Discovery of Benzocycloalkane Derivatives Efficiently Blocking Bacterial Virulence for the Treatment of Methicillin-Resistant S. aureus (MRSA) Infections by Targeting Diapophytoene Desaturase (CrtN).

Antivirulence strategies are now attracting interest for the inherent mechanism of action advantages. In our previous work, diapophytoene desaturase (CrtN) was identified to be an attractive and drugable target for fighting pigmented S. aureus infections. In this research, we developed a series of effective benzocycloalkane-derived CrtN inhibitors with submicromolar IC50. Analogue 8 blocked the pigment biosynthesis of three MRSA strains with a nanomolar IC50 value. Corresponding to its mode of action, 8 did not function as a bactericidal agent. 8 could sensitize S. aureus to immune clearance. In vivo, 8 was proven to be efficacious in an S. aureus Newman sepsis model and abscess formation model. For two typical MRSAs, USA400 MW2 and Mu50, 8 significantly decreased the staphylococcal loads in the liver and kidneys. Moreover, 8 showed minimal antifungal activity compared to that of NTF. In summary, 8 has the potential to be developed as a therapeutic drug, especially against intractable MRSA issues.

Synthesis and spectral characterization of new bis(2-(pyrimidin-2-yl)ethoxy)alkanes and their pharmacological activity.

The pyrimidine nucleus is an important component of nucleic acids (DNA and RNA) and vitamins (B(2) and folic acid). It is evident from the literature that pyrimidine derivatives possess a wide spectrum of biological activities such as antioxidant, anticancer, antibacterial, and anti-inflammatory activities. On the basis of diverse biological activities, we attempted to synthesize a series of novel bis(2-(pyrimidin-2-yl)ethoxy)alkanes 5a-j in four steps with good yields. 2-Chloropyrimidine (1) was reacted with diethyl malonate in the presence of sodium hydride in dry dimethyl formamide to yield the intermediate diethyl 2-(pyrimidin-2-yl)malonate (2), which on further reaction with sodium chloride and dimethyl sulfoxide yielded ethyl 2-(pyrimidin-2-yl)ethanoate (3). Reduction with sodium borohydride (NaBH(4) ) resulted in the formation of 2-(pyrimidin-2-yl)ethanol (4). This was further reacted with various dibromoalkanes to obtain the title compounds 5a-j. In this current study, we evaluated the antioxidant properties of the title compounds using four in vitro test systems: the 2,2-diphenyl-2-picrylhydrazyl radical-, superoxide radical-, and hydroxyl radical-scavenging assays, and the anti-lipid peroxidation activity test. The title compounds showed promising antioxidant activity when compared to butylated hydroxytoluene. The potency of their antioxidant activity was mainly influenced by the alkyl fragment attached to 2-(pyrimidin-2-yl)ethanol. The ethyl and butyl fragments linked to oxygen led to increased antioxidant activity of the title compounds (i.e., 5b and 5d) in all our in vitro assays.

Stereoselective synthesis of five biologically active, naturally occurring medium and large ring lactones.

Stereoselective syntheses of five naturally occurring, pharmacologically active medium and large ring lactones are described. Key synthetic methods used were, depending on the cases, olefin metatheses, asymmetric allylations and C-glycosidations.

Investigating the influence of extractives on the oil yield and alkane production obtained from three kinds of biomass via deoxy-liquefaction.

The aim of this study is to investigate the influence of extractives on the yield and composition of oil obtained from biomass samples (Artemisia ordosica, corn stalk and wheat straw). Direct deoxy-liquefaction experiments of original and extracted biomass were performed at certain temperature in a stainless steel tubular reactor. Benzene-alcohol solvent extraction had significant effect on the product distribution of biomass, especially on the yield and composition of the product oils. The oil yield of original biomass and alkane content in the oil were in the range of 5.44-9.27% and 8.23-23.64%, while decreased to 3.83-4.45% and 1.07-6.03% for the extracted biomass. This study concludes that most of alkanes in the oil mainly derive from the decomposition of triglyceride and hydrocarbon existed in the extractives of biomass. The results might be helpful to study the origin of alkanes and benzene derivatives in the oil obtained from biomass via direct deoxy-liquefaction.

