Structure-activity relationships of lipopolysaccharide sequestration in N-alkylpolyamines.
Structure-activity relationships of lipopolysaccharide sequestration in N-alkylpolyamines.
复制标题
N-烷基多胺中脂多糖螯合的结构-活性关系。
DOI：
10.1016/j.bmcl.2009.03.055
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发表时间：
2009
影响因子：
2.7
通讯作者：
David,SunilA
中科院分区：
文献类型：
--
作者：
Shrestha,Anurupa;Sil,Diptesh;Malladi,SubbalakshmiS;Warshakoon,HemamaliJ;David,SunilA
我们以前已经表明，简单的N-酰基或N-烷基多胺结合和螯合革兰氏阴性细菌脂多糖，提供保护，防止内毒素中毒的动物模型中的致死性。SAR研究的几个迭代设计和测试循环，包括高通量筛选，已经集中在具有多胺支架的化合物上，这些多胺支架已经根据酰基或烷基附属物的数量、位置和长度进行了广泛的研究。然而，聚胺骨架本身尚未得到充分研究，并且尚不清楚聚亚甲基间距的增量变化是否会影响LPS结合和中和性质。我们现在已经系统地探索了不同伸长的亚精胺[NH 2-（CH 2）3-NH-（CH 2）4-NH 2]和去甲亚精胺[NH 2-（CH 2）3-NH-（CH 2）3-NH 2]主链之间的关系，其中N-烷基在C16保持恒定，以检查改变内部仲胺之间的间距是否可以产生额外的SAR信息。我们发现，norspermine型化合物始终表现出较高的活性相比，相应的精胺同系物。
We have previously shown that simple N-acyl or N-alkyl polyamines bind to and sequester Gram-negative bacterial lipopolysaccharide, affording protection against lethality in animal models of endotoxicosis. Several iterative design-and-test cycles of SAR studies, including high-throughput screens, had converged on compounds with polyamine scaffolds which have been investigated extensively with reference to the number, position, and length of acyl or alkyl appendages. However, the polyamine backbone itself had not been explored sufficiently, and it was not known if incremental variations on the polymethylene spacing would affect LPS-binding and neutralization properties. We have now systematically explored the relationship between variously elongated spermidine [NH2–(CH2)3–NH–(CH2)4–NH2] and norspermidine [NH2–(CH2)3–NH–(CH2)3–NH2] backbones, with the N-alkyl group being held constant at C16in order to examine if changing the spacing between the inner secondary amines may yield additional SAR information. We find that the norspermine-type compounds consistently showed higher activity compared to corresponding spermine homologues.