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The orally bioavailable 1-deoxy-sphingosine analog, Enigmol, has demonstrated anticancer activity in numerous in vivo settings. However, as no Enigmol analog with enhanced potency in vitro has been identified, a new strategy to improve efficacy in vivo by increasing tumor uptake was adopted. Herein, synthesis and biological evaluation of two novel fluorinated Enigmol analogs, CF3-Enigmol and CF2-Enigmol, are reported. Each analog was equipotent to Enigmol in vitro, but achieved higher plasma and tissue levels than Enigmol in vivo. Although plasma and tissue exposures were anticipated to trend with fluorine content, CF2-Enigmol absorbed into tissue at strikingly higher concentrations than CF3-Enigmol. Using mouse xenograft models of prostate cancer, we also show that CF3-Enigmol underperformed Enigmol-mediated inhibition of tumor growth and elicited systemic toxicity. By contrast, CF2-Enigmol was not systemically toxic and demonstrated significantly enhanced antitumor activity as compared to Enigmol.

Despite highly active antiretroviral therapy (HAART), human immunodeficiency virus-1 (HIV-1) continues to elude eradication. Even in the setting of plasma virologic suppression, HIV-1 RNA can be found in peripheral blood mononuclear cells (PBMCs), genital secretions, gastrointestinal lymphoid tissue, and cerebrospinal fluid (CSF).1,2 Limited penetration of antiretrovirals (ARVs) into these sites may play a role in viral persistence.2,3 HIV-1 invades the central nervous system (CNS) early after infection via macrophages, monocytes, and dendritic cells.4 Over time, HIV-associated neurocognitive disorders (HAND) can develop,5 contributing significantly to morbidity6 and early mortality.7 While severity of HAND has decreased, prevalence remains unchanged since the pre-HAART era: 36.2–44.8%,6 prompting a concern for suboptimal CNS control of HIV. This is supported by reports of elevated neopterin, an inflammatory biomarker, and measurable HIV RNA in the CSF of patients on long term HAART,8,9 both predictive markers for development of HIV-associated dementia.10,11 Some studies suggest that limited CNS penetration by ARVs is associated with HAND.12,13 Molecular size, lipophilicity, affinity for efflux pump transporters, and degree of plasma protein binding are factors that impact drug CNS penetration.14 Lipophilic drugs, including HIV protease inhibitors (PIs), are highly bound to plasma protein, predominantly alpha1-acid glycoprotein (AAG). The plasma unbound (free) drug component is considered pharmacologically active and readily crosses the blood–brain and blood–CSF barriers15,16 therefore highly bound drugs such as PIs may have limited CNS penetration. Two PIs, atazanavir (ATV) and darunavir (DRV), are recommended by the Department of Health and Human Services (DHHS) as part of first-line once daily regimens for ARV-naive patients when boosted with ritonavir (RTV) and given with a backbone of tenofovir disoproxil fumarate/emtricitabine (TDF/FTC).17 Both PIs have characteristics that could impede tissue and CNS penetration, including large molecular size and affinity for efflux pump transporters. However, they differ in their affinity for plasma AAG: ATV is 86% plasma protein bound in vitro whereas DRV is 95% bound.18,19 The degree to which they successfully penetrate the CNS remains unclear. Best et al showed low or undetectable CSF ATV levels in nearly 25% of study participants.20 but measured only total drug concentrations with a lower quantitation limit of 5 ng/mL. In contrast, 3 prior studies have shown that DRV can attain drug concentrations in the CSF exceeding IC50 21–23 ; however, the single study measuring unbound drug concentrations22 examined participants receiving twice daily DRV rather than the DHHS recommended once daily dosing schedule for patients without history of DRV resistance.17 Additionally, measuring random total drug concentrations rather than troughs limited all previous studies. To address these limitations, we evaluated the CSF penetration of once daily DRV relative to ATV, both boosted with RTV and administered with the same background TDF/FTC regimen. We hypothesized that ATV, a PI with lower degree of plasma protein binding, would achieve a higher CSF/plasma unbound drug concentration ratio than DRV. In addition, we compared unbound CSF PI concentrations to their drug-specific IC50 and assessed relationships with CSF HIV-1 RNA and neopterin.