Production of alkanes (C(7)-C(29)) from different part of poplar tree via direct deoxy-liquefaction.

Poplar leaves, poplar bark and poplar wood were deoxy-liquefied directly in an air-proof stainless steel reactor at different temperatures. The oils from leaves at 350 degrees C, from bark at 400 degrees C and from wood at 450 degrees C, at which the liquid product yields were the maximum, were analyzed by GC-MS. The oils obtained from three parts of poplar tree were quite different from each other in the relative contents of their compositions. The oil from leaves was rich in hydrocarbons (alkanes: C(7)-C(29); aromatics) and poor in phenolics, while oil from wood was rich in phenolics and poor in hydrocarbons. The oil from bark was moderate. Relative contents of hydrocarbons in the leaves oil were as high as 60.01% but decreased to 29.71% in bark oil and 11.43% in wood oil. GC analysis of gases and FT-IR, GC-MS and elemental analysis of oils were performed in this study.

Synthesis and cannabinoid receptor activity of ketoalkenes from Echinacea pallida and nonnatural analogues.

Despite its popularity and widespread use, the efficacy of Echinacea products remains unclear and controversial. Among the various compounds isolated from Echinacea, ketoalkenes and ketoalkenynes exclusively found in the pale purple coneflower (E. pallida) are major components of the extracts. In contrast to E. purpurea alkamides, these compounds have not been synthesized and studied for immunostimulatory effects. We present a practical and useful synthetic approach to the ketoalkenes using palladium-catalyzed cross-coupling reactions and the pharmaceutical results at the human cannabinoid receptors. The synthetic route developed provides overall good yields for the ketoalkenes and is applicable to other natural products with similar 1,4-diene motifs. No significant activity was observed at either receptor, indicating that the ketoalkenes from E. pallida are not responsible for immunomodulatory effects mediated via the cannabinergic system. However, newly synthesized non-natural analogues showed micro-molar potency at both cannabinoid receptors.

Characterization of alkanoyl-10-O-minocyclines in micellar dispersions as potential agents for treatment of human neurodegenerative disorders.

Minocycline is a widely used antibacterial agent. Moreover, it is also demonstrated to be effective in several neurodegenerative disorders, due to its antioxidant and anti-inflammatory activities. However, the last activity is only apparent at very high doses. In fact, minocycline poorly crosses the blood-brain barrier (BBB) due to its low lipophilicity and half-life. The present work details the physicochemical characterization of a series of alkanoyl-10-O-minocycline derivatives (2-6), which are able to produce self-assembled aggregates in aqueous solution. The n-octanol/aqueous phase lipophilicity of minocycline and its derivatives were assessed by theoretical calculation, by shake-flask method, and by reversed-phase HPLC. Moreover, we determined their affinity for membrane phospholipids measuring their HPLC retention on phospholipid-based stationary phases, the so-called "Immobilized Artificial Membranes" (IAMs). Our results indicate high lipophilicity values for the minocycline derivatives (compounds 2-6); these values and the corresponding phospholipid affinities increase with the length of the hydrocarbon moiety substituent. Furthermore, the ability of the investigated alkanoyl-10-O-minocycline derivatives to self-assemble could allow a direct administration by oral and intraperitoneal routes as supramolecular systems. The advantages are an enhancement of drug solubilization, a sustained release, and the consequent less frequent drug administration. Moreover, we can hypothesize the potential solubilization in the micellar core of other poorly water soluble drugs which could improve the therapeutic effects of the pharmaceutical formulation in a combined therapy. Given the high lipophilicity of the title derivatives, they can be supposed to offer higher half-life and a better BBB penetration than minocycline. Since the new derivatives retain the structural features related to the antioxidant and anti-inflammatory effects of minocycline, they can be regarded not only as long-acting antimicrobial agents but also as candidate drugs for a targeted treatment of mental illness.

