Total synthesis and antifungal evaluation of cyclic aminohexapeptides

Klein, Larry L.; Li, Leping; Chen, Hui-Ju; Curty, Cynthia B.; DeGoey, David A.; Grampovnik, David J.; Leone, Christina L.; Thomas, Samuel; Yeung, Clinton M.; Funk, Kenneth W.; Kishore, Vimal; Lundell, Edwin O.; Wódka, Dariusz; Meulbroek, Jonathan A.; Alder, Jeffrey; Nilius, Angela M.; Lartey, Paul A.; Plattner, Jacob J.

doi:10.1016/s0968-0896(00)00097-3

Cited by 36 publications

(30 citation statements)

References 15 publications

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“…However, in our hands dehydroalanine is formed almost quantitatively, with similar results using mesylates and tosylates [70]. Diphenylphosphoroyl azide can be used as a replacement for the explosive and toxic hydrazoic acid in the Mitsunobu reactions [75]. However, this method is unattractive as it requires two additional synthetic steps to install and remove the Weinreb amide.…”

Section: Building Blocks For the Synthesis Of Triazole-modified Peptisupporting

confidence: 76%

“…The synthesis of both enantiomeric series was reported for 4-azido proline (10 and 11) but only the two diastereoisomers 12 and 13 of 3-azido proline were published. Klein et al has reported the synthesis of Fmoc-protected 4-azido proline 14 by mesylation and nucleophilic displacement with azide, which gives easy access to this stereoisomer [75]. G omez-Vidal and Silverman synthesized all six azido prolines using Mitsunobu methodology employing the reagent diphenylphosphoroyl azide as a substitute for the highly explosive and toxic reagent hydrazoic acid.…”

Section: Building Blocks For the Synthesis Of Triazole-modified Peptimentioning

confidence: 99%

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Huisgen Cycloaddition in Peptidomimetic Chemistry

Pedersen¹,

Abell²

2011

Amino Acids, Peptides and Proteins in Organic Chemistry

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Section: Building Blocks For the Synthesis Of Triazole-modified Peptisupporting

confidence: 76%

Section: Building Blocks For the Synthesis Of Triazole-modified Peptimentioning

confidence: 99%

Huisgen Cycloaddition in Peptidomimetic Chemistry

Pedersen¹,

Abell²

2011

Amino Acids, Peptides and Proteins in Organic Chemistry

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“…Without reliable in vitro testing, it is possible that promising new compounds would be missed in the initial screening procedures. Although structure– in vitro activity relationships have been frequently investigated in antifungal drug research (5, 9–14), there are no reports from a pharmacodynamic point of view that data from a given MIC method correlates with in vivo activity. Indeed, in vitro susceptibility assays of antifungal activity do not always accurately predict in vivo efficacy (15).…”

mentioning

confidence: 99%

Use of a serum‐based antifungal susceptibility assay to predict the in vivo efficacy of novel echinocandin compounds

