A Simple Analogue of Tumor-Promoting Aplysiatoxin Is an Antineoplastic Agent Rather Than a Tumor Promoter: Development of a Synthetically Accessible Protein Kinase C Activator with Bryostatin-like Activity
A Simple Analogue of Tumor-Promoting Aplysiatoxin Is an Antineoplastic Agent Rather Than a Tumor Promoter: Development of a Synthetically Accessible Protein Kinase C Activator with Bryostatin-like Activity
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DOI：
10.1021/ja808447r
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发表时间：
2009-06-10
影响因子：
15
通讯作者：
Irie, Kazuhiro
中科院分区：
文献类型：
--
作者：
Nakagawa, Yu;Yanagita, Ryo C.;Irie, Kazuhiro
蛋白激酶C（PKC）是公认的治疗癌症、阿尔茨海默病（AD）和获得性免疫缺陷综合征（AIDS）等难治性疾病的靶点。虽然抑制PKC是治疗癌症的一般治疗策略，但PKC激活剂是AD和AIDS的潜在治疗剂。然而，由于PKC激活剂如佛波醇酯表现出有效的肿瘤促进活性，因此对其治疗用途的关注已经增加。天然存在的苔藓抑素1（bryo-1），prostratin和12-脱氧佛波醇13-苯乙酸酯（DPP）是迷人的PKC激活剂，没有肿瘤促进活性。Bryo-1目前正在进行治疗癌症的临床试验，对AD也有效。Prostratin和DPP是治疗人类免疫缺陷病毒（HIV）感染的两种有效药物。然而，它们从天然来源的有限可用性和合成的复杂性阻碍了作为治疗剂的进一步开发。我们在这里报告了一种简单的促肿瘤生长毒素（ATX）类似物（1）的简单方法（22步），该类似物是一种具有抗癌和抗肿瘤促进活性的新型PKC激活剂。1对几种人癌细胞系的抗癌活性与bryo-1相当。此外，1以及bryo-1显着抑制肿瘤促进剂12-O-十四烷酰基佛波醇13-乙酸酯（TPA）的EB病毒早期抗原（EBV-EA）的诱导，而ATX强烈诱导EBV-EA。这种抑制作用是抗肿瘤促进剂的特征。化合物1以及bryo-1显示出显著的PKC δ结合和活化，并诱导其在CHO-K1细胞中易位至核膜。这项研究提供了一种合成的具有bryo-1样活性的PKC激活剂，这可能是癌症，AD和AIDS的另一种治疗方法。
Protein kinase C (PKC) is widely recognized as a therapeutic target in intractable diseases such as cancer, Alzheimer's disease (AD), and acquired immune deficiency syndrome (AIDS). While inhibition of PKC is a general therapeutic strategy for the treatment of cancer, PKC activators are potential therapeutic agents for AD and AIDS. However, concerns have been raised about their therapeutic use since PKC activators such as phorbol esters exhibit potent tumor-promoting activities. Naturally occurring bryostatin 1 (bryo-1), prostratin, and 12-deoxyphorbol 13-phenylacetate (DPP) are fascinating PKC activators without tumor-promoting activities. Bryo-1 is currently in clinical trials for the treatment of cancer and is also effective against AD. Prostratin and DPP are attractive candidates for the adjunctive treatment of human immunodeficiency virus (HIV) infection. However, their limited availability from natural sources and synthetic complexity have hampered further development as therapeutic agents. We report here easy access (22 steps) to a simple analogue (1) of the tumor-promoting aplysiatoxin (ATX) as a novel PKC activator with anticancer and anti-tumor-promoting activities. Anticancer activities of 1 against several human cancer cell lines were comparable to those of bryo-1. Moreover, 1 as well as bryo-1 significantly inhibited the Epstein-Barr virus early antigen (EBV-EA) induction by the tumor promoter 12-O-tetradecanoylphorbol 13-acetate (TPA), whereas ATX strongly induced EBV-EA. This inhibitory effect is characteristic of antitumor promoters. Compound 1 as well as bryo-1 displayed significant binding and activation of PKC delta and induced its translocation to the nuclear membrane in CHO-K1 cells. This study provides a synthetically accessible PKC activator with bryo-1-like activities, which could be another therapeutic lead for cancer, AD, and AIDS.