Cross-coupling reaction of saccharide-based alkenyl boronic acids with aryl halides: the synthesis of bergenin.

A convenient synthetic pathway enabling D-glucal and D-galactal pinacol boronates to be prepared in good isolated yields was achieved. Both pinacol boronates were tested in a series of cross-coupling reactions under Suzuki-Miyaura cross-coupling conditions to obtain the corresponding aryl, heteroaryl, and alkenyl derivatives in high isolated yields. This methodology was applied to the formal synthesis of the glucopyranoside moiety of papulacandin D and the first total synthesis of bergenin.

Synthesis and antifungal activity of ASP9726, a novel echinocandin with potent Aspergillus hyphal growth inhibition.

The synthesis and antifungal activity of ASP9726, a novel echinocandin with potent Aspergillus hyphal growth inhibition and significantly improved MIC against Candida parapsilosis and echinocandin resistant-Candida is described.

Evaluation of fungal-specific fluorescent labeled echinocandin probes as diagnostic adjuncts.

The diagnosis of invasive fungal infections from radiographic imaging is non-specific and problematic. As a first step toward increasing specificity, we describe the development of a broad-spectrum fungal-specific targeting molecule, which when modified with a fluorescent label fully retains its targeting properties, and provides a basis for future imaging applications.

Evaluation of the Sensititre Yeast One microdilution method for susceptibility testing of Candida species to anidulafungin, caspofungin, and micafungin

Introducción. Las equinocandinas representan un nuevo grupo de antifúngicos con gran actividad frente a especies de Candida. El propósito de este estudio fue evaluar el método Sensititre Yeast One para determinar la actividad in vitro de anidulafungina, micafungina y caspofungina frente a especies de Candida aisladas de muestras clínicas. Métodos. Un total de 131 cepas de Candida identificadas como: 42 C. albicans, 36 C. glabrata, 21 C. parapsilosis, 12 C. tropicalis, 10 C. krusei, 3 C. guilliermondii, 2 C. famata, 3 C. kefyr, 1 C. lusitaniae, 1 C. zeylanoides y 1 C. lipolytica, fueron ensayadas mediante el método colorimétrico de microdilución Sensititre Yeast One. Se consideraron sensibles las cepas inhibidas por concentraciones <=2 mg/L de anidulafungina, caspofungina o micafungina. Resultados. El 80,1% de las cepas fueron inhibidas por concentraciones <=0,25 mg/L de anidulafungina y micafungina. La actividad de caspofungina fue ligeramente inferior (78,6% de las cepas inhibidas por concentraciones <=0,25 mg/L). El 96,9% de las cepas resultaron sensibles frente a las tres equinocandinas. Dos cepas de C. parapsilosis (9,5%), 1 de C. guilliermondii y 2 de C. famata no mostraron sensibilidad a una o más equinocandinas. Conclusiones. En nuestra serie, anidulafungina, micafungina y caspofungina fueron efectivas frente a C. albicans, C. glabrata, C. tropicalis, C. krusei, C. kefyr, C. lusitaniae y C. lipolytica. El 96,9% de las cepas fueron sensibles a las tres equinocandinas. Se puede afirmar que las equinocandinas tienen una excelente actividad frente a las especies de Candida más frecuentes en infecciones humanas, excepto Candida parapsilosis(AU)

Introduction. Echinocandins represent a new antifungal group with potent activity against Candida species. The purpose of our study was to evaluate the utility of the Sensititre Yeast One method to determine the in vitro activity of anidulafungin, micafungin, and caspofungin against Candida species isolated from clinical specimens. Methods. A total of 131 Candida strains were tested using Sensititre Yeast One colorimetric microdilution method. They belonged to the following species: 42 C. albicans, 36 C. glabrata, 21 C. parapsilosis, 12 C. tropicalis, 10 C. krusei, 3 C. guilliermondii, 2 C. famata, 3 C. kefyr, 1 C. lusitaniae, 1 C. zeylanoides, and 1 C. lipolytica. For being considered susceptible the strains had to be inhibited by concentrations <=2 mg/L of anidulafungin, caspofungin or micafungin. Results. The 80.1% of the strains tested were inhibited by concentrations <=0.25 mg/L of anidulafungin and micafungin. The activity of caspofungin was slightly lower (78.6% of strains inhibited by concentrations <=0.25 mg/L). The 96.9% of strains turned out susceptible to concentrations <=2 mg/L against the three echinocandins. Two strains of C. parapsilosis (9.5%), one of C. guilliermondii, and two of C. famata showed non-susceptible to one or more echinocandins. Conclusions. In our series, anidulafungin, micafungin, and caspofungin were effective against C. albicans, C. glabrata, C. tropicalis, C. krusei, C. kefyr, C. lusitaniae and C. lipolytica. The 96.9% of strains were susceptible to all three echinocandins. Thus, echinocandins are proved to exhibit excellent activity to the Candida species most frequently involved in human infections, except Candida parapsilosis(AU)

Mutual influence of backbone proline substitution and lipophilic tail character on the biological activity of simplified analogues of caspofungin.

