Han Yinglin, Mierke Dale F, Chorev Michael
Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue (HIM 944), Boston, MA 02215, USA.
Biopolymers. 2002 Jun;64(1):1-15. doi: 10.1002/bip.10079.
Structurally constraint dipeptidomimetics represent an important class of conformationally rigid dipeptide surrogates and molecular scaffolds, which are frequently employed in peptide-based structure-activity relationships (SAR) and construction of combinatorial libraries. We report on the design of an improved and general synthetic procedure to prepare synthons related to the trisubstituted 1,2,5-hexahydro-3-one-1H-1,4-diazepines [DAP(Xxx)(alpha7)] (DAP: 1,2,5-hexahydro-3-one-1H-1,4-diazepine; DAP(Xxx)(alpha7): the homologous series of DAP in which alpha refers to the location of the chiral carbon in the i(th) amino acid, Xxx represents the three letter notation for the i-1 amino acids, and 7 denotes the number of atoms in the ring) and their higher homologs [DAP(Xxx)(alphaN)] [Xxx = Phe, Asp(beta-OcHex) (cHex: cyclohexyl), and Arg(N(G)-Tos] (Tos: p-toluenesulfonyl); N = 8-10]. These dipetidomimetic structures are generated by reductive alkylation-mediated Calpha(i)-to-N(i-1) bridging between a Calpha (i)-(CH(2))(i-1)(n)-COSEt (n = 1-4) and H(2)N-C(i-1)HR-CO(2)Fm (Fm: 9-fluorenylmethyl) followed by H(2)N(i)-to-C(i-1)-CO(2)H lactam formation. We also describe the preparation of blocked N-Ac-[DAP(Phe)(alphaN)]-CONMe(2) (N = 8-10), which serve as model systems for detailed conformational analysis reported in the accompanying article.
结构受限的二肽模拟物代表了一类重要的构象刚性二肽替代物和分子支架，常用于基于肽的构效关系（SAR）研究和组合文库的构建。我们报道了一种改进的通用合成方法的设计，用于制备与三取代的1,2,5-六氢-3-酮-1H-1,4-二氮杂卓[DAP(Xxx)(α7)]（DAP：1,2,5-六氢-3-酮-1H-1,4-二氮杂卓；DAP(Xxx)(α7)：DAP的同系物系列，其中α指第i个氨基酸中手性碳的位置，Xxx代表第i-1个氨基酸的三字母表示法，7表示环中的原子数）及其更高同系物[DAP(Xxx)(αN)] [Xxx = Phe、Asp(β-OcHex)（cHex：环己基）和Arg(N(G)-Tos]（Tos：对甲苯磺酰基）；N = 8 - 10]相关的合成子。这些二肽模拟结构是通过还原烷基化介导的α(i)-碳到N(i - 1)在α(i)-(CH₂)(i - 1)(n)-COSEt（n = 1 - 4）和H₂N-C(i - 1)HR-CO₂Fm（Fm：9-芴甲基）之间的桥连，随后形成H₂N(i)-到-C(i - 1)-CO₂H内酰胺而产生的。我们还描述了封闭的N-Ac-[DAP(Phe)(αN)]-CONMe₂（N = 8 - 10）的制备，它们作为在随附文章中报道的详细构象分析的模型系统。
