High-throughput synthesis and screening of platinum drug candidates.
High-throughput synthesis and screening of platinum drug candidates.
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铂类候选药物的高通量合成与筛选。
DOI：
10.1007/s007750000170
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发表时间：
2000
期刊：
影响因子：
--
通讯作者：
Lippard,SJ
中科院分区：
文献类型：
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作者：
Ziegler,CJ;Silverman,AP;Lippard,SJ
铂类药物在癌症治疗中发挥着重要作用，但仍有改进的空间。在这里，我们提出了一种新的铂类药物发现策略，以确定具有与顺铂同等疗效的化合物，期望其中一些可能会增加可治疗肿瘤的光谱和/或降低剂量限制毒性。铂候选药物是通过使用自动合成来产生的，利用这种合成的效果或通过使用氯化银沉淀来激活起始材料。在高通量转录实验中对反应产物进行活性筛选，并对最有希望的候选进行了表征。通过监测连接荧光共振能量转移(FRET)染料CCF_2/AM两半的内酰胺环的裂解，筛选了超过3600种反应产物，以了解它们抑制BLAM HeLa细胞中β-内酰胺酶转录的能力。从这个筛选中，有三个反应产生了很好的候选物，在这些反应产物中鉴定了四个物种。其中三个化合物，顺-[(异丙胺)2PtCl2]，顺-[(环丁胺)2PtCl2]和顺-[胺(环丁胺)PtCl2]，已被确定为顺铂的活性类似物。第四个化合物顺式-[氨基(2-氨基-3-甲基)吡啶]PtCl2代表了一种新的抗肿瘤候选药物，类似于最近报道的类似物ZD0473。这些化合物的发现是一个重要的原则证明，可以用这种方式快速制备和筛选铂类抗癌药物候选药物。
Platinum drugs play an important role in the treatment of cancer, but there is room for improvement. Here we present a new platinum drug-discovery strategy to identify compounds having efficacy equivalent to that of cisplatin with the expectation that some may increase the spectrum of treatable tumors and/or reduce dose-limiting toxicity. Platinum drug candidates were generated through the use of automated synthesis, taking advantage either of thetranseffect or by using silver chloride precipitation to activate the starting materials. Reaction products were screened for activity in a high-throughput transcription assay and the most promising candidates characterized. Over 3600 reaction products were screened for their ability to inhibit transcription of β-lactamase in the BlaM HeLa cell line by monitoring cleavage of a lactam ring linking the two halves of a fluorescent resonance energy transfer (FRET) dye, CCF2/AM. From this screen, three reactions produced good candidates, and four species were identified among these reaction products. Three of the compounds,cis-[(isopropylamine)2PtCl2],cis-[(cyclobutylamine)2PtCl2], andcis-[ammine(cyclobutylamine)PtCl2], have been previously determined to be active cisplatin analogs. The fourth compound,cis-[ammine(2-amino-3-picoline)PtCl2], represents a new kind of antitumor drug candidate similar to ZD0473, a recently reported analog. The discovery of these compounds represents an important proof of principle that platinum anticancer drug candidates can be rapidly prepared and screened in this manner.