New amide-bearing benzolactam-based protein kinase C modulators induce enhanced secretion of the amyloid precursor protein metabolite sAPPα
New amide-bearing benzolactam-based protein kinase C modulators induce enhanced secretion of the amyloid precursor protein metabolite sAPPα
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DOI：
10.1021/jm020350r
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发表时间：
2003-01-30
影响因子：
7.3
通讯作者：
Blumberg, PM
中科院分区：
文献类型：
--
作者：
Kozikowski, AP;Nowak, I;Blumberg, PM
已知蛋白激酶C（PKC）参与淀粉样前体蛋白（APP）的加工。通过β-和γ-分泌酶的作用，APP的异常加工导致产生39-43个氨基酸的Abeta片段，其具有神经毒性，并且被认为在阿尔茨海默病的病因学中起重要作用。PKC激活增强α-分泌酶活性，这导致β-分泌酶的淀粉样蛋白生成产物减少。在这篇文章中，我们描述了10个新的苯并内酰胺V8为基础的PKC激活剂具有不同的饱和度和亲脂性的侧链连接到芳环通过酰胺基团的合成。测量的佛波酯与PKCalpha结合的抑制的Ki值在纳摩尔范围内，并显示与其亲脂性的一些相关性。化合物5g和5 h在合成的10种苯并内酰胺中显示出最好的结合亲和力。通过使用来自AD患者的细胞系，对于大多数研究的化合物，在1 μ M浓度下，以及对于化合物5e和5 f，在0.1 μ M浓度下，实现了sAPP α分泌的显著增强。在1 μ M时，化合物5c-h对sAPP α分泌的增强高于对照化合物8-（1-癸炔基）苯并内酰胺（BL）所观察到的增强。令人感兴趣的是，对于具有11 nM的Ki的高度亲脂性配体5i，没有发现活性。另一方面，其饱和对应物5i（其具有相当的Ki和ClogP）在分泌酶测定中保留活性。在增生研究中，5 f在100 μ g时显示出适度的反应，5e在300 μ g时显示出适度的反应，这表明5 f的效力比PKC激活剂美泽瑞因低约30倍，比TPA低100倍。5e的活性比5 f低约3倍。基于对其他有效PKC配体的不饱和效应，我们预测5e在大多数测定中将保留生物活性，但将显示促肿瘤活性的显著丧失。因此，化合物5e成为寻找能够调节淀粉样蛋白加工的阿尔茨海默病治疗剂的可行候选化合物。
Protein kinase C (PKC) is known to participate in the processing of the amyloid precursor protein (APP). Abnormal processing of APP through the action of the beta- and gamma-secretases leads to the production of the 39-43 amino acid Abeta fragment, which is neurotoxic and which is believed to play an important role in the etiology of Alzheimer's disease. PKC activation enhances alpha-secretase activity, which results in a decrease of the amyloidogenic products of beta-secretase. In this article, we describe the synthesis of 10 new benzolactam V8 based PKC activators having side chains of varied saturation and lipophilicity linked to the aromatic ring through an amide group. The K-i values measured for the inhibition of phorbol ester binding to PKCalpha are in the nanomolar range and show some correlation with their lipophilicity. Compounds 5g and 5h show the best binding affinity among the 10 benzolactams that were synthesized. By use of a cell line derived from an AD patient, significant enhancement of sAPPalpha secretion was achieved at 1 muM concentration for most of the compounds studied and at 0.1 muM for compounds 5e and 5f. At 1 muM the enhancement of sAPPalpha secretion for compounds 5c-h is higher than that observed for the control compound 8-(1-decynyl)benzolactam (BL). Of interest is the absence of activity found for the highly lipophilic ligand 5i, which has a K-i of 11 nM. On the other hand, its saturated counterpart 5i, which possesses a comparable K-i and ClogP, retains activity in the secretase assay. In the hyperplasia studies, 5f showed a modest response at 100 mug and 5e at 300 mug, suggesting that 5f was approximately 30-fold less potent than the PKC activator mezerein and 100-fold less potent than TPA. 5e was approximately 3-fold less active than 5f. On the basis of the effect of unsaturation for other potent PKC ligands, we would predict that 5e would retain biological activity in most assays but would show a marked loss of tumor-promoting activity. Compound 5e thus becomes a viable candidate compound in the search for Alzheimer's therapeutics capable of modulating amyloid processing.