After more than 30 years of research and 30 failed clinical trials with as many different treatments, progesterone is the first agent to demonstrate robust clinical efficacy as a treatment for traumatic brain injuries. It is currently being investigated in two, independent phase III clinical trials in hospital settings; however, it presents a formidable solubility challenge that has so far prevented the identification of a formulation that would be suitable for emergency field response use or battlefield situations. Accordingly, we have designed and tested a novel series of water-soluble analogues that address this critical need. We report here the synthesis of C-20 oxime conjugates of progesterone as therapeutic agents for traumatic brain injuries with comparable efficacy in animal models of traumatic brain injury and improved solubility and pharmacokinetic profiles. Pharmacodynamic analysis reveals that a nonprogesterone steroidal analogue may be primarily responsible for the observed activity.

Enigmol is a synthetic, orally active 1-deoxysphingoid base analogue that has demonstrated promising activity against prostate cancer. In these studies, the pharmacologic roles of stereochemistry and N-methylation in the structure of enigmols were examined. A novel enantioselective synthesis of all four possible 2S-diastereoisomers of enigmol (2-aminooctadecane-3,5-diols) from l-alanine is reported, which features a Liebeskind-Srogl cross-coupling reaction between l-alanine thiol ester and (E)-pentadec-1-enylboronic acid as the key step. In vitro biological evaluation of the four enigmol diastereoisomers and 2S,3S,5S-N-methylenigmol against two prostate cancer cell lines (PC-3 and LNCaP) indicates that all but one diastereomer demonstrate potent oncolytic activity. In nude mouse xenograft models of human prostate cancer, enigmol was equally effective as standard prostate cancer therapies (androgen deprivation or docetaxel), and two of the enigmol diastereomers, 2S,3S,5R-enigmol and 2S,3R,5S-enigmol, also caused statistically significant inhibition of tumor growth. A pharmacokinetic profile of enigmol and N-methylenigmol is also presented.

Atherosclerosis is a disease of oxidative stress and inflammation. AGI-1067 [butanedioic acid, mono[4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-,hydroxyphenyl]thio]-1-methylethyl]thio]-2,6-bis (1,1-dimethylethyl)phenyl] ester] is a metabolically stable derivative of, yet pharmacologically distinct from, the antioxidant drug probucol. It is a member of a novel class of orally active, antioxidant, anti-inflammatory compounds termed vascular protectants and exhibits antiatherosclerotic properties in multiple animal models and in humans. To elucidate its antiatherosclerotic mechanisms, we have evaluated several cellular and molecular properties of AGI-1067 in vitro. AGI-1067 exhibited potent lipid peroxide antioxidant activity comparable with probucol yet demonstrated significantly enhanced cellular uptake over that observed with probucol. AGI-1067, but not probucol, inhibited basal levels of reactive oxygen species (ROS) in cultured primary human endothelial cells and both basal and hydrogen peroxide-induced levels of ROS in the promonocytic cell line, U937. Furthermore, AGI-1067 inhibited the inducible expression of the redox-sensitive genes, vascular cell adhesion molecule-1 (VCAM-1) and monocyte chemoattractant protein-1, in endothelial cells as well as tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta, and IL-6 production in peripheral blood mononuclear cells, whereas probucol had no effect. cDNA array hybridization experiments demonstrated that AGI-1067 selectively inhibited the expression of only a subset of TNF-alpha-responsive and nuclear factor-kappaB (NF-kappaB)-inducible genes in endothelial cells. The inhibitory effect of AGI-1067 on inducible VCAM-1 gene expression occurred at the transcriptional level, yet AGI-1067 had no effect on the activation of the redox-sensitive transcription factor NF-kappaB. These studies suggest that the anti-inflammatory and antiatherosclerotic properties of AGI-1067 may be due to selective inhibition of redox-sensitive endothelial and monocyte inflammatory gene expression. These studies provide a molecular basis for understanding the mechanism of action of this new class of therapeutic antiatherosclerotic compounds.

