Johannesson Petra, Lindeberg Gunnar, Johansson Anja, Nikiforovich Gregory V, Gogoll Adolf, Synnergren Barbro, Le Grèves Madeleine, Nyberg Fred, Karlén Anders, Hallberg Anders
Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, Uppsala University, Box 574, SE-751 23 Uppsala, Sweden.
J Med Chem. 2002 Apr 25;45(9):1767-77. doi: 10.1021/jm011063a.
Vinyl sulfide cyclized analogues of the octapeptide angiotensin II that are structurally related to the cyclic disulfide agonist c[Hcy(3,5)]Ang II have been prepared. The synthesis relies on the reaction of the mercapto group of a cysteine residue in position 3 with the formyl group of allysine incorporated in position 5 of angiotensin II. A mixture of the cis and the trans isomers was formed, and these were separated and isolated by RP-HPLC. Thus, the three-atom CH(2)[bond]S[bond]S element of the AT(1) receptor agonist c[Hcy(3,5)]Ang II has been displaced by a bioisosteric three-atom S[bond]CH[double bond]CH element. A comparative conformational analysis of the 13-membered ring systems of c[Hcy(3,5)]Ang II and the 13-membered cyclic vinyl sulfides with cis and trans configuration, respectively, suggested that all three systems adopted very similar low-energy conformations. This similarity was also reflected in the bioactivity. Both of the compounds that contained the ring systems encompassing the cis or trans vinyl sulfide elements between positions 3 and 5 exhibited K(i) values less than 2 nM and exerted full agonism at the AT(1) receptor. In contrast, vinyl sulfide cyclization involving the amino acid residues 5 and 7 rendered inactive compounds. The cyclic vinyl sulfides that have agonist activity were both shown to possess low-energy conformers compatible with the previously proposed 3D model for the bioactive conformation of Ang II.
已制备出八肽血管紧张素II的乙烯基硫醚环化类似物，它们在结构上与环状二硫键激动剂c[Hcy(3,5)]Ang II相关。合成过程依赖于血管紧张素II第3位半胱氨酸残基的巯基与引入第5位的烯赖氨酸的甲酰基之间的反应。形成了顺式和反式异构体的混合物，并通过反相高效液相色谱法将它们分离和纯化。因此，AT(1)受体激动剂c[Hcy(3,5)]Ang II的三原子CH(2)[键]S[键]S单元已被生物电子等排体三原子S[键]CH[双键]CH单元取代。分别对c[Hcy(3,5)]Ang II的13元环系统以及具有顺式和反式构型的13元环状乙烯基硫醚进行的比较构象分析表明，所有这三种系统都采用了非常相似的低能量构象。这种相似性也反映在生物活性上。在第3位和第5位之间包含顺式或反式乙烯基硫醚单元的环状系统的两种化合物均表现出小于2 nM的K(i)值，并在AT(1)受体上发挥完全激动作用。相反，涉及氨基酸残基5和7的乙烯基硫醚环化产生无活性的化合物。具有激动剂活性的环状乙烯基硫醚均显示出具有与先前提出的血管紧张素II生物活性构象的3D模型兼容的低能量构象体。
