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Taxus wallachiana, Nepalase yew, has many associated endophytic fungi. One of these is a Phoma sp. that lives primarily in the intercellular spaces of tissues in the phloem/cambial region of the tree limbs producing two antibiotic substances: altersolanol A and 2-hydroxy-6-methylbenzoic acid. These compounds were isolated from fungal culture, crystallized, bioassayed, and structurally characterized by X-ray crystallography. The presence of endophytic fungi raises the question as to their role in the tree, however, we suggest that the T. wallachiana/Phoma sp. relationship is a mutualistic one. Normally, the organic solvent extract of yew is not antibacterial, however the organic solvent extract of T. media c.v. Hicksii, inoculated with Phoma sp., possessed antibacterial activity. This extract contains altersolanol A as demonstrated by chromatographic and mass spectroscopic analyses.

Compounds from a soil isolate of Penicillium sp. MG-11 showed remarkable convulsive activity against silkworms. Activity-based fractionation of an acetone extract of the fermentation products resulted in the isolation of four compounds. One was identified as verruculogen, which was an active principle. Another compound, acetoxydehydroaustin, was new and was structurally characterized by spectral data and a single-crystal X-ray analysis. The two other compounds were identified as dehydroaustin and austin on the basis of the spectral data. Although the latter three compounds were not active themselves, they enhanced the convulsive activity of verruculogen in a silkworm bioassay. Three additional compounds with no identifiable activity were also isolated. Two of them were identified as austinol and dehydroaustinol, and the third was determined to be a new related compound named neoaustin by an X-ray analysis of crystals.

The study of bacterial symbionts of eukaryotic hosts has become a powerful discovery engine for chemistry. This highlight looks at four case studies that exemplify the range of chemistry and biology involved in these symbioses: a bacterial symbiont of a fungus and a marine invertebrate that produce compounds with significant anticancer activity, and bacterial symbionts of insects and nematodes that produce compounds that regulate multilateral symbioses.

This study characterizes aminoindole molecules that are analogs of Genz-644442. Genz-644442 was identified as a hit in a screen of ∼70,000 compounds in the Broad Institute's small-molecule library and the ICCB-L compound collection at Harvard Medical School. Genz-644442 is a potent inhibitor of Plasmodium falciparum in vitro (50% inhibitory concentrations [IC 50 s], 200 to 285 nM) and inhibits P. berghei in vivo with an efficacy of >99% in an adapted version of Peters' 4-day suppressive test (W. Peters, Ann. Trop. Med. Parasitol. 69:155–171, 1975). Genz-644442 became the focus of medicinal chemistry optimization; 321 analogs were synthesized and were tested for in vitro potency against P. falciparum and for in vitro absorption, distribution, metabolism, and excretion (ADME) properties. This yielded compounds with IC 50 s of approximately 30 nM. The lead compound, Genz-668764, has been characterized in more detail. It is a single enantiomer with IC 50 s of 28 to 65 nM against P. falciparum in vitro . In the 4-day P. berghei model, when it was dosed at 100 mg/kg of body weight/day, no parasites were detected on day 4 postinfection. However, parasites recrudesced by day 9. Dosing at 200 mg/kg/day twice a day resulted in cures of 3/5 animals. The compound had comparable activity against P. falciparum blood stages in a human-engrafted NOD -scid mouse model. Genz-668764 had a terminal half-life of 2.8 h and plasma trough levels of 41 ng/ml when it was dosed twice a day orally at 55 mg/kg/day. Seven-day rat safety studies showed a no-observable-adverse-effect level (NOAEL) at 200 mg/kg/day; the compound was not mutagenic in Ames tests, did not inhibit the hERG channel, and did not have potent activity against a broad panel of receptors and enzymes. Employing allometric scaling and using in vitro ADME data, the predicted human minimum efficacious dose of Genz-668764 in a 3-day once-daily dosing regimen was 421 mg/day/70 kg, which would maintain plasma trough levels above the IC 90 against P. falciparum for at least 96 h after the last dose. The predicted human therapeutic index was approximately 3, on the basis of the exposure in rats at the NOAEL. We were unable to select for parasites with >2-fold decreased sensitivity to the parent compound, Genz-644442, over 270 days of in vitro culture under drug pressure. These characteristics make Genz-668764 a good candidate for preclinical development.