Measles virus is a highly infectious morbillivirus responsible for major morbidity and mortality in unvaccinated humans. The related, zoonotic canine distemper virus (CDV) induces morbillivirus disease in ferrets with 100% lethality. We report an orally available, shelf-stable pan-morbillivirus inhibitor that targets the viral RNA polymerase. Prophylactic oral treatment of ferrets infected intranasally with a lethal CDV dose reduced viremia and prolonged survival. Ferrets infected with the same dose of virus that received post-infection treatment at the onset of viremia showed low-grade viral loads, remained asymptomatic, and recovered from infection, whereas control animals succumbed to the disease. Animals that recovered also mounted a robust immune response and were protected against rechallenge with a lethal CDV dose. Drug-resistant viral recombinants were generated and found to be attenuated and transmission-impaired compared to the genetic parent virus. These findings may pioneer a path toward an effective morbillivirus therapy that could aid measles eradication by synergizing with vaccination to close gaps in herd immunity due to vaccine refusal.

HIV-1 protease inhibitors (PIs) exhibit different protein binding affinities and achieve variable plasma and tissue concentrations. Degree of plasma protein binding may impact central nervous system penetration. This cross-sectional study assessed cerebrospinal fluid (CSF) unbound PI concentrations, HIV-1 RNA, and neopterin levels in subjects receiving either ritonavir-boosted darunavir (DRV), 95% plasma protein bound, or atazanavir (ATV), 86% bound. Unbound PI trough concentrations were measured using rapid equilibrium dialysis and liquid chromatography/tandem mass spectrometry. Plasma and CSF HIV-1 RNA and neopterin were measured by Ampliprep/COBAS® Taqman® 2.0 assay (Roche) and enzyme-linked immunosorbent assay (ALPCO), respectively. CSF/plasma unbound drug concentration ratio was higher for ATV, 0.09 [95% confidence interval (CI) 0.06–0.12] than DRV, 0.04 (95%CI 0.03–0.06). Unbound CSF concentrations were lower than protein adjusted wild-type inhibitory concentration-50 (IC50) in all ATV and 1 DRV-treated subjects (P < 0.001). CSF HIV-1 RNA was detected in 2/15 ATV and 4/15 DRV subjects (P = 0.65). CSF neopterin levels were low and similar between arms. ATV relative to DRV had higher CSF/plasma unbound drug ratio. Low CSF HIV-1 RNA and neopterin suggest that both regimens resulted in CSF virologic suppression and controlled inflammation.

Targeting host cell factors required for virus replication provides an alternative to targeting pathogen components and represents a promising approach to develop broad-spectrum antiviral therapeutics. High-throughput screening (HTS) identified two classes of inhibitors (2 and 3) with broad-spectrum antiviral activity against ortho- and paramyxoviruses including influenza A virus (IAV), measles virus (MeV), respiratory syncytial virus (RSV), and human parainfluenza virus type 3 (HPIV3). Hit-to-lead optimization delivered inhibitor 28a, with EC50 values of 0.88 and 0.81 μM against IAV strain WSN and MeV strain Edmonston, respectively. It was also found that compound 28a delivers good stability in human liver S9 fractions with a half-life of 165 min. These data establish 28a as a promising lead for antiviral therapy through a host-directed mechanism.

The natural compound curcumin has been investigated as an anticancer agent in many cellular systems, in animal models and in the clinic. The overriding negative characteristics of curcumin are its low solubility, weak potency and poor bioavailability. We have examined the efficacy and mechanism of action of a synthetic curcumin analog, UBS109, in head and neck squamous cell carcinoma. By nephelometry, this analog exhibits considerably greater solubility than curcumin. Pharmacokinetic studies of a single oral dose of UBS109 in mice revealed that peak plasma concentrations were reached at 0.5 hours post-dose (Tmax) with average plasma concentrations (Cmax) of 131 and 248 ng/mL for oral doses of 50 and 150 mg/kg, respectively. The terminal elimination half-lives (T½) for these doses averaged 3.7 and 4.5 hours, respectively. In both in vitro and in vivo studies, we found that UBS109 decreased the levels of phosphorylated IKKβ and phosphorylated p65 and, unexpectedly, increased the levels of phosphorylated IκBα by Western blot analysis. These observations may suggest that UBS109 suppresses tumor growth through, in part, inhibition of NF-κB p65 phosphorylation by PKAc and not through IκBα. Finally, we demonstrate that UBS109 is efficacious in retarding the growth of Tu212 (head and neck) squamous cell carcinoma (SCC) xenograft tumors in mice and may be useful for treating head and neck SCC tumors.

