Synthesis and characterization of cyclic pseudopeptide libraries containing thiomethylene and thiomethylene-sulfoxide amide bond surrogates.
Synthesis and characterization of cyclic pseudopeptide libraries containing thiomethylene and thiomethylene-sulfoxide amide bond surrogates.
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含有硫代亚甲基和硫代亚甲基亚砜酰胺键替代物的环状伪肽库的合成和表征。
DOI：
10.1023/a:1009665929182
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发表时间：
1997
影响因子：
3.8
通讯作者：
Spatola,AF
中科院分区：
文献类型：
--
作者：
Crozet,Y;Wen,JJ;Loo,RO;Andrews,PC;Spatola,AF
我们描述了一系列的环状假肽库，已准备在一个系统的方法，以促进合成和随后的去卷积尝试的第一个例子。我们的合成策略涉及的附件的三功能氨基酸（天冬氨酸，天冬酰胺或谷氨酸）的聚苯乙烯树脂通过其侧链，并逐步链延长使用保护的氨基酸或假二肽构建块。通过除去临时的N-和C-末端保护基团，然后通过酰胺形成闭环，形成头-尾环肽。环化的hexa，hepta，和octapropyldopeptides上的树脂避免二聚体的形成，通过质谱监测。我们利用了一种“psi-scan”方法，其中第二个固定位置通过在环周围步进二肽替代物Pro-[CH 2S]Gly来连续寻址，以产生一组环状假肽子文库。将[CH 2S]氧化为[CH 2SO]有助于验证合成，并且还提供了用于形成一组新的假肽文库（先前描述为“来自文库的文库”）的策略。我们的研究结果表明，环状假肽库是制备和测定这些合成更具挑战性的实体作为潜在药物先导物的有效方法。
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, Proψ[CH2S]Gly around the rings to generate a group of cyclic pseudopeptide sub-libraries. Oxidation of ψ[CH2S] to ψ[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.