Synthesis of Marine-Derived 3-Alkylpyridinium Alkaloids with Potent Antiprotozoal Activity
Synthesis of Marine-Derived 3-Alkylpyridinium Alkaloids with Potent Antiprotozoal Activity
复制标题
DOI：
10.1021/ml200160k
复制
发表时间：
2011-12-01
影响因子：
4.2
通讯作者：
de Koning, Harry P.
中科院分区：
文献类型：
--
作者：
Rodenko, Boris;Al-Salabi, Mohammed I.;de Koning, Harry P.
鉴于迫切需要新的抗原动物药物没有交叉耐药性与目前（失败）的化疗，我们已经探讨了3-十三烷基吡啶生物碱（3 TPAs），衍生物的viscosamine，作为抗寄生虫剂。我们已经开发了一种简单的合成路线，对viscosamine和相关的环状和线性单体和低聚物。对原生动物寄生虫布氏锥虫、利什曼原虫属、和恶性疟原虫揭示了几种具有纳摩尔范围内的抗原生动物活性的3 TPA。它们在体外有希望的选择性指数促使我们更详细地研究对锥虫的细胞毒性动力学。在治疗安全浓度下，寄生虫被相对缓慢地杀死，这一过程并不针对细胞周期。清除T.在1-10 μ M的药物浓度下观察到布氏培养物。
Given the pressing need for new antiprotozoal drugs without cross-resistance with current (failing) chemotherapy, we have explored 3-tridecylpyridinium alkaloids (3TPAs), derivatives of viscosamine, as antiparasitic agents. We have developed a simple synthetic route toward viscosamine and related cyclic and linear monomers and oligomers. Evaluation for cytotoxicity on the protozoan parasites Trypanosoma brucei, Leishmania spp., and Plasmodium falciparum revealed several 3TPAs with antiprotozoal activity in the nanomolar range. Their promising selectivity index in vitro prompted us to study the dynamics of cytotoxicity on trypanosomes in more detail. Parasites were killed relatively slowly at therapeutically safe concentrations, in a process that did not target the cell cycle. Clearance of T. brucei cultures was observed at drug concentrations of 1-10 mu M.