Collective Synthesis of Highly Oxygenated (Furano)germacranolides Derived from Elephantopus mollis and Elephantopus tomentosus.

Germacranolides, secondary metabolites produced by plants, have garnered academic and industrial interest due to their diverse and complex topology as well as a wide array of pharmacological activities. Molephantin, a highly oxygenated germacranolide isolated from medicinal plants, Elephantopus mollis and Elephantopus tomentosus, has exhibited antitumor, inflammatory, and leishmanicidal activities. Its chemical structure is based on a highly strained ten-membered macrocyclic backbone with an (E,Z)-dienone moiety, which is fused with an α-methylene-γ-butyrolactone and adorned with four successive stereogenic centers. Herein, we report the first synthesis of molephantin in 12 steps starting from readily available building blocks. The synthesis features the highly diastereoselective intermolecular Barbier allylation of the ß,γ-unsaturated aldehyde with optically active 3-bromomethyl-5H-furan-2-one intermediate and ensuing Nozaki-Hiyama-Kishi (NHK) macrocyclization for the construction of the highly oxygenated ten-membered macrocyclic framework. This synthetic route enabled access to another germacranolide congener, tomenphantopin F. Furthermore, cycloisomerization of molephantin into 2-deethoxy-2ß-hydroxyphantomolin could be facilitated by irradiation with ultraviolet A light (λmax=370 nm), which opened a versatile and concise access to the related furanogermacranolides such as EM-2, phantomolin, 2-O-demethyltomenphantopin C, and tomenphantopin C.

Synthesis and in vitro antifungal activity of new Michael-type amino derivatives of xanthatin, a natural sesquiterpene lactone from Xanthium strumarium L.

Structural optimization using plant secondary metabolites as templates is one of the important approach to discover pesticide molecules with novel skeletons. Xanthatin, a natural sesquiterpene lactone isolated from the Xanthium plants (Family: Compositae), exhibits important biological properties. In this work, a series of Michael-type amino derivatives were prepared from xanthatin and their structures were characterized by 1H NMR, 13C NMR and HR-MS, and their antifungal activities against several phytopathogenic fungi were evaluated according to the spore germination method and mycelium growth rate method in vitro. The results illustrated that compounds 2g (IC50 = 78.91 µg/mL) and 2o (IC50 = 64.51 µg/mL) exhibited more promising inhibition activity against spores of F. solani than precursor xanthatin, compounds 2g, 2l, and 2r exhibited remarkable antifungal effect on C. mandshurica with the average inhibition rates (AIRs) >90%, whereas the AIR of xanthatin was only 59.34%. Meanwhile, the preliminary structure-activity relationships suggested that the amino containing 2-methoxyethyl or 4-chlorophenylmethyl group appended in the C-13 position of xanthatin could yield potential compounds against fungal spores, and the exocyclic double bond of xanthatin is essential to maintain its mycelial growth inhibitory activity. Therefore, the aforementioned findings indicate that partial xanthatin amino-derivatives could be considered for further exploration as the potential lead structures toward development of the new environmentally friendly fungicidal candidates for sustainable crop protection.

Fabrication of self-healing pectin/chitosan hybrid hydrogel via Diels-Alder reactions for drug delivery with high swelling property, pH-responsiveness, and cytocompatibility.

Self-healing hydrogels with pH-responsiveness could protect loaded drugs from being destroyed till it arrives to the target. The pectin-based hydrogel is a candidate due to the health benefit, anti-inflammation, antineoplastic activity, nontoxicity, and biospecific degradation, et al. However, the abundant existence of water-soluble branched heteropolysaccharide chains influenced its performance resulting in limitation of the potential. In the present study, we prepared a series of self-healing pectin/chitosan hydrogels via the Diels-Alder reaction. Moreover, pectin/chitosan composite hydrogel was prepared as a contrast. By comparison, it can be seen that the Diels-Alder reaction greatly improved the cross-linking density of hydrogels. The self-healing experiments showed excellent self-healing performance. In different swelling mediums, significant transformation in the swelling ratio was shown, indicating well-swelling property, pH- and thermo-responsiveness. The drug loading and release studies presented high loading efficiency and sustained release performance. The cytotoxicity assay that showed a high cell proliferation ratio manifested great cytocompatibility.

