Rezai Taha, Yu Bin, Millhauser Glenn L, Jacobson Matthew P, Lokey R Scott
Department of Chemistry and Biochemistry, University of California, Santa Cruz, 95064, USA.
J Am Chem Soc. 2006 Mar 1;128(8):2510-1. doi: 10.1021/ja0563455.
Little is known about the effect of conformation on passive membrane diffusion rates in small molecules. Evidence suggests that intramolecular hydrogen bonding may play a role by reducing the energetic cost of desolvating hydrogen bond donors, especially amide N-H groups. We set out to test this hypothesis by investigating the passive membrane diffusion characteristics of a series of cyclic peptide diastereomers based on the sequence cyclo[Leu-Leu-Leu-Leu-Pro-Tyr]. We identified two cyclic hexapeptide diastereomers based on this sequence, whose membrane diffusion rates differed by nearly two log units. Results of solution NMR studies and hydrogen/deuterium (H/D) exchange experiments showed that membrane diffusion rates correlated with the degree of intramolecular hydrogen bonding and H/D exchange rates. The most permeable diastereomer, cyclo[d-Leu-d-Leu-Leu-d-Leu-Pro-Tyr] (1), exhibited a passive membrane diffusion rate comparable to that of the orally available drug cyclosporine A.
关于构象对小分子被动膜扩散速率的影响，人们所知甚少。有证据表明，分子内氢键可能通过降低氢键供体（尤其是酰胺N-H基团）去溶剂化的能量成本来发挥作用。我们着手通过研究一系列基于环[亮氨酸-亮氨酸-亮氨酸-亮氨酸-脯氨酸-酪氨酸]序列的环肽非对映异构体的被动膜扩散特性来验证这一假设。我们基于该序列鉴定出两种环六肽非对映异构体，它们的膜扩散速率相差近两个对数单位。溶液核磁共振研究和氢/氘（H/D）交换实验结果表明，膜扩散速率与分子内氢键程度和H/D交换速率相关。渗透性最强的非对映异构体环[D-亮氨酸-D-亮氨酸-亮氨酸-D-亮氨酸-脯氨酸-酪氨酸]（1）的被动膜扩散速率与口服可用药物环孢素A相当。
