Sharma R, Lee J, Wang S, Milne G W, Lewin N E, Blumberg P M, Marquez V E
Laboratory of Medicinal Chemistry, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
J Med Chem. 1996 Jan 5;39(1):19-28. doi: 10.1021/jm950276v.
5,5-Bis(hydroxymethyl)tetrahydro-2-furanone and its isomer 4,4-bis(hydroxymethyl)tetrahydro-2-furanone were investigated as possible templates for the construction of conformationally constrained analogues of the biologically important second messenger, diacylglycerol (DAG). The former lactone contains embedded within its structure an exact glycerol moiety, while in the latter the ring oxygen has been transposed to the other side of the carbonyl group. All target compounds were synthesized as racemates from 1,3-dihydroxy-2-propanone. The 5,5-bis(hydroxymethyl)tetrahydro-2-furanone proved to be the better template for the construction of DAG surrogates that were demonstrated to have high binding affinities for the biological target, protein kinase C (PK-C). The simplest target compounds derived from this template (3e and 3f) have one of the hydroxyl moieties functionalized either as a myristate or as an oleate ester. The simplest target compound (9c) derived from the ineffective 4,4-bis-(hydroxymethyl)tetrahydro-2-furanone template was investigated only with a myristoyl acyl chain. Reducing the long acyl chain to an acetyl moiety and attaching a compensating lipophilic chain to the lactone ring as an alpha-alkylidene moiety produced compounds 10e and 10f (Z-isomers) and 11e and 11f (E-isomers), which were constructed on the more effective 5,5-bis(hydroxymethyl)tetrahydro-2-furanone template. Targets 14c (Z-isomer) and 15c (E-isomer) were derived, in turn, from 4,4-bis(hydroxymethyl)tetrahydro-2-furanone. The affinities of these ligands for PK-C were assessed in terms of their ability to displace bound [3H-20]phorbol 12,13-dibutyrate (PDBU) from the single isozyme PK-C alpha. The biological data support the hypothesis that the increase in binding affinity for PK-C shown by some of these constrained DAG mimetics appears to be entropic in nature. Two of the designed ligands (10e and 10f) showed the highest affinities (34 and 24 nM, respectively) reported so far for a DAG analogue. Assuming that the interaction between these racemic compounds and PK-C is stereospecific, the potency of the active enantiomer is anticipated to double.
5,5-双（羟甲基）四氢-2-呋喃酮及其异构体4,4-双（羟甲基）四氢-2-呋喃酮被作为构建具有构象限制的生物重要第二信使二酰基甘油（DAG）类似物的可能模板进行了研究。前一种内酯在其结构中包含一个确切的甘油部分，而在后一种内酯中，环氧已转移到羰基的另一侧。所有目标化合物均由1,3-二羟基-2-丙酮合成外消旋体。5,5-双（羟甲基）四氢-2-呋喃酮被证明是构建DAG替代物的更好模板，这些替代物被证明对生物靶点蛋白激酶C（PK-C）具有高结合亲和力。源自该模板的最简单目标化合物（3e和3f）具有一个羟基部分，其功能化为肉豆蔻酸酯或油酸酯。仅用肉豆蔻酰基链研究了源自无效的4,4-双（羟甲基）四氢-2-呋喃酮模板的最简单目标化合物（9c）。将长酰基链还原为乙酰基部分，并在内酯环上连接一个补偿性亲脂链作为α-亚烷基部分，得到了化合物10e和10f（Z-异构体）以及11e和11f（E-异构体），它们是在更有效的5,5-双（羟甲基）四氢-2-呋喃酮模板上构建的。目标化合物14c（Z-异构体）和15c（E-异构体）依次源自4,4-双（羟甲基）四氢-2-呋喃酮。根据这些配体从单一同工酶PK-Cα上取代结合的[3H-20]佛波醇12,13-二丁酸酯（PDBU）的能力，评估了它们对PK-C的亲和力。生物学数据支持这样的假设，即这些构象受限的DAG模拟物中一些对PK-C结合亲和力增加似乎本质上是熵驱动的。两种设计的配体（10e和10f）显示出迄今为止报道的DAG类似物的最高亲和力（分别为34和24 nM）。假设这些外消旋化合物与PK-C之间存在立体特异性相互作用，预计活性对映体的效力会加倍。
