibitory activities (IC₅₀ from 37.7 ± 1.5 to 370.0 ± 2.9 μM).     

Stereoselective Synthesis and Characterization of (Z)-(−)-4-(1′-Alkoxyl-1′-alkyloxycarbonyl-methylidene)-5(R)-[(1R)-menthyloxy]-γ-butyrolactones

Abstract

A series of enantiomerically pure (Z)-(?)-4-(1′-alkyloxy-1′-alkyloxycarbonyl-methylidene)-5(R)-[(1R)-menthyloxy]-γ-butyrolactones were synthesized and characterized in good to excellent yields via O-alkylation of (4R,5R)-(?)-4-ethoxyoxalyl-5-[(1R)-menthyloxy]-γ-butyrolactone with alkyl halides in the presence of K₂CO₃ in acetone at room temperature.     

Three new secoiridoid glycosides from the rhizomes and roots of Gentiana scabra and their anti-inflammatory activities

Three new (1–3) and 17 known (4–20) iridoid and secoiridoid glycosides were isolated from a methanol extract of the rhizomes and roots of Gentiana scabra. Their chemical structures were elucidated from 1D and 2D NMR, IR absorption, and HR-ESI-MS spectra, as well as comparisons of these data with reported values. The effects of the isolated compounds on lipopolysaccharide (LPS)-stimulated bone marrow-derived dendritic cells were investigated. Compounds 6, 10 and 20 exhibited significant inhibitory effects on LPS-induced IL-12 p40 and IL-6 production with IC₅₀ values of 1.62–14.29 μM. Compound 10 also showed a strong inhibitory effect on the LPS-stimulated production of TNF-α with an IC₅₀ value of 10.45 μM.