Anti-inflammatory and anti-diabetic properties of indanone derivative isolated from Fernandoa adenophylla in vitro and in silico studies.

Fernandoa adenophylla, due to the presence of phytochemicals, has various beneficial properties and is used in folk medicine to treat many conditions. This study aimed to isolate indanone derivative from F. adenophylla root heartwood and assess in-vitro anti-inflammatory and anti-diabetic characteristics at varying concentrations. Heat-induced hemolysis and glucose uptake by yeast cells assays were conducted to evaluate these properties. Besides, docking analyses were performed on four molecular targets. These studies were combined with molecular dynamics simulations to elucidate the time-evolving inhibitory effect of selected inhibitors within the active pockets of the target proteins (COX-1 and COX-2). Indanone derivative (10-100 µM) inhibited the lysis of human red blood cells from 9.12 ± 0.75 to 72.82 ± 4.36% and, at 5-100 µM concentrations, it significantly increased the yeast cells' glucose uptake (5.16 ± 1.28% to 76.59 ± 1.62%). Concluding, the isolated indanone might act as an anti-diabetic agent by interacting with critical amino acid residues of 5' adenosine monophosphate-activated protein kinase (AMPK), and it showed a binding affinity with anti-inflammatory targets COX-1, COX-2, and TNF-α. Besides, the obtained results may help to consider the indanone derivative isolated from F. adenophylla as a promising candidate for drug delivery, subject to outcomes of further in vivo and clinical studies.

Cytotoxic Natural Products Isolated from Cryptogramma crispa (L.) R. Br.

Parsley fern, Cryptogramma crispa, is a common fern in arctic-alpine regions, and even though this species has been known since ancient times and has been presumed to cause the poisoning of horses, its natural products have not previously been investigated. Here, we characterise 15 natural products isolated from the aerial parts of Cryptogramma crispa, including the previously undescribed compound 3-malonyl pteroside D. The structure determinations were based on several advanced 1D and 2D NMR spectroscopic techniques, Circular Dichroism spectroscopy and high-resolution mass spectrometry. The pteroside derivatives exhibited selective moderate cytotoxic activity against the acute myeloid leukaemia MOLM13 cell line and no cytotoxicity against the normal heart and kidney cell lines, suggesting that their potential anticancer effect should be further investigated.

Synthesis, in silico Studies and Pharmacological Evaluation of a New Series of Indanone Derivatives as Anti-Parkinsonian and Anti-Alzheimer's Agents.

OBJECTIVE: Parkinson's disease (PD) and Alzheimer's disease (AD) are the most common forms of neurodegenerative disorders. The aim of the current work is to study the potential of some new indanone derivatives for the treatment of these neurological disorders. METHODS: A new series of 4-(2-oxo-2-aminoethoxy)-2-benzylidene substituted indanone derivatives have been synthesized and studied for anti-Parkinsonian and anti-Alzheimer's effects. Substitution of different aminoalkyl functionalities at the para position of 2-benzylidene moiety of indanone ring resulted in the formation of potent anti-parkinsonian and anti-Alzheimer's agents (5-10). The neuroprotective effects of newly synthesized compounds were evaluated using perphenazine (PPZ)-induced catatonia in rats and LPS-induced cognitive deficits in mice models. Further, in silico molecular modelling studies of the new indanone derivatives were performed by docking against the 3D structures of various neuroinflammatory mediators, such as interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α) and monoamine oxidase-B (MAO-B), to gain the mechanistic insights of their anti-Alzheimer's and antiparkinsonian effects. RESULTS: The newly synthesized indanone analogues 5-10 were found effective against PPZinduced motor dysfunction and LPS-induced memory impairment in animal models. Among all the synthesized analogues, morpholine-substituted indanone 9 displayed maximum anti-parkinsonian activity, even better than the standard drug L-DOPA, while pyrrolidine and piperidine substituted analogues 5 and 6 were found to be the most potent anti-Alzheimer's agents. CONCLUSION: The new 2-arylidene-1-indanone analogues show good potential as promising leads for designing compounds against Parkinson's and Alzheimer's diseases.

