Precursor-Directed Generation of Amidine Containing Ammosamide Analogs: Ammosamides E-P.
Precursor-Directed Generation of Amidine Containing Ammosamide Analogs: Ammosamides E-P.
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DOI：
10.1039/c2sc21442c
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发表时间：
2013-01
期刊：
影响因子：
8.4
通讯作者：
Macmillan JB
中科院分区：
文献类型：
--
作者：
Pan E;Oswald NW;Legako AG;Life JM;Posner BA;Macmillan JB
氨酰胺E-F（1-2）是从海洋来源的可变链霉菌中分离的生物碱的氨酰胺家族的脒类似物。进一步研究了S. variabilis揭示了添加到发酵培养基中的各种芳基和烷基胺可以有效地掺入氨基酰胺骨架中，以产生亲核因子导向的脒类似物，氨基酰胺G-P（9 - 18）的文库。我们证明了胺是通过非酶促加成到氨基酰胺C的亚胺离子上而引入的。脒类似物对醌还原酶2（QR 2）的生物学评价显示许多类似物的低nM效力。当检测对一组非小细胞肺癌（NSCLC）细胞系的体内活性时，通过掺入亲脂性烷基胺，效价明显增加，最有效的化合物具有低于μM的IC 50值（0.4至0.8 μM）。
Ammosamides E-F (1-2), are amidine analogs of the ammosamide family of alkaloids isolated from a marine-derived Streptomyces variabilis. Further studies with S. variabilis revealed a variety of aryl and alkyl amines added into the fermentation media could be efficiently incorporated into the ammosamide framework to generate a library of precursor-directed amidine analogs, ammosamides G-P (9 – 18). We demonstrate that the amines are introduced via non-enzymatic addition to the iminium ion of ammosamide C. Biological evaluation of the amidine analogs against quinone reductase 2 (QR2) showed low nM potency for a number of analogs. When tested for in vivo activity against a panel of non-small cell lung cancer (NSCLC) cell-lines there was a clear increase in potency by incorporation of lipophilic alkylamines, with the most potent compounds having sub μM IC50 values (0.4 to 0.8 μM).