INTRODUCTION AND OBJECTIVES: Retroviral replicating vectors (RRVs) represent a novel gene delivery platform that can achieve efficient transduction of solid tumors through virus propagation within actively dividing cancer cells. FDA has already approved a first-in-human clinical trial of RRV-mediated prodrug-activator gene therapy, which is currently on-going. To further improve their tumor specificity and safety profile in prostate cancer, we have developed RRVs regulated by prostate-specific promoters. METHODS: Prostate-specific promoter sequences ARR2PB (synthetic variant of androgen-dependent probasin promoter) or PSES (androgen-independent, synthetic PSA/PSMA composite promoter) were used to replace the wild-type virus promoter in RRV expressing either the GFP reporter gene (RRVs ACE-GFP-ARR2PB and ACEGFP-PSES, respectively) or the yeast cytosine deaminase prodrugactivator gene, which converts the prodrug 5-fluorocytosine into the active drug 5-fluorouracil (RRVs ACE-CD-ARR2PB and ACE-CDPSES, respectively). RRV replication kinetics and selectivity were examined in prostate (LNCaP, MDA-PCa-2b and PC3) and non-prostate (293T) cell lines and primary human T cells, and in LNCaP subcutaneous xenograft tumors. Cytotoxic effects of prodrug-activator gene therapy were also examined both in vitro and in vivo. Systemic biodistribution was examined by qPCR in male athymic mice after intravenous RRV injection. RESULTS: RRV ACE-GFP-ARR2PB showed efficient replication only in androgen receptor-positive prostate cancer cells, and only in the presence of androgen. RRV ACE-GFP-PSES replication was highly specific for PSA/PSMA-positive prostate cancer cells, with or without androgen. In primary T cells, transgene expression and replication of both prostate-targeted RRVs were highly suppressed compared to non-targeted wild type RRV. In vivo, prostate-targeted RRVs showed efficient spread within LNCaP tumors, and both ACE-CDARR2PB and ACE-CD-PSES achieved effective tumor growth inhibition even after initial transduction at very low levels. Systemic biodistribution of prostate-targeted RRVs was highly restricted to tumor tissues. CONCLUSIONS: ARR2PBand PSES-targeted RRVs exhibit selective replication and efficient gene delivery in prostate cancer models, achieving potent therapeutic efficacy in vitro and in vivo. In particular, PSES-targeted RRVs may be highly useful for gene therapy in castration-resistant prostate cancer. The ability to target RRVs specifically to cancer cells will limit and control the replicative process, and minimize risk to normal cells.

Objectives are to examine the efficacy of new synthetic curcumin analogs EF31 in head and neck squamous cell carcinoma in vitro and in vivo, and study their pharmacokinetic and toxicologic effects in vivo. The synthesis of EF31 was described for the first time. Solubility of EF24, EF31 was compared using nephelometric analysis. Human head and neck squamous cell carcinoma Tu212 xenograft tumors were established in athymic nude mice and treated with EF31 i.p. once daily five days a week for about 5 – 6 weeks. The long term effect of EF31 on the NF-κB signaling system in the tumors was examined by Western blot analysis. EF31 at 25 mg/kg, i.p. inhibited tumor growth almost completely. Solubility of EF24 and EF31 are

The measles virus (MeV), a member of the paramyxovirus family, is an important cause of pediatric morbidity and mortality worldwide. In an effort to provide therapeutic treatments for improved measles management, we previously identified a small, non-nucleoside organic inhibitor of the viral RNA-dependent RNA polymerase (RdRp) by means of high-throughput screening (HTS). Subsequent structure-activity relationship (SAR) studies around the corresponding pyrazole carboxamide scaffold led to the discovery of 2 (AS-136a), a first generation lead with low nanomolar potency against life MeV and attractive physical properties suitable for development. However, its poor water solubility and low oral bioavailability (F) in the rat suggested that the lead could benefit from further SAR studies to improve the biophysical characteristics of the compound. Optimization of in vitro potency and aqueous solubility led to the discovery of 2o (ERDRP-00519), a potent inhibitor of MeV (EC50 = 60 nM) with aqueous solubility of approximately 60 μg/ml. The agent shows a 10-fold exposure (AUC/Cmax) increase in the rat model relative to 2, displays near dose proportionality in the range of 10 mg/kg to 50 mg/kg, and exhibits good oral bioavailability (F = 39%) in the rat. The significant solubility increase appears linked to the improved oral bioavailability.

