Crozet Y, Wen J J, Loo R O, Andrews P C, Spatola A F
Department of Chemistry, University of Louisville, KY 40292, USA.
Mol Divers. 1997;3(4):261-76. doi: 10.1023/a:1009665929182.
We describe the first examples of a series of cyclic pseudopeptide libraries that have been prepared in a systematic approach in order to facilitate both synthesis and subsequent deconvolution attempts. Our synthetic strategy involved the attachment of a trifunctional amino acid (Asp, Asn or Glu) to a polystyrene resin via its side chain, and stepwise chain elongation using either protected amino acids or a pseudodipeptide building block. Head to tail cyclic peptides were formed by removal of the temporary N- and C-terminal protecting groups followed by ring closure by amide formation. Cyclization of the hexa, hepta, and octapseudopeptides on the resin avoided dimer formation, as monitored by mass spectrometry. We utilized a 'psi-scan' approach in which a second fixed position was serially addressed by stepping a dipeptide surrogate, Pro psi [CH2S]Gly around the rings to generate a group of cyclic pseudopeptide sub-libraries. Oxidation of psi [CH2S] to psi [CH2SO] helped validate the synthesis and also provides a strategy for forming a new set of pseudopeptide libraries (previously described as 'libraries from libraries'). Our results suggest that libraries of cyclic pseudopeptides are an efficient method of preparing and assaying these synthetically more challenging entities as potential drug leads.
我们描述了一系列环化假肽文库的首个实例，这些文库是通过系统方法制备的，以便于合成以及后续的去卷积尝试。我们的合成策略包括通过三官能氨基酸（天冬氨酸、天冬酰胺或谷氨酸）的侧链将其连接到聚苯乙烯树脂上，并使用受保护的氨基酸或假二肽构建块进行逐步链延长。通过去除临时的N端和C端保护基团，然后通过酰胺形成进行环化，形成头对尾环化肽。如通过质谱监测的那样，树脂上六肽、七肽和八肽假肽的环化避免了二聚体形成。我们采用了一种“psi扫描”方法，其中通过使二肽替代物Pro psi[CH2S]Gly围绕环逐步移动来连续处理第二个固定位置，以生成一组环化假肽子文库。将psi[CH2S]氧化为psi[CH2SO]有助于验证合成过程，并且还提供了一种形成新的假肽文库组的策略（先前称为“来自文库的文库”）。我们的结果表明，环化假肽文库是制备和检测这些合成上更具挑战性的实体作为潜在药物先导物的有效方法。