The Norsesquiterpene Glycoside Ptaquiloside as a Poisonous, Carcinogenic Component of Certain Ferns.

Previous studies related to the ptaquiloside molecule, a carcinogenic secondary metabolite known from the world of ferns, are summarised. Ptaquiloside (PTA) belongs to the group of norsesquiterpenes of the illudane type. The name illudane refers to the fungal taxa from which the first representatives of the molecular group were identified. Ptaquiloside occurs mainly in Pteridium fern species, although it is also known in other fern taxa. The species of the genus Pteridium are common, frequent invasive species on all continents, and PTA is formed in smaller or larger amounts in all organs of the affected species. The effects of PTA and of their derivatives on animals and humans are of great toxicological significance. Its basic chemical property is that the molecule can be transformed. First, with the loss of sugar moiety, ptaquilosine is formed, and then, under certain conditions, a dienone derivative (pteridienone) may arise. The latter can alkylate (through its cyclopropane groups) certain molecules, including DNA, in animal or human organisms. In this case, DNA adducts are formed, which can later have a carcinogenic effect through point mutations. The scope of the PTA is interdisciplinary in nature since, for example, molecules from plant biomass can enter the body of animals or humans in several ways (directly and indirectly). Due to its physico-chemical properties (excellent water solubility), PTA can get from the plant into the soil and then into different water layers. PTA molecules that enter the soil, but mainly water, undergo degradation (hydrolytic) processes, so it is very important to clarify the toxicological conditions of a given ecosystem and to estimate the possible risks caused by PTA. The toxicoses and diseases of the animal world (mainly for ruminant farm animals) caused by PTA are briefly described. The intake of PTA-containing plants as a feed source causes not only various syndromes but can also enter the milk (and meat) of animals. In connection with the toxicological safety of the food chain, it is important to investigate the transport of carcinogenic PTA metabolites between organisms in a reassuring manner and in detail. This is a global, interdisciplinary task. The present review aims to contribute to this.

Design, synthesis and biological evaluation of a new series of arylidene indanones as small molecules for targeted therapy of non-small cell lung carcinoma and prostate cancer.

In an attempt to identify small molecules for targeted therapy of non-small cell lung carcinoma (NSCLC) and prostate cancer (PCa), new arylidene indanones (1-10) were synthesized via the Claisen-Schmidt condensation of 5,6-methylenedioxy-1-indanone with p-substituted benzaldehyde. Compounds 1-10 were assessed for their cytotoxic effects on human lung adenocarcinoma (A549) and human pancreatic ductal carcinoma (PANC-1) cells as well as human normal lung fibroblast (CCD-19Lu) and human normal pancreatic ductal epithelial (hTERT-HPNE) cells. Among them, compounds 2, 4 and 10 were more effective on A549 and PANC-1 cells than cisplatin. Compounds 1 and 9 also showed more potent cytotoxic activity towards PANC-1 cells than cisplatin. In vitro assays were performed to assess their effects on DNA synthesis, apoptosis, caspase-3, mitochondrial membrane potential, intracellular calcium levels, morphological changes in cancer cells. Furthermore, all compounds were investigated for their inhibitory effects on cathepsin L (CatL) and cathepsin D (CatD). Compounds 2 and 4 exerted potent anti-NSCLC action through caspase-independent apoptosis induced by an increase in intracellular calcium level and correspondingly the disruption of the ΔΨm. These compounds also caused apoptotic morphological alterations in A549 cells. Compound 4 also inhibited both cathepsins but its inhibitory potency on CatL was more significant. Based on in vitro mechanistic assays, compound 4 was identified as a promising anticancer agent for targeted therapy of NSCLC. On the other hand, the marked anti- PCa activity of compound 1 mediated by apoptotic cell death is also noteworthy, but further enzymatic assays are required to elucidate its main mechanism of action.

Design, synthesis and biological evaluation of 7-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-2,3-dihydro-1H-inden-1-one derivatives as potent FAK inhibitors for the treatment of ovarian cancer.