Photothermally Active Cryogel Devices for Effective Release of Antimicrobial Peptides: On-Demand Treatment of Infections.

There has been significant interest in the use of peptides as antimicrobial agents, and peptide containing hydrogels have been proposed as biological scaffolds for various applications. Limited stability and rapid clearance of small molecular weight peptides pose challenges to their widespread implementation. As a common approach, antibacterial peptides are physically loaded into hydrogel scaffolds, which leads to continuous release through the passive mode with spatial control but provides limited control over drug dosage. Although utilization of peptide covalent linkage onto hydrogels addresses partially this problem, the peptide release is commonly too slow. To alleviate these challenges, in this work, maleimide-modified antimicrobial peptides are covalently conjugated onto furan-based cryogel (CG) scaffolds via the Diels-Alder cycloaddition at room temperature. The furan group offers a handle for specific loading of the peptides, thus minimizing passive and burst drug release. The porous nature of the CG matrix provides rapid loading and release of therapeutic peptides, apart from high water uptake. Interfacing the peptide adduct containing a CG matrix with a reduced graphene oxide-modified Kapton substrate allows "on-demand" photothermal heating upon near-infrared (NIR) irradiation. A fabricated photothermal device enables tunable and efficient peptide release through NIR exposure to kill bacteria. Apart from spatial confinement offered by this CG-based bandage, the selective ablation of planktonic Staphylococcus aureus is demonstrated. It can be envisioned that this modular "on-demand" peptide-releasing device can be also employed for other topical applications by appropriate choice of therapeutic peptides.

Natural product-based semisynthesis and biological evaluation of thiol/amino-Michael adducts of xanthatin derived from Xanthium strumarium as potential pesticidal agents.

Xanthatin, a natural sesquiterpene lactone, occurs as one of the major constituents of Xanthium plants (Compositae) and exhibits many important biological properties. To discover natural products-based pesticides, forty-nine Michael-type thiol/amino adducts of xanthatin were synthesized and characterized, while their pesticidal activities were investigated. Among them, compounds 2c, 2h, 2i, and 2t exhibited more potent antifungal activity against Botrytis cinerea (IC50 = 0.96, 0.38, 6.33, and 7.21 µg/mL, respectively) than xanthatin and the two commercial fungicides. Compounds 2t and 2u displayed broad-spectrum and excellent antifungal effects against all tested phytopathogenic fungi, while their IC50 values ranged from 7.21 to 75.88 µg/mL. Compounds 2a, 2f, 2l, 2m, 2v, 7c, 7e, 7h, 7i, and 7j showed moderate larvicidal activity against Plutella xylostella Linnaeus. Furthermore, compounds 2b, 7g, and 7h demonstrated significant ovicidal activity against P. xylostella with the LC50 values of 14.04, 10.00, and 11.95 mg/L, respectively. These findings suggest that thiol/amino appended in the C-13 position of xanthatin may improve antifungal and ovicidal activities for the derivatives. It was also noticed that the exocyclic double bond of xanthatin is crucial for its larvicidal activity. This work also provides some important hints for further design, synthesis, and structural modification of the xanthanolides sesquiterpene lactones toward development of the new environmentally friendly pesticides for sustainable agricultural production.

Furanoflavones pongapin and lanceolatin B blocks the cell cycle and induce senescence in CYP1A1-overexpressing breast cancer cells.

