Synthesis of novel xylose free occidiofungin analogues and methods of using them
a technology of xylose and ocidiofungin, which is applied in the field of synthesis of novel xylose free ocidiofungin analogues, can solve the problems of infection and mortality in all hospitalized patients, invasive fungal infections are still a major cause of morbidity and mortality in transplant patients, and achieve superior pharmacological properties and reduce inflammation and toxicity
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example 1
of Semisynthetic Analogues of Occidiofungin
[0106]Occidiofungin was produced and purified as described by Lu et al. and Emrick et al. Chemicals were purchased from Sigma unless otherwise indicated. Wild-type MS14 strain and xylose transferase mutant strain used were obtained from glycerol stocks and cultured on Yeast Peptone Dextrose (YPD) agar plate or broth at 35° C. Occidiofungin was produced from these cultures and used to produce OF-Δxyl analogues as described herein.
[0107]Cleavage of diols on carbons 5 and 6 of the novel amino acid yields an aldehyde containing OF-Δxyl analogue. Sodium periodate breaks apart vicinal diols to form an aldehyde containing analogue of OF-Δxyl (FIGS. 3A-3B). Occidiofungin was dissolved in 50% ACN with 0.1% TFA at a concentration of 1 mg / mL. Sodium periodate was dissolved in ddH2O at a concentration of 1 mg / mL. Equal volume of the two solutions were mixed in a centrifuge tube and incubated at various temperatures from 30-70° C. for 30 min. The reacti...
example 2
nhibitory Concentration (Mic) of the OF-Δxyl Analogues
[0113]Minimum inhibitory concentration (MIC) susceptibility testing was performed following a modified version, as previously reported, of the CLSI M27-A3 methods for the susceptibility testing of yeasts. Incubation temperature was 35° C. and the inoculum size was 0.5-2.5×103 colony-forming units (CFU) / mL for yeasts. MICs were performed to determine the bioactivity of each new OF-Δxyl analogue (Table 3). The minimal inhibitory concentration (MIC) is the lowest concentration of compound that inhibits the visible growth of the yeast after 24 hours of incubation and the assays were performed in duplicate. The aldehyde containing OF-Δxyl analogues with the addition of an undecylamine, dodecylamine, or DL-dihydrosphingosine did not demonstrate any inhibitory activity against C. albicans at the concentration tested. However, the addition of DL-dihydrosphingosine to the aldehyde containing OF-Δxyl analogue exhibited a low micromolar inh...
example 3
l Examples OF-Δxyl Analogues
[0115]The aldehyde containing OF-Δxyl analogue can be used to create new analogues of occidiofungin besides the amine containing OF-Δxyl analogues described above. Synthesis of triazoles can be readily accomplished by addition of various aryl azide in the presence of Cu(ACAC) as a catalyst. This allows for the introduction of various aryl groups and conversion of the aldehyde into a triazole.
[0116]Synthesis of hydrazones: The aldehyde occidiofungin (1) can be treated with a variety of phenyl hydrazines such as i) 2-nitrophenyl hydrazine, 4-nitrophenyl hydrazine or 2,4-dinitrophenyl hydrazine (2,4 DNPH) to produce novel hydrazones. The nitro groups on these hydrazones can be readily reduced using a variety of reducing agents such as NaBH4 / Pd, Pd / H2 and stannous chloride to produce the corresponding amines. The resulting aromatic amines can be subjected to reductive amination with a variety of aliphatic or aromatic aldehydes, such as acetaldehyde, linear ch...
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