Department of Pediatric and Adolescent Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN, USA 55905.
Nat Prod Rep. 2016 Apr;33(4):549-61. doi: 10.1039/c5np00146c. Epub 2016 Feb 12.
Covering: 2000 up to 2016Peloruside A, a macrocyclic secondary metabolite from a New Zealand marine sponge, Mycale hentscheli, has shown potent antiproliferative activity in cultured cancer cells as well as inhibitory effects on tumor growth in mouse models. The compound also has promising effects against cell models of neurodegenerative and autoimmune diseases. In mechanistic studies, peloruside A shares with paclitaxel (Taxol®) the ability to stabilize microtubules by binding to β-tubulin. Peloruside A, however, occupies a unique external site on β-tubulin that does not overlap the classical taxoid site that is located on the inside of the microtubule. As such, peloruside A has been of central importance in defining a new microtubule-stabilizer binding site localized on the exterior surface of the microtubule that has led to increased interest in the design of an upscaled total synthesis of the natural product and its analogues. Here, we review advances in the biochemical and biological validation of peloruside A as an attractive therapeutic candidate for the treatment of cancer, neurodegeneration, and autoimmune disease.
2000 年至 2016 年佩洛里德 A，一种来自新西兰海洋海绵 Mycale hentscheli 的大环次级代谢产物，在培养的癌细胞中表现出很强的抗增殖活性，并且对小鼠模型中的肿瘤生长具有抑制作用。该化合物对神经退行性疾病和自身免疫性疾病的细胞模型也有很好的效果。在机制研究中，佩洛里德 A 与紫杉醇（Taxol®）一样，通过与β-微管蛋白结合稳定微管。然而，佩洛里德 A 占据β-微管蛋白上一个独特的外部位点，与位于微管内部的经典紫杉烷结合位点不重叠。因此，佩洛里德 A 对于定义一个新的微管稳定剂结合位点具有重要意义，该位点位于微管的外表面，这导致了人们对天然产物及其类似物的大规模全合成设计的兴趣增加。在这里，我们回顾了佩洛里德 A 的生化和生物学验证方面的进展，将其作为治疗癌症、神经退行性疾病和自身免疫性疾病的有吸引力的治疗候选药物。