Expression of cytochrome P450-1A1 (CYP1A1) is suppressed under physiologic conditions but is induced (a) by polycyclic aromatic hydrocarbons (PAHs) which can be metabolized by CYP1A1 to carcinogens, and (b) in majority of breast cancers. Hence, phytochemicals or dietary flavonoids, if identified as CYP1A1 inhibitors, may help in preventing PAH-mediated carcinogenesis and breast cancer. Herein, we have investigated the cancer chemopreventive potential of a flavonoid-rich Indian medicinal plant, Pongamia pinnata (L.) Pierre. Methanolic extract of its seeds inhibits CYP1A1 in CYP1A1-overexpressing normal human HEK293 cells, with IC50 of 0.6 µg/mL. Its secondary metabolites, the furanoflavonoids pongapin/lanceolatin B, inhibit CYP1A1 with IC50 of 20 nM. Although the furanochalcone pongamol inhibits CYP1A1 with IC50 of only 4.4 µM, a semisynthetic pyrazole-derivative P5b, has ∼10-fold improved potency (IC50, 0.49 µM). Pongapin/lanceolatin B and the methanolic extract of P. pinnata seeds protect CYP1A1-overexpressing HEK293 cells from B[a]P-mediated toxicity. Remarkably, they also block the cell cycle of CYP1A1-overexpressing MCF-7 breast cancer cells, at the G0-G1 phase, repress cyclin D1 levels and induce cellular-senescence. Molecular modeling studies demonstrate the interaction pattern of pongapin/lanceolatin B with CYP1A1. The results strongly indicate the potential of methanolic seed-extract and pongapin/lanceolatin B for further development as cancer chemopreventive agents.

Synthetic approaches to access acortatarins, shensongines and pollenopyrroside; potent antioxidative spiro-alkaloids with a naturally rare morpholine moiety.

Pyrrole spiroketal alkaloids (PSAs) are a class of novel natural products that have been recently disclosed. Acortatarin A and acortatarin B, two potent antioxidative spiroalkaloids with a naturally rare morpholine moiety, are important members of this class. These spiroalkaloids are isolated from Acorus tatarinowii, Brassica campestris, Capparis spinose, bread crust, Xylaria nigripes and medicine Shensong Yangxin and could inhibit significantly the reactive oxygen species (ROS) production in high-glucose-induced mesangial cells in a time- and dose-dependent manner. Hence, these natural products are promising starting points for the formation of new therapeutics to medicate cardiovascular diseases, cancer, diabetic complications, and other diseases in which ROS are implicated. The impressive structure combined with an interesting pharmacological activity prompted synthetic chemists to construct an asymmetric synthetic strategy that could be used to access structural derivatives in addition to the larger quantities of natural products required for further biological investigations. This review summarizes the current state of the literature regarding with the synthesis of acortatarin A and B and its other family members viz. shensongine A, B and C, and pollenopyrroside A. The present review discusses the pros and cons of synthetic methodologies, which would be beneficial for further developments in the synthetic methodologies. Hopefully, this struggle pushes the reader's mind to consider new perspectives, think differently and forge new connections.

Structure-Odor Correlations in Homologous Series of Mercapto Furans and Mercapto Thiophenes Synthesized by Changing the Structural Motifs of the Key Coffee Odorant Furan-2-ylmethanethiol.

Furan-2-ylmethanethiol (2-furfurylthiol; 2-FFT, 1) is long-known as a key odorant in roast and ground coffee and was also previously identified in a wide range of thermally treated foods such as meat, bread, and roasted sesame seeds. Its unique coffee-like odor quality elicited at very low concentrations, and the fact that only a very few compounds showing a similar structure have previously been described in foods make 1 a suitable candidate for structure-odor activity studies. To gain insight into the structural features needed to evoke a coffee-like odor at low concentrations, 46 heterocyclic mercaptans and thio ethers were synthesized, 32 of them for the first time, and their odor qualities and odor thresholds were determined. A movement of the mercapto group to the 3-position kept the coffee-like aroma but led to an increase in odor threshold. A separation of the thiol group from the furan ring by an elongation of the carbon side chain caused a loss of the coffee-like odor and also led to an increase in odor thresholds, especially for ω-(furan-2-yl)alkane-1-thiols with six or seven carbon atoms in the side chain. A displacement of the furan ring by a thiophene ring had no significant influence on the odor properties of most of the compounds studied, but the newly synthesized longer-chain 1-(furan-2-yl)- and 1-(thiophene-2-yl)alkane-1-thiols elicited interesting passion fruit-like scents. In total, only 4 out of the 46 compounds also showed a coffee-like odor quality like 1, but none showed a lower odor threshold. Besides the odor attributes, also retention indices, mass spectra, and NMR data of the synthesized compounds were elaborated, which are helpful in possible future identification of these compounds in trace levels in foods or other materials.

