Bioactive prenylated c6-c3 derivatives from the roots of Illicium brevistylum.

Three new prenylated C6-C3 compounds (1-3), together with two known prenylated C6-C3 compounds (4-5) and one known C6-C3 derivative (6), were isolated from the roots of Illicium brevistylum A. C. Smith. The structures of 1-3 were elucidated by spectroscopic methods including 1D and 2D NMR, HRESIMS, CD experiments and ECD calculations. The structure of illibrefunone A (1) was confirmed by single-crystal X-ray diffraction analysis. All compounds were evaluated in terms of their anti-inflammatory potential on nitric oxide (NO) generation in lipopolysaccharide-stimulated murine RAW264.7 macrophages and murine BV2 microglial cells, antiviral activity against Coxsackievirus B3 (CVB3) and influenza virus A/Hanfang/359/95 (H3N2). Compounds 3 and 4 exhibited potent inhibitory effects on the production of NO in RAW 264.7 cells with IC50 values of 20.57 and 12.87 µM respectively, which were greater than those of dexamethasone (positive control). Compounds 1 and 4-6 exhibited weak activity against Coxsackievirus B3, with IC50 values ranging from 25.87 to 33.33 µM.

Cadinane sesquiterpenes from the stems and branches of Illicium ternstroemioides.

Three new cadinane sesquiterpenes (1-3) and three known sesquiterpenes were isolated from the stems and branches of Illicium ternstroemioides A. C. Smith. The structures of the new compounds were elucidated by extensive analysis of spectroscopic and HRESIMS data. The structures of illiternins A-C (1-3) were confirmed by single crystal X-ray diffraction, allowing for the determination of their absolute configurations. Compounds 3 and 6 exhibited antiviral activity against Coxsackievirus B3 with IC50 values of 33.3 and 57.7 µM, respectively.

Diverse prenylated C6-C3 derivatives from the stems and branches of Illicium ternstroemioides A. C. Smith with anti-inflammatory and antiviral activities.

Fifteen unreported prenylated C6-C3 derivatives (1-15) were isolated from the stems and branches of Illicium ternstroemioides A. C. Smith, including one bis-prenylated C6-C3 derivative (1), three prenylated C6-C3 derivative-shikimic acid ester hybrids (2-4) and 11 prenylated C6-C3 monomers (5-15). The structures of compounds 1-15 were elucidated by spectroscopic analysis (UV, IR, 1D and 2D NMR, and HRESIMS). The absolute configurations of the compounds were determined using electronic circular dichroism (ECD), induced circular dichroism (ICD), and the modified Mosher's method. Among the isolates, compounds 11, 12, and 15 exhibited significant anti-inflammatory activities by inhibiting the nitric oxide with IC50 values ranging from 1.89 to 24.83 µM in lipopolysaccharide-stimulated murine RAW 264.7 macrophages and murine BV2 microglial cells; compounds 2, 3, and 7 exhibited antiviral activitives against Coxsackievirus B3 with an IC50 value of 33.3, 25.9, and 27.8 µM, respectively.

Bergamotane-type sesquiterpenes from the leaves and twigs of Illicium oligandrum and their anti-inflammatory activities.

Eight undescribed ß-bergamotene-type sesquiterpene oliganins A-H (1-8) and one known α-bergamotene-type sesquiterpene (9) were isolated from the leaves and twigs of Illicium oligandrum Merr. & Chun. The structures of compounds 1-8 were elucidated by extensive spectroscopic data, and the absolute configurations were determined by using a modified Mosher's method and electronic circular dichroism calculations. The isolates were further evaluated in terms of their anti-inflammatory potential on nitric oxide (NO) generation in lipopolysaccharide-stimulated RAW264.7 and BV2 cells. Compounds 2 and 8 exhibited potent inhibitory effects on the production of NO with IC50 values ranging from 21.65 to 49.28 µM, which were greater than or comparable to those of dexamethasone (positive control).

seco-Sesquiterpenes and acorane-type sesquiterpenes with antiviral activity from the twigs and leaves of Illicium henryi Diels.

Chemical investigation of an alcohol extract from the twigs and leaves of Illicium henryi Diels resulted in the isolation of two new acorane-related seco-sesquiterpenes (1 and 3), two new acorane-related seco-norsesquiterpenes (2 and 4), one new 2-epi-cedrane sesquiterpene (5), eight new acorane-type sesquiterpenes (6-13), and a known major constituent of acorenone B (14). Their structures were established by interpreting extensive spectroscopic data, including HRESIMS, NMR (1H and 13C NMR, 1H-1H COSY, HSQC, and HMBC), and NOE difference spectra analysis. The absolute configurations of 1, 2, 4-7, 9, 10, and 14 were determined by X-ray crystallography, while chemical transformation methods were performed with compound 14 as the starting material to elegantly solve the absolute configuration issue of compounds 8 and 11-13. Notably, 1 and 2 are seco-sesquiterpenes that are related to acorane and possess an unusual ketal-linked hemiacetal in a 6,8-dioxabicyclo[3.2.1]octan-7-ol scaffold ring system. Plausible biosynthetic pathways for compounds 1-14, which were derived from the acorane skeleton, were proposed. All the isolated compounds (1-14) were evaluated for their antiviral and cytotoxic activities.

