Chakraborty T K, Ghosh S, Jayaprakash S, Sarma J A, Ravikanth V, Diwan P V, Nagaraj R, Kunwar A C
Indian Institute of Chemical Technology and Centre for Cellular and Molecular Biology, Hyderabad, India.
J Org Chem. 2000 Oct 6;65(20):6441-57. doi: 10.1021/jo000408e.
Furanoid sugar amino acids (1) were synthesized and used as dipeptide isosteres to induce interesting turn structures in small linear peptides. They belong to a new variety of designed hybrid structures that carry both amino and carboxyl groups on rigid furanose sugar rings. Four such molecules, 6-amino-2,5-anhydro-6-deoxy-D-gluconic acid (3, Gaa) and its mannonic (4, Maa), idonic (5, Iaa), and a 3,4-dideoxyidonic (6, ddIaa) congeners were synthesized. The synthesis followed a novel reaction path in which an intramolecular 5-exo S(N)2 opening of the hexose-derived terminal aziridine ring in 2 by the gamma-benzyloxy oxygen with concomitant debenzylation occurred during pyridinium dichromate oxidation of the primary delta-hydroxyl group to carboxyl function, leading to the formation of furanoid sugar amino acid frameworks in a single step. Incorporation of these furanoid sugar amino acids into Leu-enkephalin replacing its Gly-Gly portion gave analogues 8-11. Detailed structural analysis of these molecules by circular dichroism (CD) and various NMR techniques in combination with constrained molecular dynamics (MD) simulations revealed that two of these analogues, 8a and 10a, have folded conformations composed of an unusual nine-membered pseudo beta-turn-like structure with a strong intramolecular H-bond between LeuNH --> sugarC3-OH. This, in turn, brings the two aromatic rings of Tyr and Phe in close proximity, a prerequisite for biological activities of opioid peptides. The analgesic activities of 8a,b determined by mouse hot-plate and tail-clip methods were similar to that of Leu-enkephalin methyl ester. The syn disposition of the beta-hydroxycarboxyl motif on the sugar rings appears to be the driving force to nucleate the observed turn structures in some of these molecules (8 and 10). Repetition of the motif on both sides of a furanose ring resulted in a novel molecular design of sugar diacid, 2,5-anhydro-D-idaric acid (7, Idac). Bidirectional elongation of the diacid moieties of 7 with identical peptide strands led to the formation of a C2-symmetric reverse-turn mimetic 12 which displayed a very ordered structure consisting of identical intramolecular H-bonds at two ends between LeuNH --> sugar-OH, the same as in 8 and 10.
呋喃型糖氨基酸（1）被合成出来，并用作二肽类似物，以在小型线性肽中诱导出有趣的转角结构。它们属于一类新的设计杂化结构，在刚性呋喃糖环上同时带有氨基和羧基。合成了四个这样的分子，即6-氨基-2,5-脱水-6-脱氧-D-葡萄糖酸（3，Gaa）及其甘露糖酸（4，Maa）、艾杜糖酸（5，Iaa）和3,4-二脱氧艾杜糖酸（6，ddIaa）同系物。合成遵循一条新颖的反应路径，在该路径中，在伯δ-羟基被氧化为羧基官能团的重铬酸吡啶鎓氧化过程中，γ-苄氧基氧对2中己糖衍生的末端氮丙啶环进行分子内5-外向S(N)2开环并伴随脱苄基反应，一步形成呋喃型糖氨基酸骨架。将这些呋喃型糖氨基酸掺入亮氨酸脑啡肽中取代其甘氨酰-甘氨酸部分，得到类似物8 - 11。通过圆二色性（CD）和各种核磁共振技术结合受限分子动力学（MD）模拟对这些分子进行详细的结构分析表明，其中两个类似物8a和10a具有折叠构象，由一个不寻常的九元假β-转角样结构组成，在亮氨酸氨基→糖C3-羟基之间有很强的分子内氢键。这反过来使酪氨酸和苯丙氨酸的两个芳香环紧密靠近，这是阿片样肽生物活性的一个先决条件。通过小鼠热板法和尾夹法测定的8a、b的镇痛活性与亮氨酸脑啡肽甲酯相似。糖环上β-羟基羧基基序的顺式排列似乎是在其中一些分子（8和10）中形成观察到的转角结构的驱动力。在呋喃糖环的两侧重复该基序导致了一种新型的糖二酸分子设计，即2,5-脱水-D-艾杜糖酸（7，Idac）。用相同的肽链对7的二酸部分进行双向延伸，导致形成一种C2对称的反向转角模拟物