Background Metastasis, the spread and growth of tumor cells to distant organ sites, represents the most devastating attribute and plays a major role in the morbidity and mortality of cancer. Inflammation is crucial for malignant tumor transformation and survival. Thus, blocking inflammation is expected to serve as an effective cancer treatment. Among anti-inflammation therapies, chemokine modulation is now beginning to emerge from the pipeline. CXC chemokine receptor-4 (CXCR4) and its ligand stromal cell-derived factor-1 (CXCL12) interaction and the resulting cell signaling cascade have emerged as highly relevant targets since they play pleiotropic roles in metastatic progression. The unique function of CXCR4 is to promote the homing of tumor cells to their microenvironment at the distant organ sites. Methodology/Principal Findings We describe the actions of N,N′-(1,4-phenylenebis(methylene))dipyrimidin-2-amine (designated MSX-122), a novel small molecule and partial CXCR4 antagonist with properties quite unlike that of any other reported CXCR4 antagonists, which was prepared in a single chemical step using a reductive amination reaction. Its specificity toward CXCR4 was tested in a binding affinity assay and a ligand competition assay using 18F-labeled MSX-122. The potency of the compound was determined in two functional assays, Matrigel invasion assay and cAMP modulation. The therapeutic potential of MSX-122 was evaluated in three different murine models for inflammation including an experimental colitis, carrageenan induced paw edema, and bleomycin induced lung fibrosis and three different animal models for metastasis including breast cancer micrometastasis in lung, head and neck cancer metastasis in lung, and uveal melanoma micrometastasis in liver in which CXCR4 was reported to play crucial roles. Conclusions/Significance We developed a novel small molecule, MSX-122, that is a partial CXCR4 antagonist without mobilizing stem cells, which can be safer for long-term blockade of metastasis than other reported CXCR4 antagonists.

Plasmodium-infected erythrocytes have been shown to employ sphingolipids from both endogenous metabolism as well as existing host pools. Therapeutic agents that limit these supplies have thus emerged as intriguing, mechanistically distinct putative targets for the treatment of malaria infections. In an initial screen of our library of sphingolipid pathway modulators for efficacy against two strains of the predominant human malaria species Plasmodium falciparum and Plasmodium knowlesi, a series of orally available, 1-deoxysphingoid bases were found to possess promising in vitro antimalarial activity. To better understand the structural requirements that are necessary for this observed activity, a second series of modified analogues were prepared and evaluated. Initial pharmacokinetic assessments of key analogues were investigated to evaluate plasma and red blood cell concentrations in vivo.

Ventral eversible glands (VEG) were removed from larvae of the fall army worm, Spodoptera frugiperda (J. E. Smith), and extracted with methylene chloride. GC analysis of the VEG extract showed that the volatile components were about 98% saturated hydrocarbons. The distribution of individual hydrocarbons was as follows: n-tridecane, 0.1%; n-tetradecane, 2.4%; n-pentadecane, 96.2%; n-hexadecane, 0.3%; and n-heptadecane, 1.0%. Other components present at low levels were 1-pentadecene and three sesquiterpenes. A logarithmic increase in n-pentadecane level in the VEG occurred with successive molts from the third through fifth instar. The level of n-pentadecane in the VEG was empirically higher in fifth instar larvae feeding on corn foliage than in larvae feeding on a pinto bean diet or on cotton or peanut foliage.

The complete assignment of the proton and carbon chemical shifts of 6-O-acetyl-2,3,4-tri-O-(3S-methylpentanoyl)-α-D-glucopyranosyl-β-D-fructofuranoside, a naturally occurring flavor precursor of tobacco, is presented. These assignments were made by comparison of the spectra obtained from 1H-detected heteronuclear multiple quantum coherence and 1H-detected heteronuclear multiple-bond connectivity two-dimensional NMR experiments.