Maki

Matsumoto

Watabe

et al. 2008

Microbiology and Immunology

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In vitro susceptibility assays of antifungal activity do not always accurately predict in vivo efficacy. As well as having a clear clinical importance, the ability to predict efficacy is also essential for effective screening of novel drug compounds. Initial screening of novel compounds must often be based on in vitro data. The present report describes the use of serum-MIC, an in vitro test of antifungal susceptibility, to accurately predict in vivo efficacy of echinocandin drugs in a mouse model of disseminated candidiasis. The basis of the serum-MIC method was to measure the inhibitory activity of a test compound against Candida albicans hyphal growth in the presence of pooled mouse serum. For 13 previously uncharacterized echinocandin compounds, as well as for the known echinocandin drugs, micafungin and caspofungin, serum-MIC determinations were shown to give better correlation to efficacy in the animal model than conventional, CLSI standard, in vitro antifungal susceptibility tests. The most accurate prediction of efficacy was obtained when the serum-MIC was adjusted in relation to the serum concentration at 30 min post-treatment. Furthermore, when the efficacy of micafungin was determined by measuring C. albicans kidney burden in the mouse model of infection, the adjusted serum-MIC consistently reflected the effective serum concentrations. Our data indicate that determination of serum-MIC values will facilitate prediction of the in vivo potency of new antifungal compounds such as novel echinocandins. Candida albicans, echinocandin, pharmacodynamics, serum-MIC. Echinocandins are a new class of antifungal lipopeptide which inhibit the synthesis of 1,3-β-D-glucan, a component of the cell wall in many medically important fungi (1-5). They have potent and broad-spectrum antifungal activity which is fungicidal to many Candida Correspondence Katsuyuki Maki, Pharmacology Research Laboratories, Department of Infectious Diseases, Astellas Pharma Inc., 1-6, Kashima 2-chome, Yodogawa-ku, Osaka 532-8514, Japan. Tel: +81 6 6390 1158; fax: +81 6 6304 5367; email: katsuyuki.maki@jp.astellas.com List of Abbreviations: AUC, area under the serum concentration-time curve; c.f.u., colony forming unit; CLSI, Clinical and Laboratory Standards Institute; C max , maximal serum concentration after administration; C 0.5 hr , serum concentration at 0.5 hr after administration; ED 50 , 50% effective dose of compound in mouse model of disseminated infection; HPLC, high performance liquid chromatography; MIC, minimal inhibitory concentration; RPMI-MIC, MIC determined in modified CLSI M27-A2 protocol; SDA, Sabouraud dextrose agar; serum-MIC, MIC determined from the inhibition of mycelial elongation in the presence of pooled mouse serum; sub-MIC, sub-minimal inhibitory concentration; t 1/2 , half-life of serum concentration after administration. Key wordsspp. and fungistatic to Aspergillus spp. Clinically available echinocandin drugs include caspofungin, micafungin, and anidulafungin. Micafungin (FK463) (6, 7) was developed fro...

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“…This compounds also showed bactericidal activities against Staphylococcus aureus [34]. L-homotyrosine has been shown to possess antifungal activity against Candida albicans and C. glabrata by inhibiting β-1,3-glucan synthesis [35]. Docosanedioic acid was identified from E. coli isolated from cockroach (Gromphadorhina portentosa) gut.…”

Section: Discussionmentioning

confidence: 99%

Antibacterial Activities of Selected Pure Compounds Isolated from Gut Bacteria of Animals Living in Polluted Environments

et al. 2020

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Antibiotic resistance is a global threat to public health, further accelerated by the misuse of antibiotics in humans and animals. Our recent studies have shown that gut bacteria of animals living in polluted environments are a potential source of antibacterials. Gut bacteria of cockroaches, water monitor lizards and the turtle exhibited molecules such as curcumenol, docosanedioic acid, N-acyl-homoserine lactone, L-homotyrosine and Di-rhamnolipids. Using purified compounds, assays were performed to determine their antibacterial properties using serial dilution method, cytotoxic effects using lactate dehydrogenase release, and cell viability using MTT assay. The results revealed that the purified compounds exhibited significant antibacterial activities (p < 0.05) against selected Gram-negative (Pseudomonas aeruginosa) and Gram-positive bacteria (Streptococcus pyogenes) with effective MIC50 and MIC90 at µg concentrations, and with minimal effects on human cells as observed from LDH and MTT assays. These findings are significant and provide a basis for the rational development of therapeutic antibacterials. Future studies are needed to determine in vivo effects of the identified molecules together with their mode of action, which could lead to the development of novel antibacterial(s).

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Total synthesis and antifungal evaluation of cyclic aminohexapeptides

Cited by 36 publications

References 15 publications

Huisgen Cycloaddition in Peptidomimetic Chemistry

Huisgen Cycloaddition in Peptidomimetic Chemistry

Use of a serum‐based antifungal susceptibility assay to predict the in vivo efficacy of novel echinocandin compounds

Antibacterial Activities of Selected Pure Compounds Isolated from Gut Bacteria of Animals Living in Polluted Environments

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