Irie Kazuhiro, Yanagita Ryo C
Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto, 606-8502, Japan.
Chem Rec. 2014 Apr;14(2):251-67. doi: 10.1002/tcr.201300036. Epub 2014 Feb 20.
Protein kinase C (PKC) isozymes play central roles in signal transduction on the cell surface and could serve as promising therapeutic targets of intractable diseases like cancer, Alzheimer's disease, and acquired immunodeficiency syndrome (AIDS). Although natural PKC ligands like phorbol esters, ingenol esters, and teleocidins have the potential to become therapeutic leads, most of them are potent tumor promoters in mouse skin. By contrast, bryostatin-1 (bryo-1) isolated from marine bryozoan is a potent PKC activator with little tumor-promoting activity. Numerous investigations have suggested bryo-1 to be a promising therapeutic candidate for the above intractable diseases. However, there is a supply problem of bryo-1 both from natural sources and by organic synthesis. Recent approaches on the synthesis of bryo-1 have focused on its simplification, without decreasing the ability to activate PKC isozymes, to develop new medicinal leads. Another approach is to use the skeleton of natural PKC ligands to develop bryo-1 surrogates. We have recently identified 10-methyl-aplog-1 (26), a simplified analog of tumor-promoting aplysiatoxin (ATX), as a possible therapeutic lead for cancer. This review summarizes recent investigations on the simplification of natural PKC ligands, bryo-1 and ATX, to develop potential medicinal leads.
蛋白激酶C（PKC）同工酶在细胞表面信号转导中起核心作用，有望成为癌症、阿尔茨海默病和获得性免疫缺陷综合征（艾滋病）等难治性疾病的治疗靶点。尽管佛波酯、 ingenol酯和杀鱼菌素等天然PKC配体有潜力成为治疗先导物，但它们大多是小鼠皮肤中的强效肿瘤促进剂。相比之下，从海洋苔藓虫中分离出的苔藓抑素-1（bryo-1）是一种强效PKC激活剂，几乎没有肿瘤促进活性。大量研究表明bryo-1有望成为上述难治性疾病的治疗候选药物。然而，bryo-1无论是天然来源还是有机合成方面都存在供应问题。最近合成bryo-1的方法集中在简化其结构上，同时不降低激活PKC同工酶的能力，以开发新的药用先导物。另一种方法是利用天然PKC配体的骨架来开发bryo-1替代物。我们最近鉴定出10-甲基-aplog-1（26），一种促肿瘤海兔毒素（ATX）的简化类似物，作为一种可能的癌症治疗先导物。本综述总结了最近关于简化天然PKC配体bryo-1和ATX以开发潜在药用先导物的研究。