Methodology was developed for the extraction of surface components of sweetpotato (Ipomoea batatas (L.) Lam.) storage roots. Surface components of storage roots were quantitatively extracted with methylene chloride using 8-minute ultrasonication. After removal of the solvent, the extract was treated with 3 Tri Sil-Z :1 trimethylsily lim- idazol (v/v) to convert components with hydroxyl moieties to silyl ethers and then separated on a SE-54 fused silica capillary column. Distinctly different gas chromatography profiles were found between lines displaying moderate levels of resistance ('Resisto', 'Regal', 'Jewel') to the sweetpotato weevil (Cylas formicarius elgantulus (summers)) and weevil-susceptible lines ('Centennial', SC 1149-19, W-115), indicating a possible role of surface components in insect response. Chromatographic fractionation techniques were developed for separation of major components or groups of components. The results will allow subsequent bioassaying for the presence of an ovipositional stimulant(s) and other weevil behavior-modulating compounds and their chemical characterization. The sweetpotato weevil (Cylas spp.) is the single most eco- nomically important insect pest of the sweetpotato world- wide. It attacks both the plant in the field and the edible roots during storage. Cylas spp. feeds and reproduces almost ex- clusively on members of the Ipomoea genus (Cockerham et al., 1954). Some cultivars of sweetpotato have been selected that display moderate resistance to the weevil (Jones et al., 1983, 1985) and provide a potential model for studying the chemical basis for resistance. Plant breeders have often in

(...) The structures of fraction I SE contained one acetic acid group esterified to the fructose moiety in addition to three other aliphatic acids on the glucose portion of the sucrose, while fraction II SE only contained three aliphatic acids esterified to hydroxyl groups on the glucose moiety of the sucrose molecule

In this paper, the isolation of two pentacyclic triterpenoids from the storage root of Centennial and the spectral evidence leading to the elucidation of their structures are presented

A method for the determination of testosterone and its metabolite, 6beta-hydroxytestosterone, in liver microsomal incubates employing gas chromatography with selected ion monitoring mass spectrometric detection (GC-SIM-MS) has been developed. The method is more rapid than previously reported methods. Testosterone and its metabolites are extracted from the incubation mixture in a single step with methylene chloride. The method does not require derivatization and testosterone and its metabolites are separated on a HP-5MS fused-silica capillary column in less than 15 min. The retention times of testosterone (m/z 288), methyltestosterone (m/z 302), and 6beta-hydroxytestosterone (m/z 304) are approximately 12.7, 12.8, and 13.4 min, respectively. There are no interferences from other known CYP450 metabolites of testosterone. In addition, the selectivity and specificity of the mass spectrometer helps eliminate possible interferences from drugs and new chemical entities evaluated using this methodology. Calibration curves for testosterone and 6beta-hydroxytestosterone are linear from 0.25 to 100 microM. Extraction recoveries are better than 92% for both analytes and the internal standard, methyltestosterone. Over the course of five separate runs, within-day and inter-day precision (expressed as relative standard deviation) was less than 5% for all concentrations of testosterone and 6beta-hydroxytestosterone. Accuracies ranged from 95.8 to 105.8% for testosterone and 94.6 to 104.2% for 6beta-hydroxytestosterone. The assay has been used to characterize the CYP3A metabolic activity of multiple preparations of human, rat, and dog liver microsomes.

Trichoderma koningii, isolated from the roots and soil line of an ornamental Diffenbachia sp., yielded, when cultured on shredded wheat, a novel metabolite trivially named koninginin A. The compound is a ketal that weakly inhibits the growth of etiolated wheat coleoptiles at 10-3 m, and is a white, finely crystalline compound with the molecular formula of C16H28O4 and a melting point of 80 ~ 84°C. The structure has been established by UV, IR, 1H NMR, 13C NMR, and MS.

