Rivier J E, Jiang G, Koerber S C, Porter J, Simon L, Craig A G, Hoeger C A
The Clayton Foundation Laboratories for Peptide Biology, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
Proc Natl Acad Sci U S A. 1996 Mar 5;93(5):2031-6. doi: 10.1073/pnas.93.5.2031.
Betidamino acids (a contraction of "beta" position and "amide") are N'-monoacylated (optionally, N'-monoacylated and N-mono- or N,N'-dialkylated) aminoglycine derivatives in which each N'acyl/alkyl group may mimic naturally occurring amino acid side chains or introduce novel functionalities. Betidamino acids are most conveniently generated on solid supports used for the synthesis of peptides by selective acylation of one of the two amino functions of orthogonally protected aminoglycine(s) to generate the side chain either prior to or after the elongation of the main chain. We have used unresolved Nalpha-tert-butyloxycarbonyl-N'alpha-fluorenylmethoxycarbonyl++ + aminoglycine, and Nalpha-(Nalpha-methyl)-tert-butyloxycarbonyl-N'alpha-fluo renylmethoxycarbonyl aminoglycine as the templates for the introduction of betidamino acids in Acyline [Ac-D2Nal-D4Cpa-D3Pal-Ser-4Aph(Ac)-D4Aph(A c)-Leu-Ilys-Pro-DAla-NH2, where 2Nal is 2-naphthylalanine, 4Cpa is 4-chlorophenylalanine, 3Pal is 3-pyridylalanine, Aph is 4-aminophenylalanine, and Ilys is Nepsilon-isopropyllysine], a potent gonadotropin-releasing hormone antagonist, in order to test biocompatibility of these derivatives. Diasteremneric peptides could be separated in most cases by reverse-phase HPLC. Biological results indicated small differences in relative potencies (<5-fold) between the D and L nonalkylated betidamino acid-containing Acyline derivatives. Importantly, most betide diastereomers were equipotent with Acyline. In an attempt to correlate structure and observed potency, Ramachandran-type plots were calculated for a series of betidamino acids and their methylated homologs. According to these calculations, betidamino acids have access to a more limited and distinct number of conformational states (including those associated with alpha-helices, beta-sheets, or turn structures), with deeper minima than those observed for natural amino acids.
β-氨基酸（“β”位与“酰胺”的缩合词）是N'-单酰化（任选地，N'-单酰化且N-单烷基化或N,N'-二烷基化）的氨基甘氨酸衍生物，其中每个N'-酰基/烷基可以模拟天然存在的氨基酸侧链或引入新的功能。通过对正交保护的氨基甘氨酸的两个氨基功能之一进行选择性酰化，最方便地在用于肽合成的固体支持物上生成β-氨基酸，以在主链延长之前或之后生成侧链。我们使用未拆分的Nα-叔丁氧羰基-N'α-芴甲氧羰基氨基甘氨酸和Nα-（Nα-甲基）-叔丁氧羰基-N'α-芴甲氧羰基氨基甘氨酸作为在Acyline [Ac-D2Nal-D4Cpa-D3Pal-Ser-4Aph(Ac)-D4Aph(Ac)-Leu-Ilys-Pro-DAla-NH2，其中2Nal是2-萘基丙氨酸，4Cpa是4-氯苯丙氨酸，3Pal是3-吡啶基丙氨酸，Aph是4-氨基苯丙氨酸，Ilys是Nε-异丙基赖氨酸]中引入β-氨基酸的模板，Acyline是一种有效的促性腺激素释放激素拮抗剂，以测试这些衍生物的生物相容性。在大多数情况下，非对映体肽可以通过反相高效液相色谱法分离。生物学结果表明，含D型和L型非烷基化β-氨基酸的Acyline衍生物之间的相对效价差异很小（<5倍）。重要的是，大多数β-肽非对映体与Acyline具有同等效力。为了将结构与观察到的效价相关联，计算了一系列β-氨基酸及其甲基化同系物的拉马钱德兰型图。根据这些计算，β-氨基酸能够进入更有限且独特的构象状态数量（包括与α-螺旋、β-折叠或转角结构相关的构象状态），其能量最小值比天然氨基酸的更深。
