Design of anticandidal agents: synthesis and biological properties of analogues of polyoxin L.
Design of anticandidal agents: synthesis and biological properties of analogues of polyoxin L.
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抗念珠菌剂的设计：多氧菌素L类似物的合成和生物学特性。
DOI：
10.1021/jm00364a030
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发表时间：
1983
影响因子：
7.3
通讯作者：
Naider,F
中科院分区：
文献类型：
--
作者：
Shenbagamurthi,P;Smith,HA;Becker,JM;Steinfeld,A;Naider,F
以尿苷为原料合成了6个多抗霉素L类似物。所有这些类似物都抑制白色念珠菌几丁质合成酶。多氧霉素类似物的胺端衍生化导致活性丧失，含芳香族氨基酸残基的多氧霉素类似物是最有效的几丁质合成酶抑制剂。引起几丁质合成酶活性50%抑制的异氰尿嘧啶多氧霉素C，8的浓度为1.6 × 10 - 6 μ M。这实际上与多氧霉素D的活性相同。没有一种抑制剂能有效地竞争（Met）3进入C.白色念珠菌。所有的类似物都能引起培养物中酵母菌的严重形态畸变，并且许多类似物能杀死C。白色念珠菌在毫摩尔浓度。多氧菌素是一系列肽基核苷类抗生素，对真菌和节肢动物的几丁质合成酶具有强烈的抑制作用。3、4已知它们对植物病原真菌5和昆虫4都有剧毒，但对脊椎动物无毒。6.在哺乳动物系统中没有可检测到的毒性，这使得多氧霉素作为对抗全身性真菌感染的潜在药剂具有吸引力。然而，以前的工作人员得出结论，多抗霉素对医学上重要的真菌，如白色念珠菌没有活性。6 '1 89两份报告8，9认为，这种活性的缺乏可能是由于抗生素不能穿透细胞到达几丁质合成酶的位点。支持这一建议的是，多氧菌素对来自一种植物的几丁质合成酶制剂表现出类似的活性。
Six analogues of polyoxin L were synthesized from uridine. All of these analogues inhibited chitin synthetase from Candida albicans. Derivatization of the amine terminus of the polyoxin analogues resultedin loss of activity, and analogues containing aromatic amino acid residues were the most efficient inhibitors ofchitin synthetase. The concentration of tryptophanyl uracil polyoxin C, 8, which caused 50% inhibition of chitin synthetase activity, was 1.6 X 10^ M. This was virtually identical with the activity found for polyoxin D. None of the inhibitors effectively competed with the entry of (Met) 3 into C. albicans. All of the analogues caused severe morphological distortions of the yeast in culture, and a number of analogues killed C. albicans at millimolar concentrations. The results suggest that chitin synthetase inhibitors may have potential as anticandidal drugs.The polyoxins are a series of peptidyl nucleoside antibiotics that strongly inhibit chitin synthetase from a spectrum of fungi1, 2 and arthropods. 3, 4 They are known to be highly toxic against both phytopathogenicfungi5 and insects4 but are not toxic to vertebrates. 6 The absence of detectable toxicity in mammalian systems makes the polyoxins attractive as potential agents against systemic fungal infections. However, previous workers concluded that polyoxins are not active against medically important fungi, such as Candida albicans. 6’1 89Two reports8, 9 sug-gested that this lack of activity might result from the inability of the antibiotic to penetrate the cell to the site of chitin synthetase. Support for this suggestion is found in the observations that the polyoxins exhibit similar ac-tivities against chitin synthetase preparations from a va-