Potential anticancer activity of naturally occurring and semisynthetic derivatives of aculeatins A and B from Amomum aculeatum.

Activity-guided fractionation of hexanes- and CHCl 3-soluble extracts of Amomum aculeatum leaves, collected in Indonesia, led to the isolation of three new dioxadispiroketal-type ( 3- 5) and two new oxaspiroketal-type ( 6 and 7) derivatives. Nine semisynthetic derivatives ( 1a- 1h and 2a) of the parent compounds, aculeatins A ( 1) and B ( 2), were prepared. All isolates and semisynthetic compounds were tested against a small panel of human cell lines. Of these, aculeatin A ( 1; ED 50 0.2-1.0 microM) was found to be among the most cytotoxic of the compounds tested and was further evaluated in an in vivo hollow fiber assay; it was found to be active against MCF-7 (human breast cancer) cells implanted intraperitoneally at doses of 6.25, 12.5, 25, and 50 mg/kg. However, when 1 was tested using P388 lymphocytic leukemia and human A2780 ovarian carcinoma in vivo models, it was deemed to be inactive at the doses used.

A new polymer-lipid hybrid nanoparticle system increases cytotoxicity of doxorubicin against multidrug-resistant human breast cancer cells.

PURPOSE: This work is intended to develop and evaluate a new polymer-lipid hybrid nanoparticle system that can efficiently load and release water-soluble anticancer drug doxorubicin hydrochloride (Dox) and enhance Dox toxicity against multidrug-resistant (MDR) cancer cells. METHODS: Cationic Dox was complexed with a new soybean-oil-based anionic polymer and dispersed together with a lipid in water to form Dox-loaded solid lipid nanoparticles (Dox-SLNs). Drug loading and release properties were measured spectrophotometrically. The in vitro cytotoxicity of Dox-SLN and the excipients in an MDR human breast cancer cell line (MDA435/LCC6/MDR1) and its wild-type line were evaluated by trypan blue exclusion and clonogenic assays. Cellular uptake and retention of Dox were determined with a microplate fluorometer. RESULTS: Dox-SLNs were prepared with a drug encapsulation efficiency of 60-80% and a particle size range of 80-350 nm. About 50% of the loaded drug was released in the first few hours and an additional 10-20% in 2 weeks. Treatment of the MDR cells with Dox-SLN resulted in over 8-fold increase in cell kill when compared to Dox solution treatment at equivalent doses. The blank SLN and the excipients exhibited little cytotoxicity. The biological activity of the released Dox remained unchanged from fresh, free Dox. Cellular Dox uptake and retention by the MDR cells were both significantly enhanced (p < 0.05) when Dox was delivered in Dox-SLN form. CONCLUSIONS: The new polymer-lipid hybrid nanoparticle system is effective for delivery of Dox and enhances its efficacy against MDR breast cancer cells.

Highly dispersed Ce(III) species on silica and alumina as new photocatalysts for non-oxidative direct methane coupling.

Highly dispersed cerium oxide species on silica and alumina, which mainly exist as Ce(III) species, promote non-oxidative direct methane coupling photocatalytically around room temperature, while Ce(IV) species as CeO2 particles do not behave as a catalyst for this reaction.

Synthesis of (+/-)-aculeatins A and B.

The first synthesis of two new antiprotozoal and natural products was performed using concomitant deprotecting dithiane-phenolic oxidative reactions to form in one-step the 1,7-dioxadispiro[5.1.5.2]pentadecane core.

Practical synthesis of 3-methylnonane-2,4-dione, an intense strawlike and fruity flavored compound.

A practical synthesis of 3-methylnonane-2,4-dione, which is an intense strawlike and fruity flavored compound, has been performed by the aldol condensation of n-hexanal and methyl ethyl ketone, followed by oxidation using sodium hypochlorite in the presence of 4-benzoyloxy-2,2,6,6-tetramethylpiperidine-N-oxide in an overall yield of 59%. The purification of 3-methylnonane-2,4-dione with high purity was performed via copper complexes.