Focal adhesion kinase (FAK) promotes tumor progression by intracellular signal transduction and regulation of gene expression and protein turnover, which is a compelling therapeutic target for various cancer types, including ovarian cancer. However, the clinical responses of FAK inhibitors remain unsatisfactory. Here, we describe the discovery of FAK inhibitors using a scaffold hopping strategy. Structure-activity relationship (SAR) exploration identified 36 as a potent FAK inhibitor, which exhibited inhibitory activities against FAK signaling in vitro. Treatment with 36 not only decreased migration and invasion of PA-1 cells, but also reduced expression of MMP-2 and MMP-9. Moreover, 36 inhibited tumor growth and metastasis, and no obvious adverse effects were observed during the in vivo study. These results revealed the potential of FAK inhibitor 36 for treatment of ovarian cancer.

Microwave prompted solvent-free synthesis of new series of heterocyclic tagged 7-arylidene indanone hybrids and their computational, antifungal, antioxidant, and cytotoxicity study.

In this study, we report the expeditious synthesis of ten new antifungal and antioxidant agents containing heterocyclic linked 7-arylidene indanone moiety. The solvent-free microwave technique, ample substrate scope, superfast synthesis, and very simple operation are noteworthy features of this protocol. Antifungal activities of the newly synthesized compounds were evaluated against four fungal strains namely Rhizophus oryzae, Mucor mucido, Aspergillus niger, and Candida albicans. Most of the compounds were shown strong inhibition of the investigated fungal agents. In vitro, antioxidant potential against DPPH and OH radicals affirmed that the synthesized compounds are good to excellent radicals scavenging agents. The cytotoxicity data of the synthesized compounds towards HL-60 cells uncovered that the synthesized compounds display very low to negligible cytotoxicity. The structural and quantum chemical parameters of the synthesized compounds were explored by employing density functional theory (DFT) at B3LYP functional using 6-311G(d,p) basis set. The compound 3a is discussed in detail for the theoretical and experimental correlation. Time-dependent density functional theory (TD-DFT) at CAM-B3LYP functional with 6-311G(d,p) basis set was used for the electronic absorption study in the gas phase and indichloromethane and benzene solvents. The UV-Visible absorption peaks and fundamental vibrational wavenumbers were computed and a good agreement between observed and theoretical results has been achieved. From the DFT and antifungal activity correlation, it has been found that the 7-heteroarylidene indanones with more stabilized LUMO energy levels display good antifungal potential.

Leishmanicidal and cytotoxic activities and 4D-QSAR of 2-arylidene indan-1,3-diones.

The indan-1,3-dione and its derivatives are important building blocks in organic synthesis and present important biological activities. Herein, the leishmanicidal and cytotoxicity evaluation of 16 2-arylidene indan-1,3-diones is described. The compounds were evaluated against the leukemia cell lines HL60 and Nalm6, and the most effective ones were 2-(4-nitrobenzylidene)-1H-indene-1,3(2H)-dione (4) and 4-[(1,3-dioxo-1H-inden-2(3H)-ylidene)methyl]benzonitrile (10), presenting IC50 values of around 30 µmol/L against Nalm6. The leishmanicidal activity was assessed on Leishmania amazonensis, with derivative 4 (IC50 = 16.6 µmol/L) being the most active. A four-dimensional quantitative structure-activity analysis (4D-QSAR) was applied to the indandione derivatives, through partial least-squares regression. The statistics presented by the regression models built with the selected field descriptors of Coulomb (C) and Lennard-Jones (L) nature, considering the activities against L. amazonensis, HL60, and Nalm6 leukemia cells, were, respectively, R2 = 0.88, 0.92, and 0.98; Q2 = 0.83, 0.88, and 0.97. The presence of positive Coulomb descriptors near the carbonyl groups indicates that these polar groups are related to the activities. Besides, the presence of positive Lennard-Jones descriptors close to substituents R3 or R1 indicates that bulky nonpolar substituents in these positions tend to increase the activities. This study provides useful insights into the mode of action of indandione derivatives for each biological activity involved.

A Biomimetic Aggregation-Induced Emission Photosensitizer with Antigen-Presenting and Hitchhiking Function for Lipid Droplet Targeted Photodynamic Immunotherapy.