Decomposition and metabolism of the ethylene-releasing plant growth regulator, (2-chloroethyl)methylbis(phenylmethoxy)silane (CGA-15281), was studied over a 14-month period in 3 peach orchard soils. The molecule decomposed rapidly when exposed to a soil environment. Major decomposition products were: ethylene, benzyl alcohol, and low levels of (2-chloroethyl)methyl(phenylmethoxy)chlorosilane and (dichloromethyl)(chloroethylmethylphenylmethoxy)disiloxane which appear to be formed in side reactions of CGA-15281 breakdown. The compounds have molecular ions of 247 and 341 and display molecular ion isotope patterns consistent with molecules containing 2 and 3 chlorine atoms, respectively. Methoxy positions on the parent molecule were largely metabolized to CO2, while the ethyl group was primarily liberated as ethylene. The methyl group on the parent molecule remained bound to the silicon atom, forming insoluble organosilicates; little was metabolized by soil microorganisms to CO2. Soil type had a small but statistically significant effect on degree of release of ethylene from the chloroethyl positions; however, it did not affect metabolism of the methoxy group or degree of partitioning of the methyl group into insoluble compounds. This difference in ethylene release could not be explained by differences in pH, percentage of organic matter, or cation exchange capacity of the soils tested. Soil pH had a pronounced effect on the rate of breakdown of the parent molecule with the most rapid decomposition at low pH.

Surface chemicals of green tobacco leaf were obtained by dipping the leaf into methylene chloride. Leaf wash procedures were developed and evaluated for both small and large numbers of samples. Cuticular constituents containing alcohol functions were derivatized with trimethylsilyl reagents and analyzed by glass capillary gas chromatography on SE-54 columns. Quantitative data were obtained for the major cuticular diterpenoids a- and fl-4,8,13-duvatriene-l-ols, a- and j3-4,8,13-duvatriene-l,3-diols, cis-abienol, labda-13-ene-8,15-diol, and docosanol, hydrocarbons, and sucrose esters. The application of this method allowed the characterization of the cuticular constituents of numerous tobacco varieties and introductions. The relationships between cuticular composition and insect resistance are presented and discussed. The green leaves of commercial tobacco varieties are covered with a gummy exudate, and the composition of these cuticular waxes may be of significant importance. Dietrich and Demole (1977) and Enzell (1977) have reported that the degradation of the cuticular diterpenoids of green tobacco, during curing and aging, results in the production of numerous volatile terpenes, which may be important tobacco flavor components. Reid (1975) reported that a diterpene fraction, isolated from green leaf cuticular waxes, contained precursors of aroma constituents of commercial tobacco. Cutler et al. (1977) have found that the cuticular diterpenes of green tobaccos have plant growth inhibiting properties. The levels of specific cuticular components are believed to be responsible for the observed resistances of some types of tobacco to green peach aphids [Myzus persicae (Sulzer)], tobacco budworm [Heliothis uirescens (F.)], and tobacco hornworm [Muduca sextu (L.)] (Johnson and Severson, 1982,1984; Severson

Cuticular components of the green leaves of the Repandae section of theNicotiana species contain compounds that have been shown to be toxic to larvae of the tobacco hornworm larvae,Manduca sexta. The surface constituents of leaves of greenhouse-grownN. repanda, N. stocktonii, andN. nesophila were extracted with methylene chloride in order to isolate the active compounds. Solvent partitioning and gel chromatography was used to isolate a series of hydroxyacylnornicotines (HOAcylNN). The major component was identified asN'-(3-hydroxy-12-methyltridecanoyl)nornicotine. A number of minor 3-hydroxyacylnornicotines, with the acyl group containing C13-C15, were also identified. The HOAcylNN mixture in ethanol was topically applied to first-instar tobacco hornworm larvae at rates of 10, 50, 100, and 200 μg. Mortalities after 48 hr were 33, 44, 78, and 100% respectively.

Botrytis cinerea, which was isolated from the surface of stored sunflower seed, produced a novel biologically active natural product when cultured on shredded wheat medium. The metabolite, trivially named cinereain, was a ruby red crystalline product with the molecular formula C18H21N3O3 and melting point 201~203°C. The structure was unequivocally established by single crystal X-ray diffraction; UV, IR, NMR (1H and 13C) and mass spectrometry supported the crystallographic data. Cinereain significantly inhibited the growth of etiolated wheat. coleoptiles (p < 0.01) at 10-3 and 10-4 m in bioassays. No effects were noted on treated intact greenhousegrown bean and tobacco plants, but there was mild necrosis and chlorosis in corn.

A rapid, economical method was developed for the evaluation of the potential of different tobacco varieties to produce possibly hazardous smoke compounds. This controlled pyrolysis method produces pyrolyzate fractions very nearly identical with corresponding cigarette smoke fractions, as determined by analyses of their polynuclear aromatic hydrocarbons, neutral constituents, and phenolic contents.