Preparation and root growth-modulatory activity of N-substituted 2-acetylamino-2-ethoxycarbonyl-3-(2-furyl)propanamides.

N-Substituted 2-acetylamino-2-ethoxycarbonyl-3-(2-furyl)propanamides (8) were synthesized through the reaction of amines (13) with 2-acetylamino-2-ethoxycarbonyl-3-(2-furyl)propanoic acid (3b), which was prepared via condensation of 2-(bromomethyl)furan (10b) with diethyl acetamidomalonate, followed by partial hydrolysis of the resultant diethyl ester (3a) in the presence of barium hydroxide. However, bulky amines such as tert-butylamine or 2-trifluoromethylaniline did not afford the corresponding diamides (8). The biological activity of the prepared diamides (8) as root growth modulators was examined by germination assay using rape and leek seeds. N-(5-Bromo-2-thiazolyl)- and N-(4-chloro-2-benzothiazolyl)-2-acetylamino-2-ethoxycarbonyl-3-(2-furyl)propanamides (8h, i) both potently inhibited the root growth of rape seedlings, but were less effective in the case of leek seeds. The herbicide 2,4-dichlorophenoxyacetic acid completely inhibited root growth in both cases.

Synthesis and nematocidal activity of diarylnonanoids related to malabaricones.

Twenty diarylnonanones were synthesized and their nematocidal activity was examined. Among those, the p-hydroxy compound 16 exhibited the strongest activity comparable to the natural diarylnonanoids, malabaricones A and C. Diarylundecanoid 57 also showed appreciable activity.

Synthesis and anti-HIV activity of alpha-thiophenoxy-hydroxyethylamide derivatives.

A series of new anti-HIV derivatives containing a novel alpha-thiophenoxyhydroxyethylamide core have been synthesized, using S-phenylbenzenethiosulfonate as the thiosulfenylating reagent. Some of the new synthesized compounds (1a, 1c, 1g, 1i, 1j and 1l) inhibited HIV replication in cell culture assays (syncytia formation) with effective concentrations (EC(50)) ranging from 0.1-1 microM. Incorporation of thiophenoxy substitution within various pseudomimetic peptide backbones provided a series of highly potent HIV inhibitors.

New alkenyldiarylmethanes with enhanced potencies as anti-HIV agents which act as non-nucleoside reverse transcriptase inhibitors.

Twenty-two new alkenyldiarylmethanes (ADAMs) were synthesized and evaluated for inhibition of HIV-1 replication. The most potent compound proved to be methyl 3',3"-dichloro-4',4"-dimethoxy-5', 5"-bis(methoxycarbonyl)-6,6-diphenyl-5-hexenoate (ADAM II), which displayed an EC50 of 13 nM for inhibition of the cytopathic effect of HIV-1RF in CEM-SS cells. ADAM II inhibited HIV-1 reverse transcriptase with an IC50 of 0.3 microM but was inactive as an inhibitor of HIV-1 attachment/fusion to cells, protease, integrase, and the nucleocapsid protein. Molecular target-based and cell-based assays revealed that ADAM II acted biologically as a nonnucleoside reverse transcriptase inhibitor (NNRTI). ADAM II inhibited replication of a wide variety of laboratory, clinical, and clade-representative isolates of HIV-1 in T cell lines and cultures of peripheral blood mononuclear cells or monocyte/macrophages. Mutations that conferred resistance to ADAM II clustered at residues 101, 103, 108, 139, 179, 181, and 188, which line the nonnucleoside binding pocket of HIV-1 reverse transcriptase. However, HIV-1 NL4-3 strain expressing a mutation at residue 100 of reverse transcriptase, and an AZT-resistant virus, displayed increased sensitivity to ADAM II. Thus, ADAM II could serve as an adjunct therapy to AZT and NNRTIs that select for L100I resistance mutations.