Title compound (I) shows antifungal activity against amphotericin B-resistant Candida albicans.

Identifying new sources for small molecule discovery is necessary to help mitigate the continuous emergence of antibiotic-resistance in pathogenic microbes. Recent studies indicate that one potentially rich source of novel natural products is Actinobacterial symbionts associated with social and solitary Hymenoptera. Here we test this possibility by examining two species of solitary mud dauber wasps, Sceliphron caementarium and Chalybion californicum. We performed enrichment isolations from 33 wasps and obtained more than 200 isolates of Streptomyces Actinobacteria. Chemical analyses of 15 of these isolates identified 11 distinct and structurally diverse secondary metabolites, including a novel polyunsaturated and polyoxygenated macrocyclic lactam, which we name sceliphrolactam. By pairing the 15 Streptomyces strains against a collection of fungi and bacteria, we document their antifungal and antibacterial activity. The prevalence and anti-microbial properties of Actinobacteria associated with these two solitary wasp species suggest the potential role of these Streptomyces as antibiotic-producing symbionts, potentially helping defend their wasp hosts from pathogenic microbes. Finding phylogenetically diverse and chemically prolific Actinobacteria from solitary wasps suggests that insect-associated Actinobacteria can provide a valuable source of novel natural products of pharmaceutical interest.

A new series of polychlorinated amino acid derivatives were isolated from the tropical marine sponge Dysidea herbacea (Dictyoceratida). Two major hexachlorinated metabolites, dysideathiazole (4) and N-methyldysideathiazole (5), and a minor pentachlorinated compound, 10-dechloro-N-methyldysideathizole (6), were isolated from a specimen from Pohnpei. 10-Dechlorodysideathiazole (7) was isolated as a minor constituent of a Palauan specimen, together with the major metabolites 9,10-didechloro-N-methyldysideathiazole (8) and 10-dechloro-N-methyldysideathiazole (6). A second specimen from Palau contained dysideapyrrolidone (9). The structures of 4-9 were elucidated by spectroscopic methods. The absolute stereochemistry of compounds 4-6 was determined by X-ray crystallography of the natural products and of the carbamate derivatives 17 to be S at all chiral centers

The total synthesis of (-)-ovatolide (1), a tetracyclic indole-containing β-glucosyl derivative with an unusual pyrano[2,3-b] [1,4]dioxocan-6-one system, is described. The β-glucosidic linkage arose from regio- and stereocontrolled reaction of a protected 1,2-epoxyglucal derivative with 4-hydroxy-5-(benzyloxy)indole, and a lactonization reaction afforded the central dioxocanone system. An alternative strategy that afforded the tetracyclic framework as a mixture of epimers is also described

The isolation and structure determination of two bacterial signal molecules which elicit active plant defense responses are reported. The production of these molecules by Gram-negative bacteria requires the action of avirulence gene D (avrD), cloned from Pseudomonas syringae pv. tomato. The structures of ayringolide 1 (1a) and syringolide 2 (1b) are determined by a combination of NMR experiments, biosynthetic arguments, molecular modeling, and X-ray chromatography. A proposed bisynthetic scheme based on the condensation of D-xylulose with a β-ketoalkanoic acid is presented. Further cyclization of the biosynthetic intermediates leads to C-glycosides with a novel tricyclic ring system. These are the first nonproteinaceous specific elicitors of a plant hypersensitive response

Triticones A [1], B [2], C [3], D [4], E [5], and F [6] were isolated from the culture broth of the plant pathogenic fungus Drechslera tritici-repentis(=Pyrenophoria tritici-repentis). The structures of these γ-lactams were determined by a combination of single crystal X-ray diffraction and spectroscopic analyses. A series of 2D nmr experiments has clarified the spectral assignments of triticones A [1] and B [2] and their interconversion

The structures of viridoxins A and B, two novel toxins isolated from the mycelial extract of the funcgus Metarhizium flavoviride, were established by spectroscopic methods, chemical correlations, and a single-crystal X-ray analysis of viridoxin B. The absolute configuration of the viridoxins was determined by 1 H NMR analysis of chiral (R)- and (S)-O-methyl mandelate derivatives of viridoxin A

Five new cembradiene diterpenoids (1–5) and two previously known compounds (7 and 8) have been isolated from an undescribed Caribbean gorgonian of the genus Eunicea. The structures of these compounds were assigned on the basis of chemical and spectral studies, and the relative stereochemistry of cembradiene 3 was defined by X-ray crystallographic methods.

