Total Synthesis of Ciguatoxins and Studies on The Antibodies and The Mechanism of Action

在热带和亚热带地区，雪卡毒素中毒是一个重要的医学问题。通过“统一收敛策略，即，[X+2+Y]聚醚组装体”的合成，开发出实用的第二代CTX 3C全合成方法。2.成功地应用该方法合成了51-羟基CTX 3C和CTX 1B。方法学的进一步改进使我们能够分别制备几mg的CTX 3C和51-HydroxyCTX 3C，用于跨学科研究。3.制备了高灵敏度的抗CTX 1B、51-HydroxyCTX 3C的单克隆抗体8H 2，4.单克隆抗体8H 2和10 C9的夹心免疫法检测51-羟基CTX的水平为pg/ml，5.单克隆抗体10 C9和3D 11的夹心免疫法检测了冲绳海域捕获的河豚鱼中的CTX 3C。7.雪卡毒素的中心9元F环被证明是其毒性的关键。8.合成雪卡毒素和生物素结合物等生物探针将从原子水平上揭示VSSC与配体的相互作用和门控机制。

Ciguatera poisoning is an important medical issue in the tropical and subtropical regions. The first total synthesis of ciguatoxin CTX3C, one of the causative toxins, through "unified convergent strategy, i.e., [X+2+Y] polyether assembly" was accomplished in 2001.1.We then have developed the practical second-generation total synthesis of CTX3C.2.Moreover, we have successfully applied it to synthesize 51-HydroxyCTX3C and CTX1B. Further methodological improvements allowed us to prepare a few mg of CTX3C and 51-HydroxyCTX3C, respectively, which be used for interdisciplinary researches.3.Highly sensitive monoclonal antibody 8H2 was developed against CTX1B, 51-HydroxyCTX3C, and so on.4.Sandwich Immunoassay using mAbs 8H2 and 10C9 was able to detect 51-HydroxyCTX at the level of pg/ml.5.Sandwich immunoassay using mAbs 10C9 and 3D11 detected CTX3C in ciguateric fish caught in the Okinawa sea area.6.Mice poisoned with CTX3C were cured by monoclonal antibodies we developed, which will be applied for humans. In addition, vaccines for ciguatera poisoning would be developed.7.The central 9-membered F ring of ciguatoxins is proved to be crucial for their toxicity.8.Synthetic ciguatoxins and bio-probes such as the conjugates with biotin will unveil the VSSC-ligand interaction at the atomic lebel and the gating mechanism.