Alterman M, Björsne M, Mühlman A, Classon B, Kvarnström I, Danielson H, Markgren P O, Nillroth U, Unge T, Hallberg A, Samuelsson B
Department of Chemistry, Linköping University, S-581 83 Linköping, Sweden.
J Med Chem. 1998 Sep 24;41(20):3782-92. doi: 10.1021/jm970777b.
A study on the use of derivatized carbohydrates as C2-symmetric HIV-1 protease inhibitors has been undertaken. L-Mannaric acid (6) was bis-O-benzylated at C-2 and C-5 and subsequently coupled with amino acids and amines to give C2-symmetric products based on C-terminal duplication. Potent HIV protease inhibitors, 28 Ki = 0.4 nM and 43 Ki = 0.2 nM, have been discovered, and two synthetic methodologies have been developed, one whereby these inhibitors can be prepared in just three chemical steps from commercially available materials. A remarkable increase in potency going from IC50 = 5000 nM (23) to IC50 = 15 nM (28) was observed upon exchanging -COOMe for -CONHMe in the inhibitor, resulting in the net addition of one hydrogen bond interaction between each of the two -NH- groups and the HIV protease backbone (Gly 48/148). The X-ray crystal structures of 43 and of 48 have been determined (Figures 5 and 6), revealing the binding mode of these inhibitors which will aid further design.
已开展一项关于使用衍生化碳水化合物作为C2对称HIV-1蛋白酶抑制剂的研究。L-甘露糖二酸（6）在C-2和C-5位进行双O-苄基化，随后与氨基酸和胺偶联，以基于C末端重复得到C2对称产物。已发现了强效HIV蛋白酶抑制剂，28的Ki = 0.4 nM，43的Ki = 0.2 nM，并且开发了两种合成方法，其中一种方法可以从市售材料仅通过三个化学步骤制备这些抑制剂。当在抑制剂中将-COOMe换成-CONHMe时，观察到效力从IC50 = 5000 nM（23）显著提高到IC50 = 15 nM（28），这导致两个-NH-基团中的每一个与HIV蛋白酶主链（Gly 48/148）之间净增加一个氢键相互作用。已确定了43和48的X射线晶体结构（图5和图6），揭示了这些抑制剂的结合模式，这将有助于进一步的设计。
