The synthesis and evaluation of a solution phase indexed combinatorial library of non-natural polyenes for reversal of p-glycoprotein mediated multidrug resistance
The synthesis and evaluation of a solution phase indexed combinatorial library of non-natural polyenes for reversal of p-glycoprotein mediated multidrug resistance
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DOI：
10.1021/jo000453m
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发表时间：
2000-08-11
影响因子：
3.6
通讯作者：
Ambudkar, SV
中科院分区：
文献类型：
--
作者：
Andrus, MB;Turner, TM;Ambudkar, SV
基于(-)-stipiamide的多烯组合文库已被构建和评估，用于发现新的多药耐药逆转药物。钯偶联被用来反应每一个单独的碘化乙烯与七个乙炔的混合物在接近1:1的化学计量。该偶联还用于将每个单独的乙炔与六种乙烯基碘化物的混合物反应，以创建13个二维索引池，共42种化合物。单个化合物以等摩尔浓度检测。乙烯基碘化物最初是通过添加丁基硼烷来生成抗1,2-羟甲基产物，现在使用更有效的去甲麻黄碱丙酸硼烯醇醛反应来制造。索引方法非常适合于涉及膜结合靶标的细胞分析，允许使用耐药人乳腺癌MCF7-adrR细胞的分析快速识别逆转剂。有效池的交叉点鉴定出具有良好活性的新化合物。芳基维度池显示R = ph和萘基最有效。乙炔维数R′=苯丙烯醇，丙烯醇最有效。分离的单个化合物，无论是活性的还是无效的，都进行了分析，以证实文库的结果。最有效的新化合物是4ek （R =萘酰基，R' =苯胺醇），在1.45 μ M处，其他非天然单个萘酰胺化合物包括morpholino-amide 4ej （1.69 μ M）也表现出有效的MDR逆转。还鉴定了分子两端的协同活性。通过atp酶和光亲和位移实验确定了与Pgp的直接相互作用。结果表明，多烯逆转剂的两端参与Pgp相互作用，可以进一步修饰以提高效力。
A combinatorial library of polyenes, based on (-)-stipiamide, has been constructed and evaluated for the discovery of new multidrug resistance reversal agents. A palladium coupling was used to react each individual vinyl iodide with a mixture of the seven acetylenes at near 1:1 stoichiometry. The coupling was also used to react each individual acetylene with the mixture of six vinyl iodides to create 13 pools indexed in two dimensions for a total of 42 compounds. Individual compounds were detected at equimolar concentration. The vinyl iodides, made initially using a crotylborane addition to generate the anti1,2-hydroxylmethyl products, were now made using a more efficient norephedrine propionate boron enolate aldol reaction. The indexed approach, ideally suited for cellular assays that involve membrane-bound targets, allowed for the rapid identification of reversal agents using assays with drug-resistant human breast cancer MCF7-adrR cells. Intersections of potent pools identified new compounds with promising activity. Aryl dimension pools showed R = ph and naphthyl as the most potent. The acetylene dimension had R' = phenylalaninol and alaninol as the most potent. Isolated individual compounds, both active and nonpotent, were assayed to confirm the library results. The most potent new compound was 4ek (R = naphthyl, R' = phenylaninol) at 1.45 mu M. Other nonnatural individual naphthyl-amide compounds showed potent MDR reversal including the morpholino-amide 4ej (1.69 mu M). Synergistic activities attributed to the two ends of the molecule were also identified. Direct interaction with Pgp was established by ATPase and photoaffinity displacement assays. The results indicate that both ends of the polyene reversal agent are involved in Pgp interaction and can be further modified for increased potency.