Photodynamic therapy (PDT) is a promising alternative approach for effective cancer treatment that is associated with an antitumor immune response. However, immunosuppression of the tumor microenvironment limits the immune response induced by PDT. Stimulation and proliferation of T cells is a critical step for generating immune responses and depends on the efficient presentation of tumor antigens and co-stimulatory molecules by antigen-presenting cells (APCs). Here, biomimetic aggregation-induced emission (AIE) photosensitizers with antigen-presenting and hitchhiking abilities (DC@AIEdots) are developed by coating dendritic cell (DC) membranes on the nanoaggregates of the AIEgens. Notably, the inner AIE molecules can selectively accumulate in lipid droplets of tumor cells, and the outer cell membrane can facilitate the hitchhiking of DC@AIEdots onto the endogenous T cells and enhance the tumor delivery efficiency by about 1.6 times. Furthermore, DC@AIEdots can stimulate the in vivo proliferation and activation of T cells and trigger the immune system. The potential applications of therapeutic agents targeting lipid droplets for immunotherapy are indicated and a new hitchhiking approach for drug delivery is provided. Lastly, the study presents a photoactive and artificial antigen-presenting platform for effective T cell stimulation and cancer photodynamic immunotherapy.

In vitro anti-melanogenic effects of chimeric compounds, 2-(substituted benzylidene)-1,3-indanedione derivatives with a ß-phenyl-α, ß -unsaturated dicarbonyl scaffold.

Tyrosinase is considered a key contributor to melanogenesis, and safe, potent tyrosinase inhibitors are needed for medical and cosmetic purposes to treat skin hyperpigmentation and prevent fruit and vegetable browning. According to our accumulated SAR data on tyrosinase inhibitors, the ß-phenyl-α,ß-unsaturated carbonyl scaffold in either E or Z configurations, can confer potent tyrosinase inhibitory activity. In this study, twelve indanedione derivatives were synthesized as chimeric compounds with a ß-phenyl-α,ß-unsaturated dicarbonyl scaffold. Two of these derivatives, that is, compounds 2 and 3 (85% and 96% inhibition, respectively), at 50 µM inhibited mushroom tyrosinase markedly more potently than kojic acid (49% inhibition). Docking studies predicted that compounds 2 and 3 both inhibited tyrosinase competitively, and these findings were supported by Lineweaver-Burk plots. In addition, both compounds inhibited tyrosinase activity and reduced melanin contents in B16F10 cells more than kojic acid without perceptible cytotoxicity. These results support the notion that chimeric compounds with the ß-phenyl-α,ß-unsaturated dicarbonyl scaffold represent promising starting points for the development of potent tyrosinase inhibitors.

Design, synthesis and biological evaluation of novel indanone containing spiroisoxazoline derivatives with selective COX-2 inhibition as anticancer agents.

OBJECTIVE: A new family of 3'-(Mono, di or tri-substituted phenyl)-4'-(4-(methylsulfonyl) phenyl) spiroisoxazoline derivatives containing indanone spirobridge was designed, synthesized, and evaluated for their selective COX-2 inhibitory potency and cytotoxicity on different cell lines. METHODS: A synthetic reaction based on 1,3-dipolar cycloaddition mechanism was applied for the regiospecific formation of various spiroisoxazolines. The activity of the newly synthesized compounds was determined using in vitro cyclooxygenase inhibition assay. The toxicity of the compounds was evaluated by MTT assay. In addition, induction of apoptosis, and expression levels of Bax, Bcl-2 and caspase-3 mRNA in MCF-7 cells were evaluated following exposure to compound 9f. The docking calculations and molecular dynamics simulation were performed to study the most probable modes of interactions of compound 9f upon binding to COX-2 enzyme. RESULTS: The docking results showed that the synthesized compounds were able to form hydrogen bonds with COX-2 involving methyl sulfonyl, spiroisoxazoline, meta-methoxy and fluoro functional groups. Spiroisoxazoline derivatives containing methoxy group at the C-3' phenyl ring meta position (9f and 9g) showed superior selectivity with higher potency of inhibiting COX-2 enzyme. Furthermore, compound 9f, which possesses 3,4-dimethoxyphenyl on C-3' carbon atom of isoxazoline ring, exhibited the highest COX-2 inhibitory activity, and also displayed the most potent cytotoxicity on MCF-7 cells with an IC50 value of 0.03 ± 0.01 µM, comparable with that of doxorubicin (IC50 of 0.062 ± 0.012 µM). The results indicated that compound 9f could promote apoptosis. Also, compared to the control group, the mRNA expression of Bax and caspase-3 significantly increased, while that of Bcl-2 significantly decreased upon exposure to compound 9f which may propose the activation of mitochondrial-associated pathway as the mechanism of observed apoptosis. CONCLUSION: In vitro biological evaluations accompanied with in silico studies revealed that indanone tricyclic spiroisoxazoline derivatives are good candidates for the development of new anti-inflammatory and anticancer (colorectal and breast) agents.

