Synthesis and pharmacological evaluation of 8- and 9-substituted benzolactam-v8 derivatives as potent ligands for protein kinase C, a therapeutic target for Alzheimer's disease.
Synthesis and pharmacological evaluation of 8- and 9-substituted benzolactam-v8 derivatives as potent ligands for protein kinase C, a therapeutic target for Alzheimer's disease.
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8-和9-取代苯并内酰胺-v8衍生物的合成和药理学评价作为蛋白激酶C的有效配体，蛋白激酶C是阿尔茨海默病的治疗靶点。
DOI：
10.1002/cmdc.200500068
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发表时间：
2006
期刊：
影响因子：
3.4
通讯作者：
Kozikowski,AlanP
中科院分区：
文献类型：
--
作者：
Mach,UlrichR;Lewin,NancyE;Blumberg,PeterM;Kozikowski,AlanP
阿尔茨海默病(AD)病理生理学中的一个核心因素是淀粉样斑块的形成，这是淀粉样前体蛋白(APP)异常处理的结果。APP的加工主要由三种关键酶提供，即α-，β-分泌酶和γ-分泌酶。由于后两者有助于神经毒性Aβ片段的形成，而α分泌酶不起作用，导致淀粉样蛋白生成的产物减少可以通过抑制β和γ分泌酶或激活α分泌酶来实现。现已知，蛋白激酶C(Protein Kinase C，PKC)的激活增强了α-分泌酶的活性，因此是开发治疗这种破坏性神经退行性疾病所急需的药物的一个可能的靶点。在本研究中，我们合成了基于苯内酰胺-V8的新型蛋白激酶C激活剂，并测试了它们与蛋白激酶Cα的结合亲和力。所有被测化合物的结合值都在纳摩尔浓度范围内。根据以前的文献，与相应的8-取代类似物相比，9-取代显著提高了PKC的结合亲和力。除了芳环上侧链的位置外，这些苯内酰胺类化合物的结合亲和力还取决于该附属物的取向、长度和电子性质。9-噻吩基类似物13的结合亲和力有一个有趣的下降，这表明硫原子与PKC或部分细胞膜发生了不利的电子相互作用。
A central element in the pathophysiology of Alzheimer's disease (AD) is the formation of amyloid plaques, which result from abnormal processing of the amyloid precursor protein (APP). The processing of APP is largely provided by three key enzymes, namely the α‐, β‐, and γ‐secretases. As the latter two contribute to the formation of neurotoxic Aβ fragments while α‐secretase does not, a decrease in the amyloidogenic products can be brought about either by inhibition of the β‐ and γ‐secretases or through the activation of α‐secretase. It is now known that the activation of protein kinase C (PKC) enhances α‐secretase activity and therefore represents a possible target for the development of agents urgently needed for the treatment of this devastating neurodegenerative disorder. In the present study, new benzolactam‐V8‐based PKC activators were synthesized and tested for their binding affinity toward PKCα. All compounds tested showed binding values in the nanomolar concentration range. In accordance with previous publications, 9‐substitution dramatically increased PKC binding affinity in comparison with the corresponding 8‐substituted analogues. In addition to the location of the side chain on the aromatic ring, the binding affinities of these benzolactams were found to depend on the orientation, length, and electronic properties of this appendage. An interesting decrease in binding affinity was found for the 9‐thienyl analogue13, suggesting adverse electronic interactions of the sulfur atom with PKC or parts of the cellular membrane.