Current approaches and strategies to identify Hedgehog signaling pathway inhibitors for cancer therapy.

The Hedgehog signaling pathway plays a vital role in embryonic development and tissue patterning. Aberrant regulation of this pathway is commonly associated with the occurrence, development and progression of various types of malignancies. The development of inhibitors targeting Hedgehog pathway has attracted significant interests in cancer therapy and led to the discovery of three drugs Vismodegib, Sonidegib and Glasdegib. However, their clinical application has been hampered due to adverse effects and resistance issues, highlighting the urgent need for new inhibitors. Herein we give a systematic overview of the current status and characteristics of various approaches to developing the Hedgehog pathway inhibitors, including library screening, natural product-oriented approach, analogue approach, drug repositioning, in silico tools and others. The future prospects are also discussed for the discovery and development of next-generation inhibitors.

Chemical constituents from the fruits of Illicium simonsii and their antiviral activity and neuroprotective effect.

One undescribed diterpenoid illisimonone A, four undescribed sesquiterpenes named (±)-simonones A, simonterpenoids A and B, and two undescribed lignans, illisimonins A and B, along with five known compounds were isolated from the fruits of Illicium simonsii. Their structures were elucidated by extensive spectroscopic data. The absolute configuration of illisimonone A was determined by single-crystal X-ray diffraction analysis. Illisimonone A showed potential antiviral activity against the Coxsackie B3 virus, with an IC50 value of 3.70 µM. Illisimonin B and henrylactone A showed potential neuroprotective effects against oxygen-glucose deprivation induced cell injury in SK-N-SH cells, with survival rates of 57.6%, 58.0%, respectively.

Copper-Catalyzed Cascade Annulation of o-Hydroxyphenyl Propargylamines with Pyrazolin-5-ones to Access Pyrano[2,3-c]pyrazoles.

An efficient copper-catalyzed cascade annulation of o-hydroxyphenyl propargylamines and pyrazolin-5-ones is described. This methodology leads to the rapid assembly of a series of valuable pyrano[2,3-c]pyrazoles with good yields across a wide range of substrates in a simple fashion. This novel reaction involves the formation of alkynyl ortho-quinone methides, a 1,4-conjugate addition, and a subsequent 6-endo cyclization process. The mechanistic elucidation is well supported by control experiment and literature precedents.

Prenylated C6-C3 derivatives from the stems and branches of Illicium ternstroemioides A. C. Smith with antiviral activity.

Thirteen compounds were isolated from the lipid-soluble extracts of Illicium ternstroemioides A. C. Smith, including eleven previously undescribed prenylated C6-C3 compounds, a previously undescribed prenylated C6-C3 derivative-abscisic acid ester hybrid, and a known compound (4S)-illicinone I. Their structures and configurations were mainly elucidated by spectroscopic analyses, CD experiments and X-ray crystallography. (2S,4R,11S)-4-O-methyl-12-chloroillifunone C, (2S,4R,11R)-2,3-dihydro-4-O-methyl illioliganfunone D, and illiternfunol A were found to exhibit weak activity against Coxsackievirus B3, with IC50 values ranging from 27.8 to 33.3 µM. Illiternone B exhibited more potent activities against Coxsackievirus B3 and influenza virus A than did its geometric isomer illiternone A, with IC50 values of 7.7 µM and 2.5 µM, respectively. None of these compounds displayed cytotoxic activities.

Rh(III)-Catalyzed Regioselective Annulations of 3-Arylisoxazolones and 3-Aryl-1,4,2-dioxazol-5-ones with Propargyl Alcohols: Access to 4-Arylisoquinolines and 4-Arylisoquinolones.

The Rh(III)-catalyzed dual directing group assisted C-H activation/annulation of 3-arylisoxazolones with propargyl alcohols has been developed, which expands the application scope of isoxazolones in organic synthesis. This protocol also worked well with 3-aryl-1,4,2-dioxazol-5-ones to produce synthetically and biologically important 4-arylisoquinolones.

Library construction of stereochemically diverse isomers of spirooliganin: their total synthesis and antiviral activity.