FCX-146, a potent allosteric inhibitor of Akt kinase in cancer cells: Lead optimization of the second-generation arylidene indanone scaffold.

Akt, a serine-threonine protein kinase, is regulated by class-I PI3K signaling. Akt regulates a wide variety of cell processes including cell proliferation, survival, and angiogenesis through serine/threonine phosphorylation of downstream targets including mTOR and glycogen-synthase-kinase-3-beta (GSK3ß). Targeting cancer-specific overexpression of Akt protein could be an efficient way to control cancer-cell proliferation. However, the ATP-competitive inhibitors are challenged by the highly conserved ATP binding site, and by competition with high cellular concentrations of ATP. We previously developed an allosteric inhibitor, 2-arylidene-4, 7-dimethyl indan-1-one (FXY-1) that showed promising activity against several lung cancer models. In this work, we designed a congeneric series of molecules based on FXY-1 and optimized lead based on computational, in vitro assays. Computational screening followed by enzyme-inhibition and cell-proliferation assays identified a derivative (FCX-146) as a new lead molecule with threefold greater potency than the parent compound. FCX-146 increased apoptosis in HL-60 cells, mediated in part through decreased expression of antiapoptotic Bcl-2 protein and increased levels of Bax-2 and Caspase-3. Molecular-dynamic simulations showed stable binding of FCX-146 to an allosteric (i.e., noncatalytic) pocket in Akt. Together, we propose FCX-146 as a potent second-generation arylidene indanone compound that binds to the allosteric pocket of Akt and potently inhibits its activation.

Turning Donepezil into a Multi-Target-Directed Ligand through a Merging Strategy.

Thanks to the widespread use and safety profile of donepezil (1) in the treatment of Alzheimer's disease (AD), one of the most widely adopted multi-target-directed ligand (MTDL) design strategies is to modify its molecular structure by linking a second fragment carrying an additional AD-relevant biological property. Herein, supported by a proposed combination therapy of 1 and the quinone drug idebenone, we rationally designed novel 1-based MTDLs targeting Aß and oxidative pathways. By exploiting a bioisosteric replacement of the indanone core of 1 with a 1,4-naphthoquinone, we ended up with a series of highly merged derivatives, in principle devoid of the "physicochemical challenge" typical of large hybrid-based MTDLs. A preliminary investigation of their multi-target profile identified 9, which showed a potent and selective butyrylcholinesterase inhibitory activity, together with antioxidant and antiaggregating properties. In addition, it displayed a promising drug-like profile.

Design, synthesis and biological evaluation of indanone-chalcone hybrids as potent and selective hCES2A inhibitors.

Human carboxylesterase 2 (hCES2A), one of the major serine hydrolases distributed in the small intestine, plays a crucial role in hydrolysis of ester-bearing drugs. Accumulating evidence has indicated that hCES2A inhibitor therapy can modulate the pharmacokinetic and toxicological profiles of some important hCES2A-substrate drugs, such as the anticancer agent CPT-11. Herein, a series of indanone-chalcone hybrids are designed and synthesized to find potent and highly selective hCES2A inhibitors. Inhibition assays demonstrated that most indanone-chalcone hybrids displayed strong to moderate hCES2A inhibition activities. Structure-hCES2A inhibition activity relationship studies showed that introduction of a hydroxyl at the C4' site and introduction of an N-alkyl group at the C6 site were beneficial for hCES2A inhibition. Particularly, B7 (an N-alkylated 1-indanone-chalcone hybrid) exhibited the most potent inhibition on hCES2A and excellent specificity (this agent could not inhibit other human esterases including hCES1A and butyrylcholinesterase). Inhibition kinetic analyses demonstrated that B7 potently inhibited hCES2A-mediated FD hydrolysis in a mixed inhibition manner, with a calculated Ki value of 0.068 µM. Furthermore, B7 was capable of inhibiting intracellular hCES2A in living cells and displayed good metabolic stability. Collectively, our findings show that indanone-chalcone hybrids are good choices for the development of hCES2A inhibitors, while B7 is a promising candidate for the development of novel anti-diarrhea agents to ameliorate irinotecan-induced intestinal toxicity.

