Design and synthesis of new bicyclic diketopiperazines as scaffolds for receptor probes of structurally diverse functionality
Design and synthesis of new bicyclic diketopiperazines as scaffolds for receptor probes of structurally diverse functionality
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DOI：
10.1039/b416349d
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发表时间：
2005-01-01
影响因子：
3.2
通讯作者：
Jacobson, KA
中科院分区：
文献类型：
--
作者：
Besada, P;Mamedova, L;Jacobson, KA
二酮哌嗪（DKPs）是多种具有生物活性的天然产物中的一种常见基序，因此它们可能是合理设计受体探针和治疗药物的有用支架。我们构建了一种新的双环支架，其结合了DKP与10元环桥接。以这种方式，我们获得了一个三维分子骨架，与几个可重复的网站，提供了一个起点，设计一个新的组合库具有不同的取代基。结构变化基于DKP的氮原子和侧链烯烃的烷基化的灵活性。我们使用第二代Grubbs催化剂通过闭环复分解反应获得了一个10元仲环。同时含有O-醚和S-醚的环进行了比较。任选地在两个N α-原子处引入N-烷基或芳烷基。这是一个通用的方案，将使我们能够测试不同大小，链接和立体化学参数的环。检测DKP衍生物在表达与磷脂酶C偶联的受体的星形细胞瘤细胞中的活性。观察到对由人核苷酸P2 Y受体而不是m3毒蕈碱受体的激活引起的信号传导的抑制作用。化合物20选择性抑制由选择性P2 Y（1）受体激动剂引起的钙动员（IC 50值为486 +/- 16 nM）和磷酸肌醇周转，但该化合物不竞争放射性标记的核苷酸竞争性受体拮抗剂的结合。因此，新类别的DKP衍生物显示出作为P2 Y受体的药理学工具的效用。
Diketopiperazines (DKPs) are a common motif in various biologically active natural products, and hence they may be useful scaffolds for the rational design of receptor probes and therapeutic agents. We constructed a new bicyclic scaffold that combines a DKP bridged with a 10-membered ring. In this way we obtained a three-dimensional molecular skeleton, with several amendable sites that provide a starting point to design a new combinatorial library having diverse substituent groups. Structural variation is based upon the flexibility of alkylation of the nitrogen atoms of the DKP and on the side-chain olefin. We obtained a 10-membered secondary ring through a ring-closure metathesis reaction using the second generation Grubbs catalyst. Rings containing both O-ethers and S-ethers were compared. N-Alkyl or arylalkyl groups were introduced optionally at the two N alpha-atoms. This is a general scheme that will allow us to test rings of varying sizes, linkages, and stereochemical parameters. The DKP derivatives were tested for activity in astrocytoma cells expressing receptors coupled to phospholipase C. Inhibitory effects were observed for signaling elicited by activation of human nucleotide P2Y receptors but not m3 muscarinic receptors. Compound 20 selectively inhibited calcium mobilization (IC50 value of 486 +/- 16 nM) and phosphoinositide turnover elicited by a selective P2Y(1) receptor agonist, but this compound did not compete for binding of a radiolabeled nucleotide-competitive receptor antagonist. Therefore, the new class of DKP derivatives shows utility as pharmacological tools for P2Y receptors.