The construction of libraries of stereoisomers of natural products serves as an important approach to investigating the correlation between the stereostructure and biological activity. However, the total synthesis and isomerzation of polycyclic scaffolds with multiple chrial centers are rare. Spirooliganin (1), a new skeleton natural product isolated from the plant Illicium oligandrum, was structurally characterized by comprehensive analysis of NMR spectroscopic data and ECD which revealed an unprecedented 5-6-6-6-7 polycyclic framework with six chiral centers. Here we report a 17-step total synthesis to prepare a library of stereochemically diverse isomers of spirooliganin, including 16 diastereoisomers and 16 regioisomers. In addition to a regioselective hetero-Diels-Alder cycloaddition, the synthetic strategy involves a photo-induced stereoselective Diels-Alder reaction, which gives only the abnormal trans-fused product as rationalized by density functional theory calculations. Preliminary biological evaluation showed that spirooliganin and regioisomers 39 exhibited potent inhibition of Coxsackievirus B3. It also revealed the pharmacophore effect of the D-ring (16R,18R,24R, and 26R) for their antiviral activities.

Bioactive prenylated C6-C3 derivatives from the stems and leaves of Illicium fargesii.

Seventeen new prenylated C6-C3 derivatives, namely, illifargeins A-M (1-13), including three pairs of enantiomers (1, 5, and 12) and one norillifargeal A (14), together with eight known analogues (15-22), were isolated from the stems and leaves of Illicium fargesii. The structures of the new compounds were elucidated using spectroscopic data (UV, IR, 1D and 2D NMR, and HRESIMS). Their absolute configurations were determined by using experimental and calculated ECD data analysis, as well as a modified Mosher's method. Compounds 1a, 1b, 2, 3, 5a, 7, 10, 11, 15, 16, 19, and 20 showed potential activity against Coxsackie virus B3, with IC50 values ranging from 6.23 to 33.33 µM. Compounds 9 and 15 exhibited potential activity against influenza virus A, with IC50 values of 11.11 and 19.24 µM, respectively. Compounds 2, 3, and 18 exhibited potential anti-oxidant activity, with IC50 values ranging from 1.43 to 6.71 µM.

Illihenin A: An Antiviral Sesquiterpenoid with a Cage-like Tricyclo[6.2.2.01,5]dodecane Skeleton from Illicium henryi.

Illihenin A (1), a novel sesquiterpenoid, was isolated from the roots of Illicium henryi. The structure was determined by spectroscopic analyses, ECD calculation, and single-crystal X-ray diffraction. Compound 1 represents a class of novel 5/7/6 tricyclic sesquiterpenoids featuring a rare cage-like tricyclo[6.2.2.01,5]dodecane core. A plausible biosynthetic pathway of 1 by rearrangement of allo-cedrane is proposed. Additionally, 1 showed potent antiviral activity against coxsackievirus B3 with an IC50 value of 2.87 µM.

Burchellin and its stereoisomers: total synthesis, structural elucidation and antiviral activity.

Burchellin and its analogues are a class of neolignan natural products containing a rare core with three contiguous stereogenic centers. In previous reports, racemic burchellin was synthesized without accessing each of the enantiomers. In this paper, a concise and efficient total synthetic route to divergently access the enantiomers of burchellin and those of its 1'-epi-diastereoisomer over six steps for each is disclosed, where each of the enantiomers was obtained by preparative chiral phase HPLC purification. The key steps include the construction of a 2,3-dihydrobenzofuran moiety by two Claisen rearrangements and a one-step rearrangement/cyclization and subsequent tandem ester hydrolysis/oxy-Cope rearrangement/methylation to furnish the basic skeleton of burchellin. The structures and absolute configurations of the four stereoisomers were determined using spectroscopic data analyses and comparison of experimental and calculated electronic circular dichroism data. These stereoisomers were found to have potent antiviral effects against coxsackie virus B3, and is the first time that bioactivity has been reported for these compounds.

A Role for Isatin Azomethine Imines as a Dipolarophile in Cycloaddition Reactions.

An unusual [2 + 3] cycloaddition of isatin azomethine imines (AIs) and in situ generated azaoxyallyl cations has been developed. It is the first example where AIs serve as the [C,O] 2-atom synthon in organic synthesis. This work not only reveals a new role of isatin AIs in cycloaddition reaction but also provides an efficient access to unprecedented spiroheterocycle compounds.

Highly oxidized sesquiterpenes from the fruits of Illicium lanceolatum A. C. Smith.

