Synthesis and Binding Studies of Alzheimer Ligands on Solid Support

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• 作者：Petra Rzepecki ; Nina Geib ; Manuel Peifer ; Frank Biesemeier ; Thomas Schrader
• 刊名：Journal of Organic Chemistry
• 出版年：2007
• 出版时间：May 11, 2007
• 年：2007
• 卷：72
• 期：10
• 页码：3614 - 3624
• 全文大小：454K
• 年卷期：v.72,no.10(May 11, 2007)
• ISSN：1520-6904

文摘

Aminopyrazole derivatives constitute the first class of nonpeptidic rationally designed -sheet ligands.Here we describe a double solid-phase protocol for both synthesis and affinity testing. The presentedsolid-phase synthesis of four types of hybrid compounds relies on the Fmoc strategy and circumventssubsequent HPLC purification by precipitating the final product from organic solution in pure form.Hexa- and octapeptide pendants with internal di- and tetrapeptide bridges are now amenable in highyields to combinatorial synthesis of compound libraries for high-throughput screening purposes. Solid-phase peptide synthesis (SPPS) on an acid-resistant PAM allows us, after PMB deprotection, to subjectthe free aminopyrazole binding sites in an immobilized state to on-bead assays with fluorescence-labeledpeptides. From the fluorescence emission intensity decrease, individual binding constants can be calculatedvia reference curves by simple application of the law of mass action. Gratifyingly, host/guest complexationcan be monitored quantitatively even for those ligands, which are almost insoluble in water.