Ohioensins A (1), B (2), C (3), D (4), and E (6), containing the novel polycyclic skeleton of (7bβ,-12bα,14cα)-7b,12b,13,14c-tetrahydro-14H-benzo[c]naphtho[2,1,8-mna]xanthen-14-one,have been isolated from the moss Polytrichum ohioense (Polytrichaceae) following bioassay-directed fractionation. The structures and relative stereochemistry of ohioensins were established on the basis of spectral analysis (UV, IR, MS, 2D NMR, and CD), chemical correlation, and X-ray diffraction

Two chlorine-containing metabolites, nostoclide I and II have been isolated from the culture of a symbiotic blue-green alga, Nostoc sp., in Peltigera canina , a common lichen. Their structures were determined by spectroscopic data and x-ray diffraction.

Three pregnanes, 3,4-dihydroxypregna-5,17-diene-10,2-carbolactone (1), 3,4-dihydroxypregna-5,20-diene-10,2-carbolactone (2) and 3,4-dihydroxypregna-5,15-dien-20-one-10,2-carbolactone (3) were isolated from a sponge, Strongylophora sp. The structures were assigned on the basis of spectral data and confirmed by X-ray crystallography of 1.

The isolation and structure determination of a new chlorinated benzophenone antibiotic, pestalone (1), is described. The new compound was produced by a cultured marine fungus only when a unicellular marine bacterium, strain CNJ-328, was co-cultured in the fungal fermentation. The fungus, isolated from the surface of the brown alga Rosenvingea sp. collected in the Bahamas Islands, was identified as an undescribed member of the genus Pestalotia. The structure of 1, initially assigned with only modest confidence by combined spectral and chemical data, was confirmed by single-crystal X-ray analysis. Pestalone (1) exhibits moderate in vitro cytotoxicity in the National Cancer Institute's 60 human tumor cell line screen (mean GI(50) = 6.0 microM). More importantly, pestalone shows potent antibiotic activity against methicillin-resistant Staphylococcus aureus (MIC = 37 ng/mL) and vancomycin-resistant Enterococcus faecium (MIC = 78 ng/mL), indicating that pestalone should be evaluated in advanced models of infectious disease.

The target compounds are prepared from isatins in two steps by using tert-butyldimethylsilyl amine as an ammonia equivalent.

While the popularity of and expenditures for herbal therapies (aka “ethnomedicines”) have increased globally in recent years, their efficacy, safety, mechanisms of action, potential as novel therapeutic agents, cost-effectiveness, or lack thereof, remain poorly defined and controversial. Moreover, published clinical trials evaluating the efficacy of herbal therapies have rightfully been criticized, post hoc, for their lack of quality assurance and reproducibility of study materials, as well as a lack of demonstration of plausible mechanisms and dosing effects. In short, clinical botanical investigations have suffered from the lack of a cohesive research strategy which draws on the expertise of all relevant specialties. With this as background, US and Chinese co-investigators with expertise in Traditional Chinese Medicine (TCM), botany, chemistry and drug discovery, have jointly established a prototype library consisting of 202 authenticated medicinal plant and fungal species that collectively represent the therapeutic content of the majority of all commonly prescribed TCM herbal prescriptions. Currently housed at Harvard University, the library consists of duplicate or triplicate kilogram quantities of each authenticated and processed species, as well as “detanninized” extracts and sub-fractions of each mother extract. Each species has been collected at 2–3 sites, each separated geographically by hundreds of miles, with precise GPS documentation, and authenticated visually and chemically prior to testing for heavy metals and/or pesticides contamination. An explicit decision process has been developed whereby samples with the least contamination were selected to undergo ethanol extraction and HPLC sub-fractionation in preparation for high throughput screening across a broad array of biological targets including cancer biology targets. As envisioned, the subfractions in this artisan collection of authenticated medicinal plants will be tested for biological activity individually and in combinations (i.e., “complex mixtures”) consistent with traditional ethnomedical practice. This manuscript summarizes the rationale, methods and preliminary “proof of principle” for the establishment of this prototype, authenticated medicinal plant library. It is hoped that these methods will foster scientific discoveries with therapeutic potential and enhance efforts to systematically evaluate commonly used herbal therapies worldwide.