Acid-Induced Rearrangement of Epoxygermacranolides: Synthesis of Furanoheliangolides and Cadinanes from Nobilin.

The acid-induced rearrangement of three epoxyderivatives of nobilin 1, the most abundant sesquiterpene lactone in Anthemisnobilis flowers, was investigated. From the 1,10-epoxyderivative 2, furanoheliangolide 5 was obtained, while the 4,5-epoxy group of 3 did not react. Conversely, when the 3-hydroxy function of nobilin was acetylated (12), the 4,5-epoxy derivative did cyclize into cadinanes (15 and 16) under Lewis acid catalysis. The reactivity of the 4,5- and 1,10-epoxy derivatives of nobilin (2 and 3) was compared with that of parthenolide, and rationalized on the basis of quantum chemical calculations. All isolated reaction products were fully characterized by spectroscopic and computational methods, and their in vitro anti-protozoal activity was evaluated. The paper could provide new insights into the biosynthesis of this class of natural products.

Stabilization of the cyclodecadiene derivative isofuranodiene by silver (I) coordination. Mechanistic and biological aspects.

The industrial extraction and further applications of isofuranodiene are limited because at room temperature it spontaneously converts to curzerene, a structurally less active isomer. This work definitively identified the structure of isofuranodiene in the solid state, showing the two methyl groups in syn position. In addition, two bioactive metal cations, namely, silver(I) and copper(II) ions, were used in the attempt to obtain the chemical stability of isofuranodiene: in the case of silver(I), a labile adduct was formed, while in the case of copper(II), a more stable 1:1 adduct was achieved. In the former, the presence of silver did not significantly affect the biological activities of isofuranodiene, while in the latter, the copper(II) coordination suppressed them. The biological activities of the isofuranodiene adducts were then evaluated as antiproliferative agents against human tumor cell lines (HCT116, MDA-MB 231, and T98G). In addition, for the first time, isofuranodiene was tested as an inhibitor of DHFR (DiHydroFolateReductase) from Escherichia coli. Anticancer activity was observed in the isofuranodiene with the AgCF3SO3 adduct, in the tested cell lines, with IC50 values ranging from 4.89µM to 13.06µM, while inhibition assays highlighted a Ki of 6.22µM for isofuranodiene and of 0.17µM for the related silver adduct. Docking studies indicated a binding mode score of -6.83Kcal/mol for isofuranodiene, and an energy value of -11.82Kcal/mol for methotrexate (a classic DHFR inhibitor).

Synthesis and optimization of furano[3,2-d]pyrimidines as selective spleen tyrosine kinase (Syk) inhibitors.

A series of furano[3,2-d]pyrimidine Syk inhibitors were synthesized and optimized for their enzyme potency and selectivity versus other kinases. In addition, ADME properties were assessed and compounds were prepared with optimized profiles for in vivo experiments. Compound 23 was identified as having acceptable pharmacokinetic properties and demonstrated efficacy in a rat collagen induced arthritis model.

The Role of Spongia sp. in the Discovery of Marine Lead Compounds.

A comprehensive review on the chemistry of Spongia sp. is here presented, together with the biological activity of the isolated compounds. The compounds are grouped in sesquiterpene quinones, diterpenes, C21 and other linear furanoterpenes, sesterterpenes, sterols (including secosterols), macrolides and miscellaneous compounds. Among other reports we include studies on the intraspecific diversity of a Mediterranean species, compounds isolated from associated sponge and nudibranch and compounds isolated from S. zimocca and the red seaweed Laurentia microcladia. Under biological activity a table of the reported biological activities of the various compounds and the biological screening of extracts are described. The present review covers the literature from 1971 to 2015.