Ten undescribed highly oxidized sesquiterpenes and six known sesquiterpenes were isolated from H2O-soluble part of the fruits of Illicium lanceolatum A. C. Smith. The structures of undescribed compounds were elucidated by interpretation of spectroscopic data, and the absolute configurations of 2α-hydroxyneoanisatinic acid, (1R,5R,6S,7R,9R,10R)-3,4-dehydro-12-hydroxy-floridanolide, and (1R,4S,5R,6S,7S,9S)-1-deoxy-13-hydroxymerrilactone B were determined by the single-crystal X-ray diffraction analysis. Illilanceolatin A was the first example of a seco-prezizaane type sesquiterpene with a hemiacetal moiety located at C-10. 2α-Hydroxyneoanisatinic acid and anisatinic acid were two naturally occurring undescribed seco-prezizaane type sesquiterpenes with a 5/5/6 tricyclic carbon skeleton. Plausible biosynthetic pathways of the isolated polycyclic and highly oxidized sesquiterpenes derived from the intermediate allo-cedrane were proposed. (1R,5R,6S,7R,9R,10R)-3,4-dehydro-12-hydroxy-floridanolide, 1,3-dihydroxyneoanisatin, and 2α-hydroxyneoanisatin displayed neuroprotective effects with protection rates of 19.9, 22.7 and 24.3% at 10 µM, respectively. Additionally, the preliminary acute toxicity of anisatinic acid was also evaluated.

Simultaneous determination of a promising anti-brain tumor agent CAT3 and its two major metabolites in mouse plasma and brain by a LC-MS/MS method.

A rapid and reproducible method with high selectivity was developed for simultaneous determination of a promising anti-brain tumor agent CAT3 and its two metabolites PF403 and GLU-PF403 in mouse plasma and brain. An economic deproteinization with septuple acetonitrile (v/v) was applied to pretreat the samples in this study. All analytes were well retained and separated on a CAPCELL CORE PC (2.7 µm, 2.1 mm I.D. × 150 mm, SHISEIDO Technologies) column with an eluting solvent of acetonitrile /water containing 0.1 % formic acid (v/v) at the flow rate of 0.2 mL per minute. The detection was carried out on a Q Exactive high resolution mass spectrometer equipped with a HESI ion source in parallel reaction monitoring (PRM) mode. The corresponding transitions for quantitation were 434.23→ 70.07 for CAT3, 350.17→70.07 for PF403, 526.21→70.07 for GLU-PF403, 364.19→70.07 for IS-1 and 625.18→317.07 for IS-2, respectively. A well-linear fit curve was achieved among the range of 0.1∼50 ng/mL for CAT3, 0.2∼100 ng/mL for PF403 and 2.5∼600 ng/mL for GLU-PF403 both in mouse plasma and brain homogenate. The intra-/inter-day accuracies of three analytes were within ±14.5 % and precisions were below to 13.44 %. The mean values of recovery of three compounds in mouse plasma and brain homogenate were among 98.06 ∼ 118.63 % and 81.04∼108.69 %. The analytes in NaF-treated ice cold blood of mouse was stable within tested 30 min. Plasma and brain homogenate samples had no obvious changes during all storage, sample treatment and analytic process of mouse plasma sample. The reproducible and reliable method was well employed to the research of CAT3 pharmacokinetic characteristics in mouse plasma and brain after a single intragastric administration at dose of 10 mg/kg.

New hexalactone derivatives and a pair of new oxaspiro-carbon epimeric glycosides from the fruits of Illicium lanceolatum.

Five new compounds (1-5), including three hexalactone derivatives (1-3) and a pair of new oxaspiro-carbon epimeric glycosides (4 and 5), and six known compounds (6-11) were obtained from the fruits of Illicium lanceolatum. The structures of the new compounds were elucidated using extensive spectroscopic data. The absolute configurations of compounds 1-3 were determined by an analysis of their CD spectra. It was determined that compounds 4 and 5, which are epimeric at C-5, possess the same 1-oxaspiro[4,5]decane-7α,8α,9ß-triol moiety. Plausible biogenetic pathways for 4 and 5 derived from the key precursor shikimic acid were proposed. Compounds 1-11 were all assayed on monosodium glutamate-induced human neuroblastoma SH-SY5Y cell damage. The results demonstrated that compounds 4, 5, and 8-10 possess potential neuroprotective effects. The anti-inflammatory, antiviral, and cytotoxic activities of 1-11 were also evaluated.

DABCO-mediated [3+3] cycloaddition of azomethine imines with in situ generated nitrile oxides from hydroximoyl chlorides.

A novel cross 1,3-dipolar cycloaddition between azomethine imines with in situ generated nitrile oxides has been developed. This is the first example of employing a reaction partner containing two heteroatoms in the [3+3] cycloaddition involving azomethine imines. This strategy not only provides structurally diverse N,O-heterocycles but also greatly enriches the chemistry of azomethine imines and nitrile oxides.

New glycosides from the twigs and leaves of Rhododendron latoucheae.

Six new glycosides (1-6), together with three known ones, were isolated from the twigs and leaves of Rhododendron latoucheae. Their structures were elucidated based on the spectroscopic data, including infrared spectrometry, mass spectrometry, and nuclear magnetic resonance experiments, along with Mosher's method. In addition, all compounds were tested their antiviral (herpes simplex virus-1 and influenza A/95-359) activities.