Design, synthesis and biological evaluation of rasagiline-clorgyline hybrids as novel dual inhibitors of monoamine oxidase-B and amyloid-ß aggregation against Alzheimer's disease.

A series of rasagiline-clorgyline hybrids was designed, synthesized and investigated in vitro for their inhibition of monoamine oxidase and amyloid-ß aggregation. Most of compounds were found to be selective and highly potent hMAO-B inhibitors showing IC50 values in the nanomolar, and exhibited a moderate inhibition of amyloid-ß aggregation. 7-((5-(methyl(prop-2-yn-1-yl)amino) pentyl)oxy)chroman-4-one (6j) was the most interesting compound identified in this research, endowed with higher hMAO-B potency (IC50 = 4 nM) and selectivity (SI > 25000) compared to the reference selective inhibitor rasagiline (IC50 = 141 nM, SI > 355), and exhibited good inhibitory activity against Aß1-42 aggregation (40.78%, 25 µM). Kinetic and molecular modeling studies revealed that 6j was a competitive reversible inhibitor for hMAO-B. Moreover, compound 6j displayed low toxicity and good neuroprotective effects in SH-SY5Y cell assay, and could penetrate the blood-brain barrier according to the parallel artificial membrane permeability assay. Pharmacokinetics assay revealed that compound 6j possessed good pharmacokinetic profiles after intravenous and oral administrations. Overall, these results highlighted that compound 6j was an effective and promising multitarget agent against Alzheimer's disease.

Bioactive indanes: insight into the bioactivity of indane dimers related to the lead anti-inflammatory molecule PH46A.

OBJECTIVES: PH46A (1) demonstrates significant anti-inflammatory activity in phenotypic models but its mechanism and site of action have been elusive. Current study focused on the bioactivity of PH46 (2) and related novel indane dimers (6-10) to investigate the impact of changes in substitution and stereochemistry at the C-1 and C-2 positions of the PH46 (2) scaffold. METHODS: Cytotoxicity profiles of compounds were established using THP-1 macrophages and SW480 cells. Effects of the compounds were then evaluated at 10 µm using 5-lipoxygenase (LOX) and 15-LOX enzymes, and 5-LOX binding was evaluated in silico against NDGA, nitric oxide (NO) released from LPS-induced SW480 cells and cytokines in THP-1 macrophages (IL-6, IL-1ß, TNF-α and IFN-γ) and in SW480 cells (IL-8). KEY FINDINGS: PH46 (2) and 7 cause reduction in NO, inhibition of 5-LOX with high binding energy and no cytotoxicity effects in THP-1 macrophages and SW480 cell lines (up to 50 µm). The cytokine profiling of the series demonstrated inhibition of IL-6 and TNF-α in THP-1 macrophages together with IL-8 in SW480 cells. CONCLUSIONS: The observed profile of cytokine modulation (IL-6/ TNF-α, IL-8) and inhibition of release of NO and 5-LOX may contribute to the in vivo effects demonstrated by indane dimers and PH46A (1) in murine models of colitis.

Cytotoxic Activity of Aplykurodin A Isolated From Aplysia kurodai against AXIN1-Mutated Hepatocellular Carcinoma Cells by Promoting Oncogenic ß-Catenin Degradation.