The Synthesis and Evaluation of Arctigenin Amino Acid Ester Derivatives.

The use of arctigenin (ARG), a traditional medicine with many pharmacological activities, has been restricted due to its poor solubility in water. Five amino acid derivatives of ARG have been synthesized using glycine, o-alanine, valine, leucine, and isoleucine, which have t-butyloxy carbonyl (BOC) as a protective group. In this study, we examined the effects of removing these protective groups. The results showed that the amino acid derivatives have better solubility and nitrite-clearing ability than ARG. Among the compounds tested, the amino acid derivatives without protective group were the best. Based on these results, ARG and its two amino acid derivatives without protective group (ARG8, ARG10) were selected to evaluate their anti-tumor activity in vivo at a dosage of 40 mg/kg. The results indicated that ARG8 and ARG10 both exhibit more anti-tumor activity than ARG in H22 tumor-bearing mice. The tumor inhibition rates of ARG8 and ARG10 were 69.27 and 43.58%, which was much higher than ARG. Furthermore, the mice treated with these compounds exhibited less damage to the liver, kidney and immune organs compared with the positive group. Furthermore, ARG8 and ARG10 improved the serum cytokine levels significantly compared to ARG. In brief, this study provides a method to improve the water solubility of drugs, and we also provide a reference basis for new drug development.

Natural and Synthetic Furanones with Anticancer Activity.

This paper describes the enantioselective synthesis of analogues of sapinofuranones A and B, namely 5-substitutes dihydro- and 5H-furan-ones, and their in vitro growth inhibitory activity against six cancer cell lines in comparison with fungal furanones such as diplofuranone A, diplobifuranylones A and B, as well as (S,S)-enantiomer of sapinofuranone B. The compounds under study displayed weak if any in vitro growth inhibitory activity against the analysed cancer cell lines. -However, it seems that among dihydro- and 5H-furan-ones bearing a 1-hydroxypentyl side chain, the stereochemistry of the furanone ring and that of hydroxylated methine could modify the in vitro growth activity of these compounds. The natural furanones that showed a different unsaturated chain at C-4 or rearranged into a dihydrofuran ring appeared to be inactive in terms of growth inhibitory activity, e.g. displaying growth inhibitory concentration at 50% (GIs) > 100 ptM in all six cancer cell lines analysed.

One-Pot 2-Methyltetrahydrofuran Production from Levulinic Acid in Green Solvents Using Ni-Cu/Al2 O3 Catalysts.

The one-pot hydrogenation of levulinic acid to 2-methyltetrahydrofuran (MTHF) was performed using a series of Ni-Cu/Al2 O3 catalysts in green solvents, such as water and biomass-derived alcohols. Ni/Al2 O3 provided the highest activity, whereas Cu/Al2 O3 was the most selective, reaching a 75 % MTHF yield at 250 °C after 24 h reaction time. Synergetic effects were observed when bimetallic Ni-Cu/Al2 O3 catalysts were used, reaching a 56 % MTHF yield in 5 h at 250 °C for the optimum Ni/Cu ratio. Remarkably, these high yields were obtained using non-noble metal-based catalysts and 2-propanol as the solvent. The catalytic activity and selectivity results are correlated to temperature programmed reduction (TPR), XRD, and STEM characterization data, identifying the role associated with mixed Ni-Cu particles in addition to monometallic Cu and Ni.

Preclinical evaluation of [18F]2FNQ1P as the first fluorinated serotonin 5-HT6 radioligand for PET imaging.

