Synthesis of Peptide Mimetics of RNA that Regulate the Activity of Teromerase

端粒酶是一类逆转录酶，在肿瘤和生殖细胞中表现出强大的活性，利用RNA作为霉菌（称为端粒酶RNA）延长DNA 3'端具有端粒结构的重复DNA序列。在将重复的DNA序列延长几次后，补体RNA合成并作为引物进行DNA复制。因此，复制的DNA不短于原始DNA，引物RNA和端粒酶RNA应具有相同的碱基序列“UAACCCUAA”。因此，引物RNA（相当于teromerase RNA）的模拟物可能是调节teromerase活性以抑制肿瘤细胞无止境生长的新药的理想候选物，而肿瘤细胞的teromerase活性较高。现在，我们设计了一种引物RNA（肽RNA）的肽模拟物作为端粒酶的抑制剂，并开始了合成研究。首先，在l -苏氨酸醛缩酶存在下，分别用甘氨酸处理α-碳上有尿嘧啶(U)、腺嘌呤(A)或胞嘧啶(C)残基的乙醛衍生物，得到携带γ -碳上RNA碱基的β-羟基-α- l氨基酸（氨基酸缩写为γU-Thr、γA-Thr、γC-Thr）。通过与Boc-Gly- osu反应，得到Boc-Gly-γUThr（Obn）、Boc-Gly-γAThr（Obn）和Boc-Gly-γCThr（Obn）三种二肽。采用DCC/HOBt/NMM合成多肽，用HC1对Boc进行脱保护，用碱性水解或氢化裂解苄酯，正确连接二肽的合成过程得到了两个残基上具有UAA或CCC编码的已鉴定的六肽。编码UAACCCUAA碱基的目标肽RNA的合成正在进行中，并将在不久的将来完成。

Teromerases, a family of reverse transcription enzymes, show potent activity in tumor and generative cells, and utilizes RNA as a mold (referred to teromerase RNA) on elongating the repeating DNA sequences, which feature the teromea structure, at the 3'-terminus of DNA. After elongating the several times of the repeating DNA sequences, the complement RNA is synthesized and works as a primer and duplication of DNA proceeds. As a result, the duplicated DNA is no shorter than the original DNA, and both the primer RNA and the teromerase RNA should have the same base sequences "UAACCCUAA". Therefore, mimetics of primer RNA (equivalent to teromerase RNA) could be an excellent candidate of novel medicines that regulates teromerase activities to ssuppress the endless growth of tumor cells, of which teromerase activity is high.Now, we designed a peptide mimetic of the primer RNA (peptidic RNA) as an inhibitor of teromerases, and embarked on the synthetic study. At first, the acetaldehyde derivatives having uracil (U), adenine (A), or cytosine (C) residue at α-carbon were respectively treated with glycine in the presence of L-threonine aldolase to afford β-hydroxy-α-L-ammo acids carrying the RNA bases at γcarbon (The amino acids are abbreviated as γU-Thr, γA-Thr, γC-Thr). The amino acids were derived to benzyl esters, and followed by the reaction with Boc-Gly-Osu to give dipeptides, Boc-Gly-γUThr(Obn), Boc-Gly-γAThr(Obn), and Boc-Gly-γCThr(Obn). The conventional peptide synthesis using DCC/HOBt/NMM, deprotection of Boc with HC1, and cleavage of benzyl ester by alkaline hydrolysis or hydrogenation were repeated, and this synthetic procedure linking the dipeptides correctly gave two identified hexa-peptides having UAA or CCC codes on the residues. Final stage for the synthesis of the target peptidic RNA coding UAACCCUAA bases is in progress and will be accomplished in the near future.