Dysregulation of the Wnt/ß-catenin signaling pathway is involved in the development of human hepatocellular carcinoma and has thus emerged as a therapeutic target for this malignant tumor. In this study, we employed sensitive cell-based assays to identify aplykurodin A isolated from Aplysia kurodai as an antagonist of Wnt/ß-catenin signaling. Aplykurodin A inhibited ß-catenin responsive transcription, which was stimulated by a Wnt3a-conditioned medium or a glycogen synthase kinase 3ß inhibitor by accelerating intracellular ß-catenin degradation. Aplykurodin A downregulated the level of oncogenic ß-catenin and decreased the expression of ß-catenin-dependent gene, leading to inhibition of human hepatoma Hep3B and SNU475 cell proliferation. Moreover, apoptosis and autophagy were elicited by aplykurodin A, as indicated by an increase the number of Annexin V-FITC-stained cells and the formation of microtubule-associated protein 1 light chain 3 puncta, respectively, in Hep3B and SNU475 cells. Our findings suggest that aplykurodin A provides a novel therapeutic strategy for human hepatocellular carcinoma via stimulation of oncogenic ß-catenin degradation.

Fast LC-MS quantification of ptesculentoside, caudatoside, ptaquiloside and corresponding pterosins in bracken ferns.

Ptaquiloside (PTA) is an illudane glycoside partly responsible for the carcinogenicity of bracken ferns (Pteridium sp.). The PTA analogues ptesculentoside (PTE) and caudatoside (CAU) have similar biochemical reactivity. However, both compounds are highly under-investigated due to the lack of analytical standards and appropriate methods. This study presents a robust method for preparation of analytical standards of PTE, CAU, PTA, the corresponding hydrolysis products: pterosins G, A and B, and an LC-MS based method for simultaneous quantification of the six compounds in bracken. The chromatographic separation of analytes takes 5 min. The observed linear range of quantification was 20-500 µg/L for PTA and pterosin B, and 10-250 µg/L for the remaining compounds (r > 0.999). The limits of detection were 0.08-0.26 µg/L for PTE, CAU and PTA and 0.01-0.03 µg/L for the pterosins, equivalent to 2.0-6.5 µg/g and 0.25-0.75 µg/g in dry weight, respectively. The method was applied on 18 samples of dried fern leaves from 6 continents. Results demonstrated high variation in concentrations of PTE, CAU and PTA with levels prior to hydrolysis up to 3,900, 2,200 and 2,100 µg/g respectively. This is the first analytical method for simultaneous and direct measurement of all six compounds. Its application demonstrated that bracken ferns contain significant amounts of PTE and CAU relative to PTA.

Two-Carbon Ring Expansion of 1-Indanones via Insertion of Ethylene into Carbon-Carbon Bonds.

A rhodium-catalyzed direct insertion of ethylene into a relatively unstrained carbon-carbon bond in 1-indanones is reported, which provides a two-carbon ring expansion strategy for preparing seven-membered cyclic ketones. As many 1-indanones are commercially available and ethylene is inexpensive, this strategy simplifies synthesis of benzocycloheptenones that are valuable synthetic intermediates for bioactive compounds but challenging to prepare otherwise. In addition, the reaction is byproduct-free, redox neutral, and tolerant of a wide range of functional groups, which may have implications on unconventional strategic bond disconnections for preparing complex cyclic molecules.

Four New Pterosins from Pteris cretica and Their Cytotoxic Activities.

Phytochemical investigation of the aerial parts of Pteris cretica led to the isolation and elucidation of nine pterosins, including four new pterosins, creticolacton A (1), 13-hydroxy-2(R),3(R)-pterosin L (2), creticoside A (3), and spelosin 3-O-ß-d-glucopyranoside (4), together with five known pterosins 5-9. Their structures were identified mainly on the basis of 1D and 2D NMR spectral data, ESI-MS and literature comparisons. Compounds 1 and 3 were new type of petrosins with a six membered ring between C-14 and C-15. The new compounds were tested in vitro for their cytotoxic activities against four human tumor cell lines (SH-SY5Y, SGC-7901, HCT-116, Lovo). Results showed that compounds 1 and 2 exhibited cytotoxic activity against HCT-116 cells with IC50 value of 22.4 µM and 15.8 µM, respectively.