Department of Medical Chemistry, Faculty of Chemistry, Adam Mickiewicz University, Uniwersytetu Poznańskiego 8, 61‒614, Poznań, Poland.
Bob Champion Research & Education Building, Norwich Medical School, University of East Anglia, Norwich, UK.
Eur J Med Chem. 2021 Jan 1;209:112900. doi: 10.1016/j.ejmech.2020.112900. Epub 2020 Oct 2.
Polyether ionophores, with >120 molecules belonging to this group, represent a class of naturally-occurring compounds that exhibit a broad range of pharmacological properties, including promising activity towards a variety of parasites. In this context, salinomycin (SAL) seems to be interesting, as this ionophore has been found to be active against parasites that are responsible for a number of human and animal diseases. On the other hand, less explored is the investigation into the anti-parasitic activity of SAL derivatives. Recently, we identified C1 amides and esters of SAL and its analogue, C20-oxosalinomycin, as promising structures for trypanocidal drug candidates. In search for novel compounds effective against African trypanosomes, the synthetic access to a completely new series of C20-epi-salinomycin (compound 2) analogues is described in this paper. This series includes products obtained via derivatisation of either the C1 carboxyl or the C20 hydroxyl of 2, but also C1/C20 double modified derivatives. The anti-trypanosomal activity as well as the cytotoxic activity of these analogues were evaluated with bloodstream forms of T. brucei and human myeloid HL-60 cells, respectively. It was found that the C20 single modified derivatives 8, 12, and 18 (C20 decanoate, C20 ethyl carbonate, and C20 allophanate of 2, respectively) were the most active compounds in selectively targeting bloodstream-form trypanosomes, with 50% growth inhibition (GI) values of 0.027-0.043 μM and selectivity indices of 165-353. These results indicate that modification at the C20 position of C20-epi-salinomycin 2 can provide semi-synthetic products with enhanced trypanocidal activity that could be of great value for the development of new drugs to treat African trypanosomiasis.
多醚离子载体属于一大类天然化合物，有超过 120 种分子，具有广泛的药理活性，包括对多种寄生虫的有效活性。在这种情况下，莫能菌素（SAL）似乎很有前途，因为已经发现这种离子载体对许多导致人类和动物疾病的寄生虫具有活性。另一方面，对 SAL 衍生物的抗寄生虫活性的研究较少。最近，我们发现 SAL 及其类似物 C20-氧代莫能菌素的 C1 酰胺和酯具有作为抗锥虫候选药物的有前途的结构。在寻找对抗非洲锥虫有效的新型化合物时，本文描述了一种完全新型的 C20-表莫能菌素（化合物 2）类似物的合成途径。该系列包括通过衍生化 2 的 C1 羧基或 C20 羟基获得的产物，但也包括 C1/C20 双修饰衍生物。用 T. brucei 的血液期和人髓样 HL-60 细胞分别评估了这些类似物的抗锥虫活性和细胞毒性活性。发现 C20 单修饰衍生物 8、12 和 18（2 的 C20 癸酸酯、C20 碳酸乙酯和 C20 异氰尿酸酯）是选择性靶向血液期锥虫的最有效化合物，对血液期锥虫的 50%生长抑制（GI）值为 0.027-0.043 μM，选择性指数为 165-353。这些结果表明，C20-表莫能菌素 2 的 C20 位修饰可以提供增强的杀锥虫活性的半合成产物，这对于开发治疗非洲锥虫病的新药可能具有重要价值。