When Neocosmospora tenuicristata was cultured on shredded wheat medium, monorden was produced in relatively large quantities. Monorden significantly (p

The wax ester isolate consisted of a series of C 36 -C 56 homologues, with the C 40 , C 42 , C 44 , C 46 , and C 48 homologues predominating. The major wax ester fatty acids were C 16 , C 18 , C 20 , C 22 , and C 24 . Similar trends in carbon number distribution were found between free and bound fatty alcohols, with the C 22 , C 24 , C 26 , C 28 , C 30 , and C 32 homologues predominating

This work was done as part of a study of the pharmacokinetics and toxicokinetics of GX-071 (N-ethylperfluoro-octanesulfonamide) to support its registration as a pesticide. GX-071 and its major metabolite were identified in the blood of rats and dogs that had been given oral doses of GX-071

Isolement de 2 nouveaux metabolites d'A. ustus, leur structure moleculaire est precisee. On etudie leur activite biologique sur le coleophile de ble (inhibition de la croissance), sur les cultures bacteriennes (Bacillus subtilis et Escherichia coli) sur le poussin (hyperacusie)

Insects have evolved a potpourri of mechanisms for manipulating the allelochemicals that fortify their preferred host plants. A concatenation of physiological and biochemical events frequently follows the ingestion of a toxic natural product and can eventuate in a variety of fates for the compound. A particular allelochemical may be absorbed, metabolized, and sequestered, whereas the fates of concomitant natural products may be very different. Some compounds may be directly excreted in the faeces and their concentration will thus mirror that in the plant. In other cases, selective absorption and sequestration combine to biomagnify minor constituents so that the concentration of these sequestered compounds in insect tissues differs drastically from their concentrations in the host plants. The acridid Romalea guttata is utilized in this paper as a paradigmatic insect which eclectically processes ingested allelochemicals from a wide range of host plants. This generalist herbivore is eminently suitable as a model because it feeds on plants containing a veritable pharmacopoeia of toxic compounds. The proven sequestrative potential of its defensive glands further qualifies R. guttata as an excellent candidate for determining the fates of toxic phytochemicals. An analysis of this insect’s processing strategies for the compounds ingested after feeding on catnip (Nepeta cataria) reveals that for R. guttata variety is the spice of herbivorous life. The results of this investigation persuasively demonstrate that each insect species—and the phytochemical mixture that it ingests—must be regarded as a unique evolutionary case that constitutes a distinctively idiosyncratic phenomenon.

Composition des sclerotes de C. purpura provenant de fetuques elevees, orges ou bles. Comparaison des resultats avec les alcaloides trouves dans les feuilles de fetuques infectees par l'endophyte Sphacetia typhina

(1989). 3,7-Dimethyl-8-hydroxy-6-methoxy-isochroman from Penicillium corylophilum: Plant Growth Regulatory Activity. Agricultural and Biological Chemistry: Vol. 53, No. 7, pp. 1975-1977.

Adults of a generalist herbivore, the lubber grasshopper,Romalea guttata, can be converted to functional specialists by feeding them exclusively on catnip,Nepeta cataria. No obvious adverse effects on adult development resulted from this enforced monophagy. Notwithstanding the fact thatR. guttata has had no coevolutionary relationship with this Eurasian mint, it readily sequesters compounds that are identical to or derived from the terpenoid lactones that are characteristic ofN. cataria. R. guttata appears to both biomagnify minor allelochemicals and to sequester metabolites of theNepeta terpenes in its paired defensive glands. The levels of autogenously produced phenolics are not affected by feeding onN. cataria and the defensive secretions of catnip-fed grasshoppers are more repellent to ants than those of wild-fed acridids. Metabolites of theN. cataria monoterpenes are sequestered in the defensive glands when catnip is added to the natural diet ofR. guttata. The ability of a generalist,R. guttata, to facilely bioaccumulate a potpourri of foreign allelochemicals when feeding in a specialist mode is analyzed in terms of its biochemical, physiological, and functional significance. Sequestration is examined as a response to the enteric effronteries represented by the phytochemicals that can be characteristic of the “overload” in a monophagous diet.