The echinocandins represent the most recent class of antifungal drugs. Previous structure-activity relationship studies on these lipopeptides have relied mainly upon semisynthetic derivatives due to their complex chemical structures. A successful strategy for the rapid enantioselective synthesis of the branched fatty acid chain of caspofungin and analogues was developed to synthesize several simplified analogues of caspofungin. The specific minimum inhibitory activity of each mimic was determined against a panel of Candida strains. This approach gave access to new fully synthetic derived caspofungin mimics with high and selective antifungal activities against Candida strains. In addition, the data suggested an important role of the hydroxy proline residue in the bioactive conformation of the macrocyclic peptide ring structure.

Synthesis and antifungal activities of glycosylated derivatives of the cyclic peptide fungicide caspofungin.

Diseases caused by systemic fungal infections have become a significant clinical problem in recent decades. A series of glycosyl derivatives of the approved cyclic peptide antifungal drug caspofungin conjugated with ß-D-glucopyranose, ß-D-galactopyranose, ß-D-xylopyranose, ß-L-rhamnopyranose, ß-maltose and ß-lactose units were designed, synthesized, and evaluated as new potential antifungal drugs. The compounds were obtained by coupling the corresponding glycosyl amines to the free primary amino groups of caspofungin through a bifunctional glutaryl linker. In contrast to caspofungin, these glycosylated derivatives are soluble in water, but are not hygroscopic and moreover, are more stable than caspofungin under high humidity and temperature. CD studies showed that glycosylation has very little impact on the conformation of the cyclic peptide of caspofungin. In vitro antifungal tests against seven human pathogenic fungi revealed that the caspofungin-monosaccharide conjugates, but not the disaccharide conjugates, have increased antifungal activities against the majority of tested fungus species relative to caspofungin. The ß-D-glucopyranosyl derivative 2 a showed the strongest and broadest antifungal activity, providing a lead for further studies.

Synthesis of O-spiro-C-aryl glycosides using organocatalysis.

An organocatalysis strategy has been developed toward the synthesis of O-spiro-C-aryl glycosides with different configurations in the sugar part. This strategy has been extended to the synthesis of the Papulacandin class of compounds.

Synthesis and evaluation of novel macrocyclic antifungal peptides.

Echinocandins are a novel class of macrocyclic antifungal peptides that act by inhibiting the ß-(1,3)-D-glucan synthase complex, which is not present in mammalian cells. Due to the large number of hydroxyl groups present in these complex macrocyclic lipopeptides, most structure-activity relationship studies have relied upon semisynthetic derivatives. In order to probe the influence of the cyclic peptide backbone on the antifungal activity we developed a successful strategy for the synthesis of novel echinocandins analogues by on-resin ring closing metathesis or disulfide formation. The specific minimum inhibitory activity of each mimic was determined against Candida albicans. Our results indicate that ring size is an important factor for antifungal activity.

Synthesis of ß,γ-dihydroxyhomotyrosines by a tandem Petasis-asymmetric dihydroxylation approach.

Petasis reactions of substituted styrenylboronic acids and glyoxylic acid, employing tert-butylsulfinamide as the 'amine' component, proceed with high stereoselectivity to produce ß,γ-dehydrohomoarylalanine derivatives. Subsequent asymmetric dihydroxylation under neutral conditions gives the corresponding protected ß,γ-dihydroxyhomoarylalanines with up to 15:1 dr. The method has been exploited in the efficient, stereoselective synthesis of protected ß,γ-dihydroxyhomotyrosine, a component of the antifungal cyclic peptide echinocandin B.

The interplay of invention, discovery, development, and application in organic synthetic methodology: a case study.

This Perspective chronicles the conceptual development, proof of principle, exploration of scope, mechanistic investigations, and applications in natural product total synthesis of palladium-catalyzed cross-coupling reactions of silicon derivatives. The explication of how this new class of cross-coupling reactions evolved from problem formulation to use in complex molecule synthesis serves as one goal of the essay. The other goal is the presentation of the various stages of this methodological enterprise such that the reader gleans a first hand look at one approach to the creation of new synthetic reactions. These two goals are woven together such that the underlying thought processes that guide a program of reaction development emerge in clear view and imbue the chemical tapestry with a cohesive logic.

Novel echinocandin antifungals. Part 2: Optimization of the side chain of the natural product FR901379. Discovery of micafungin.

Further optimization of the potent antifungal activity of side chain analogs of the natural product FR901379 led to the discovery of compound 8 with an excellent, well-balanced profile. Potent compounds with reduced hemolytic potential were designed based upon a disruption of the linearity of the terphenyl lipophilic side chain. The optimized compound (8, FK463, micafungin) displayed the best balance and was selected as the clinical candidate.

Novel echinocandin antifungals. Part 1: novel side-chain analogs of the natural product FR901379.

A series of novel acylated analogs of the novel water-soluble echinocandin FR901379 have been prepared and evaluated for antifungal and hemolytic activity. A relationship between antifungal activity and lipophilicity of the acyl side chain, expressed as ClogP was demonstrated, and an analog (3c) with 5.5- to 8-fold superior in vivo activity relative to the previously disclosed 4-(n-octyloxy)benzoyl side chain analog, FR131535 obtained.