Peter G. Pappas, John H. Rex, Jack D. Sobel, Scott G. Filler, William E. Dismukes, Thomas J. Walsh, and John E. Edwards Division of Infectious Diseases, University of Alabama at Birmingham, Alabama; AstraZeneca Pharmaceuticals, Manchester, Great Britain; Wayne State University School of Medicine, Detroit, Michigan; Harbor–University of California-Los Angeles Medical Center, Torrance, California; and Immunocompromised Host Section, Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland

/pdf/guidelines-for-treatment-of-candidiasis-4yqbm9hcop.pdf

Guidelines for Treatment of Candidiasis

Nitric Oxide Donors: Chemical Activities and Biological Applications

Fluorine has received great attention in all fields of science. “Small atom with a big ego” was the title of the Symposium at the ACS meeting in San Francisco in 2000, where a number of the current scientific and industrial aspects of fluorine chemistry made possible by the small size and high electronegativity of the atom were discussed. This small atom has provided mankind with significant benefits in special products such as poly(tetrafluroethylene) (PTFE), freon, fluoro-liquid crystals, optical fiber, pharmaceutical and agrochemical compounds, and so on, all of which have their own unique properties that are otherwise difficult to obtain.1 For instance, at present, up to 30% of agrochemicals and 10% of pharmaceuticals currently used contain fluorine atoms. Therefore, organic fluorine compounds have received a great deal of interest and attention from the scientists involved in diverse fields of science and technology. Now, not only C-F bond formation but also selective C-F bond activation have become current subjects of active investigation from the viewpoint of effective synthesis of fluoroorganic compounds. The former is highlighted by designing a sophisticated fluorinating reagent for regioand stereocontrolled fluorination and developing versatile multifunctional and easily prepared building blocks. C-F bond formation has been treated extensively in several reviews2 and books.3 The latter is a subject that has been less explored but would be promising for selective defluorination of aliphatic fluorides, cross-coupling with aryl fluorides, and * To whom correspondence should be addressed. Phone: 81-78-803-5799. Fax: 81-78-803-5799. E-mail: amii@kobe-u.ac.jp and uneyamak@cc.okayamau.ac.jp. † Kobe University. ‡ Okayama University. Chem. Rev. 2009, 109, 2119–2183 2119

C-F bond activation in organic synthesis.

Echinocandin antifungal drugs

Natural products to drugs: natural product derived compounds in clinical trials

The currently available antifungal drugs for the treatment of deep-seated mycoses are limited to amphotericin B (AMPH-B), azole compounds, and flucytosine. AMPH-B remains the drug of choice for the treatment of most fungal diseases because it has broad-spectrum and potent fungicidal activity, but it is well known to be toxic (16). Although the azole antifungal agents are considered to be less toxic than AMPH-B, their efficacies against deep-seated, life-threatening mycoses are not satisfactory. In addition, it has been reported that the frequency of isolation of multiazole-resistant strains of Candida species other than Candida albicans is increasing (6). Therefore, there is a critical need for new antifungal agents which are fungicidal, have a broad spectrum of activity and have fewer side effects. Inhibition of glucan synthesis is an attractive target for antifungal agents, since the absence of homologous enzymes in humans may afford a high degree of selectivity for fungi (5). Moreover, an inhibitor of glucan synthesis could possess activity against fungi resistant to other antifungal agents (7, 17, 19). These considerations have led to the development of the echinocandin LY303366 by Eli Lilly & Company and the related pneumocandin MK-0991 by Merck Research Laboratories. Both of these compounds have been introduced into clinical trials (2, 14). The MICs of these compounds for various yeast isolates were determined in accordance with the standard reference method, recently developed by consensus through the National Committee for Clinical Laboratory Standards (9, 12). The guidelines for antifungal susceptibility testing of yeasts were applied to in vitro susceptibility testing of various filamentous fungi (8, 13, 15, 19). Under standard conditions, both LY303366 and MK-0991 displayed substantial activities against Candida and Aspergillus species.

FK463 is a semisynthetic derivative of {"type":"entrez-nucleotide","attrs":{"text":"FR901379","term_id":"525229666"}}FR901379, a water-soluble echinocandin-like lipopeptide with a sulfonate moiety, isolated from the culture broth of Coleophoma empedri (T. Iwamoto, N. Sakamoto, M. Yamashita, M. Ezaki, S. Hashimoto, T. Furuta, M. Okuhara, and M. Kohsaka, Program Abstr. 33rd Intersci. Conf. Antimicrob. Agents Chemother., abstr. 371, 1993). In order to define clearly the in vitro antifungal activity of FK463, we determined the susceptibilities of several clinically important pathogenic fungi under the conditions mentioned above.

In vitro activities of a new lipopeptide antifungal agent, FK463, against a variety of clinically important fungi.

FR109615, a new antibiotic active against Candida, was isolated from Streptomyces setonii No. 7562. Based on the spectroscopic data, the structure of FR109615 was elucidated as cis-2-aminocyclopentane-1-carboxylic acid (1). The compound showed the excellent in vivo efficacy in a generalized infection test of mice.

FR109615, a new antifungal antibiotic from Streptomyces setonii. Taxonomy, fermentation, isolation, physico-chemical properties and biological activity

FR109615, a new antifungal antibiotic from Streptomyces setonii. Taxonomy, fermentation, isolation, physico-chemical properties and biological activity.:TAXONOMY, FERMENTATION, ISOLATION, PHYSICO-CHEMICAL PROPERTIES AND BIOLOGICAL ACTIVITY

The structure of FR109615, a new antifungal antibiotic, was determined to be (1R, 2S)-2-aminocyclopentane-l-carboxylic acid ((-)-cis-2-ACPC: 8a) by X-ray analysis. (-)-cis-2-ACPC (8a) was also synthesized via optical resolution of 3a and 3b derived from (±)-cis-2-ACPC hydrochloride (1). 8a showed potent antifungal activity, while its antipode (+)-cis-2-ACPC (8b) had no activity.

Kazuo Sakane

Papers

In vitro activities of a new lipopeptide antifungal agent, FK463, against a variety of clinically important fungi.

FR109615, a new antifungal antibiotic from Streptomyces setonii. Taxonomy, fermentation, isolation, physico-chemical properties and biological activity

FR109615, a new antifungal antibiotic from Streptomyces setonii. Taxonomy, fermentation, isolation, physico-chemical properties and biological activity.:TAXONOMY, FERMENTATION, ISOLATION, PHYSICO-CHEMICAL PROPERTIES AND BIOLOGICAL ACTIVITY

Synthesis and structure determination of FR109615, a new antifungal antibiotic.

Discovery of FR166124, a novel water-soluble pyrazolo-[1,5-a]pyridine adenosine A1 receptor antagonist.