An endophytic fungus isolated from the small palm Asterogyne martiana produced two unusual steroid-like metabolites, asterogynin A (1) and asterogynin B (2), along with the known compounds viridiol (3) and viridin (4). Asterogynins A and B were characterized by NMR and MS spectroscopic analysis.

This paper describes a tactic which has provided satisfactory diastereomeric resolution in such a case. Configuration of the resulting isomers is established crystallographically

Summary: In the present study we wish to report the details of the diastereoselective reactions of titanium enolates derived from N-propionyloxazolidone 1 in inter- and intramolecular Michael reactions with ethyl vinyl ketone, methyl acrylate, and acrylonitrile (eq 1). Several recent publications from this laboratory have illustrated the general utility of imide-derived titanium enolates1*2 derived from N-propionyloxazolidone l3 in a range of diastereoselective bond constructions. The pur- pose of this paper is to disclose our results on the appli- cation of these and related chiral enolates to the Michael reaction. Only a few previous studies have addressed the development of enantioselective Michael reactions of chiral auxiliary based, carboxylic acid derived enolates with a,- P-unsaturated Michael acceptors.' Noteworthy examples include the use of Corey's phenmenthyl-derived ester enolate? a selection of chiral amide enolates surveyed by Yamaguchi? and the chiral Sn(II)-amine-complexed imide enolates reported by Mukaiyama.' The purpose of this Communication is to present our results on the diaster- eoselective reactions of chiral imides such

This paper describes a new class of chiral sulfinyl transfer reagents, 4 and 5 (R = aryl, alkyl), which are readily prepared from the oxazolidinones derived from (4R,SS)-norephedrine (HX,) and (4s)-phenylalanine (HX,), respectively. These N-sulfinyloxazolidinone reagents can be synthesized either by sulfinylation of the metalated oxazolidinones or by oxidation of the derived N-sulfenimides to afford the diastereomeric N-sulfinyloxazolidinones which may be readily purified by chro- matography. These sulfinylating agents react with a wide range of nucleophiles such as Grignard reagents, enolates, lithium alkoxides, or metalated amides, with inversion of configuration at the sulfur center to afford the derived chiral sulfoxides, sulfinate esters, and sulfinamides in high yields and enantioselectivities. Competition experiments have established that this family of chiral sulfinylating agents is at least 100 times as reactive as the corresponding menthyl sulfinate esters toward Grignard reagents.

Three pregnanes, 3,4-dihydroxypregna-5,17-diene-10,2-carbolactone (1), 3,4-dihydroxypregna-5,20-diene-10,2-carbolactone (2) and 3,4-dihydroxypregna-5,15-dien-20-one-10,2-carbolactone (3) were isolated from a sponge, Strongylophora sp. The structures were assigned on the basis of spectral data and confirmed by X-ray crystallography of 1.

An efficient synthesis of dithyreantrile ( 1 ), a novel insect antifeedant, is presented.

Five new cembradiene diterpenoids (1–5) and two previously known compounds (7 and 8) have been isolated from an undescribed Caribbean gorgonian of the genus Eunicea. The structures of these compounds were assigned on the basis of chemical and spectral studies, and the relative stereochemistry of cembradiene 3 was defined by X-ray crystallographic methods.

Zwittermicin A (1), a new linear aminopolyol, was isolated from Bacillus cereus UW85 and its structure was determined by spectroscopic methods.

A series of compounds was investigated in order to determine the factors that govem the cycloaromatization reaction exhibited by dynemicin A and related molecules. It was determined that the stereochemistry at ClOa dictated the thermal reactivity of compounds equipped with an exo-epoxide. Structures containing an a-substituent were unreactive while those possessing a P-substituent underwent cyclization at 80 "C. Molecular mechanics and dynamics calculations indicate that this reactivity difference is due to a steric interaction that develops as the a-substituted compounds undergo a conformational change that appears to be necessary for aromatization to occur. Additionally, a C 10a a-substituted endo-epoxide was synthesized and shown to undergo cycloaromatization under mild acidic conditions via an epoxide opening.