PURPOSE: Brain serotonin 6 receptor (5-HT6) is one of the most recently identified serotonin receptors. It is a potent therapeutic target for psychiatric and neurological diseases, e.g. schizophrenia and Alzheimer's disease. Since no specific fluorinated radioligand has yet been successfully used to study this receptor by positron emission tomography (PET) neuroimaging, the objective of the present study was to study the first 5-HT6 (18)F-labelled radiotracer. METHODS: 2FNQ1P, inspired by the quinolone core of a previous radiotracer candidate, GSK215083, was selected according its 5-HT6 affinity and selectivity and was radiolabelled by (18)F nucleophilic substitution. The cerebral distribution of [(18)F]2FNQ1P was studied in vivo in rats, cats and macaque monkeys. RESULTS: The chemical and radiochemical purities of [(18)F]2FNQ1P were >98 %. In rats, in vitro competition with the 5-HT6 antagonist, SB258585, revealed that the radioligand was displaced dose dependently. Rat microPET studies showed low brain uptake of [(18)F]2FNQ1P, reversed by the P-glycoprotein inhibitor, cyclosporin. On the contrary, PET scans in cats showed good brain penetration and specific striatal binding blocked after pretreatment with unlabelled 2FNQ1P. PET scans in macaque monkeys confirmed high specific binding in both cortical and subcortical regions, specifically decreased by pretreatment with the 5-HT6 receptor antagonist, SB258585. CONCLUSION: 2FNQ1P was initially selected because of its suitable characteristics for 5-HT6 receptor probing in vitro in terms of affinity and specificity. Although in vivo imaging in rats cannot be considered as predictive of the clinical characteristics of the radiotracer, [(18)F]2FNQ1P appeared to be a suitable 5-HT6 PET tracer in feline and primate models. These preclinical results encourage us to pursue the clinical development of this first fluorinated 5-HT6 PET radiotracer.

Synthesis of the Furan Nucleus Promoted by Ytterbium Triflate.

An efficient synthesis of differently substituted furans from acetylene dicarboxylates and ß-dicarbonyl compounds is described. The furan nucleus was built by means of an Yb(OTf)3 catalyzed cycloaddition reaction yielding desired adducts in 91%-98% yield.

Second generation synthesis of the neo-clerodane diterpenoid methyl barbascoate.

The second generation total synthesis of the neo-clerodane diterpenoid, methyl barbascoate, was accomplished in seven or nine linear steps via double enol triflation and subsequent palladium catalyzed double carbonylation, followed by regioselective samarium diiodide mediated conjugate reduction.

A versatile and practical method for regioselective synthesis of polysubstituted furanonaphthoquinones.

An efficient and attractive synthesis of a series of novel poly-functionalized phosphorus zwitterions was achieved via three-component reactions of the corresponding functional nucleophiles, aldehydes, and Bu(3)P in the presence of acidic promoter. These polysubstituted zwitterions could regioselectively undergo further transformations to synthetically important furanonaphthoquinones and related products via the intramolecular Wittig reaction. These methods could have potential application in synthetic and pharmaceutical chemistry for its facilitation and easily accessible commercial materials.

DYZ-2-90, a novel neo-tanshinlactone ring-opened compound, induces ERK-mediated mitotic arrest and subsequent apoptosis by activating JNK in human colorectal cancer cells.

Over the past several decades, there has been a considerable and still growing interest in discovering natural products with anticancer potential from traditional Chinese medicine and increasing their anticancer selectivity by chemical modification. In addition, total synthesis of active compounds from natural products can overcome problems related to poor resource availability. DYZ-2-90 is a novel ring-opened compound modified from neo-tanshinlactone, which is isolated from Chinese medicinal herb tanshen. Both in vitro and in vivo tubulin polymerization assays showed that DYZ-2-90 directly bound to microtubules and rapidly induced tubulin depolymerization, inducing ERK-mediated mitotic arrest and subsequent apoptosis by JNK activation in cancer cells, respectively. These results suggest that the fate of cells that undergo mitotic arrest is dictated by two competing networks activated by DYZ-2-90: the cytoprotective ERK pathway and the stress-related JNK pathway. DYZ-2-90 is therefore a novel microtubule-destabilizing agent and a new drug candidate for cancer therapy. This paper provides a new insight into the model of mitotic cell death, which was proposed in order to elucidate how cancer cells respond to microtubule-interfering agents and prolonged cell cycle delay.