Instituto de Investigaciones Químicas, CSIC - Universidad de Sevilla, Spain.
ChemMedChem. 2011 Jan 3;6(1):181-92. doi: 10.1002/cmdc.201000419.
Three new series of potential anthrax toxin inhibitors based on the β-cyclodextrin (βCD) scaffold were developed by exploiting face-selective Cu(I)-catalyzed azide-alkyne 1,3-cycloadditions, amine-isothiocyanate coupling, and allyl group hydroboration-oxidation/hydroxy → amine replacement reactions. The molecular design follows the "symmetry-complementarity" concept between homogeneously functionalized polycationic βCD derivatives and protective antigen (PA), a component of anthrax toxin known to form C₇-symmetric pores on the cell membrane used by lethal and edema factors to gain access to the cytosol. The synthesis and antitoxin activity of a collection of βCD derivatives differing in the number, arrangement, and face location of the cationic elements are reported herein. These results set the basis for a structure-activity relationship development program of new candidates to combat the anthrax threat.
基于 β-环糊精（βCD）支架，通过利用面选择性的 Cu（I）催化叠氮-炔 1,3-环加成、胺-异硫氰酸酯偶联以及烯丙基基团硼氢化-氧化/羟基→胺取代反应，开发了三个新的炭疽毒素抑制剂系列。分子设计遵循均相功能化聚阳离子 βCD 衍生物与炭疽毒素的保护性抗原（PA）之间的“对称互补”概念，PA 是一种已知在细胞膜上形成 C₇ 对称孔的成分，致死因子和水肿因子利用这些孔进入细胞质。本文报道了一组 βCD 衍生物的合成和抗毒素活性，这些衍生物在阳离子元素的数量、排列和位置方面存在差异。这些结果为开发新的候选药物以应对炭疽威胁的结构-活性关系发展计划奠定了基础。
