Sigano Dina M, Peach Megan L, Nacro Kassoum, Choi Yongseok, Lewin Nancy E, Nicklaus Marc C, Blumberg Peter M, Marquez Victor E
Laboratory of Medicinal Chemistry, Center for Cancer Research, National Cancer Institute at Frederick, National Institutes of Health, Frederick, Maryland 21702, USA.
J Med Chem. 2003 Apr 24;46(9):1571-9. doi: 10.1021/jm020476o.
Diacylglycerol lactones (DAG lactones), analogous to highly potent diacylglycerols (DAGs) were synthesized to demonstrate the ability of PK-C to discriminate between two differential binding modes, sn-1 and sn-2. While both sn-1 and sn-2 binding modes are allowable in terms of hydrogen bonding, it has been found that in general, DAGs prefer to bind sn-1, while the corresponding analogous DAG lactones prefer to bind sn-2. However, this binding orientation can be directly influenced by the disposition and nature of the acyl substituent, particularly if it is highly branched. When the "binding driving force" (i.e., the larger branched acyl chain) is in the sn-2 position, a dramatic increase in binding affinity is observed in the DAG lactone as compared to its open chain DAG counterpart. As these analogous DAGs and DAG lactones have almost identical log P values, this difference in binding affinity is a direct result of the entropic advantage of constraining the glycerol backbone.
合成了与高效二酰甘油（DAG）类似的二酰甘油内酯（DAG内酯），以证明蛋白激酶C（PK-C）区分两种不同结合模式（sn-1和sn-2）的能力。虽然就氢键而言，sn-1和sn-2结合模式都是可行的，但已发现，一般来说，DAG倾向于结合sn-1，而相应的类似DAG内酯则倾向于结合sn-2。然而，这种结合方向可直接受酰基取代基的布局和性质影响，尤其是当它高度分支时。当“结合驱动力”（即较大的分支酰基链）处于sn-2位置时，与开链DAG对应物相比，DAG内酯的结合亲和力会显著增加。由于这些类似的DAG和DAG内酯具有几乎相同的log P值，这种结合亲和力的差异是限制甘油主链的熵优势的直接结果。
