Generation of new derivatives of the antitumor antibiotic mithramycin by altering the glycosylation pattern through combinatorial biosynthesis.
Generation of new derivatives of the antitumor antibiotic mithramycin by altering the glycosylation pattern through combinatorial biosynthesis.
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DOI：
10.1002/cbic.200800299
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发表时间：
2008-09-22
期刊：
影响因子：
3.2
通讯作者：
Mendez, Carmen
中科院分区：
文献类型：
--
作者：
Perez, Maria;Baig, Irfan;Brana, Alfredo F.;Salas, Jose A.;Rohr, Juergen;Mendez, Carmen
光神霉素是一种由泥质链霉菌产生的抗肿瘤药物。它由一个三环糖苷配基和五个脱氧己糖组成，形成一个二糖和一个三糖链，这对靶点相互作用和抗肿瘤活性很重要。使用组合生物合成的方法，我们已经产生了9个光神霉素衍生物，其中7个是新的化合物，在糖基化模式的改变。野生型S. argillaceus菌株和突变体S.已改变d-寡糖生物合成的argillaceus M7 U1被用作宿主以表达各种“糖质粒”，每种质粒指导不同脱氧己糖的生物合成。对新生成的化合物进行了纯化，并通过MS和NMR进行了表征。与光神霉素相比，它们在三糖的第二个（d-橄榄糖、d-真菌糖或d-葡萄糖代替d-橄榄糖）和第三个（d-洋地黄糖代替d-真菌糖）糖单元以及二糖的第一个（d-amicetose代替d-橄榄糖）糖单元中含有不同的糖取代。所有化合物对不同的肿瘤细胞株均表现出抗肿瘤活性。结构-活性关系的基础上讨论的脱氧己糖存在于这些光辉霉素衍生物的数量和类型。
Mithramycin is an antitumor drug produced by Streptomyces argillaceus. It consists of a tricyclic aglycone and five deoxyhexoses that form a disaccharide and a trisaccharide chain, which are important for target interaction and therefore for the antitumor activity. Using a combinatorial biosynthesis approach, we have generated nine mithramycin derivatives, seven of which are new compounds, with alterations in the glycosylation pattern. The wild-type S. argillaceus strain and the mutant S. argillaceus M7U1, which has altered d-oliose biosynthesis, were used as hosts to express various “sugar plasmids”, each one directing the biosynthesis of a different deoxyhexose. The newly formed compounds were purified and characterized by MS and NMR. Compared to mithramycin, they contained different sugar substitutions in the second (d-olivose, d-mycarose, or d-boivinose instead of d-oliose) and third (d-digitoxose instead of d-mycarose) sugar units of the trisaccharide as well as in the first (d-amicetose instead of d-olivose) sugar unit of the disaccharide. All compounds showed antitumor activity against different tumor cell lines. Structure–activity relationships are discussed on the basis of the number and type of deoxyhexoses present in these mithramycin derivatives.
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影响因子：
14.9
作者：
Barceló F;Scotta C;Ortiz-Lombardía M;Méndez C;Salas JA;Portugal J
通讯作者：
Portugal J
影响因子：
2.9
作者：
Remsing, LL;Bahadori, HR;Rohr, J
通讯作者：
Rohr, J
影响因子：
11.2
作者：
Chatterjee, S;Zaman, K;Ratan, RR
通讯作者：
Ratan, RR
影响因子：
--
作者：
Losey, HC;Jiang, JQ;Walsh, CT
通讯作者：
Walsh, CT
影响因子：
15.9
作者：
BLUME, SW;SNYDER, RC;MILLER, DM
通讯作者：
MILLER, DM