微囊藻毒素是一大类非核糖体环状七肽，以其肝毒性而闻名，是研究最深入的蓝藻毒素之一。最近，人们将它们作为抗癌药物开发的先导进行讨论。它们的主要作用方式是抑制真核丝氨酸/苏氨酸蛋白磷酸酶 1 和 2A。与许多可以通过被动扩散穿过细胞膜的细胞毒素不同，微囊藻毒素依赖于通过有机阴离子转运多肽 1B1 或 1B3 的主动摄取。磷酸酶抑制和可转运性都强烈依赖于单个微囊藻毒素的结构。在这里，我们介绍了微囊藻毒素核心结构的位置 2 和位置 4 的化学修饰如何改变这两个特性。为了降低可运输性并增加磷酸酶抑制作用，我们使用药效团模型来研究用含有多种官能团的小分子衍生的微囊藻毒素的磷酸酶抑制潜力。使用点击化学合成各自的衍生物。我们发现一些衍生化的微囊藻毒素可以处理蛋白磷酸酶 1 的一个尚未描述的亚袋。测试了衍生化的微囊藻毒素对表达转运蛋白的细胞系的磷酸酶 1 抑制和细胞毒性，揭示了微囊藻毒素的目标抑制和可转运性可以独立地受到理化性质，特别是位于微囊藻毒素2位的残基的理化性质。用小酸或氨基酸衍生化产生的微囊藻毒素具有良好的抑制与转运比，使得这些衍生物可能适合药物开发。

Microcystins, a large family of nonribosomal cyclic heptapeptides known for their hepatotoxicity, are among the best-studied cyanobacterial toxins. Recently, they have been discussed as leads for the development of anticancer drug substances. Their main mode-of-action is inhibition of the eukaryotic serine/threonine protein phosphatases 1 and 2A. Unlike many cytotoxins that can cross cell membranes by passive diffusion, microcystins depend on active uptake via organic anion transporting polypeptides 1B1 or 1B3. Both phosphatase inhibition and transportability strongly depend on the structure of the individual microcystin. Here, we present how chemical modification of positions 2 and 4 of the microcystin core structure can alter these two properties. Aiming to reduce transportability and increase phosphatase inhibition, we used pharmacophore modeling to investigate the phosphatase inhibition potential of microcystins derivatized with small molecules containing a variety of functional groups. The respective derivatives were synthesized using click chemistry. We discovered that some derivatized microcystins can address a yet undescribed subpocket of the protein phosphatase 1. The derivatized microcystins were tested for phosphatase 1 inhibition and cytotoxicity on transporter-expressing cell lines, revealing that target inhibition and transportability of microcystins can independently be influenced by the physicochemical properties, especially of the residue located in position 2 of the microcystin. Derivatization with small acids or amino acids resulted in microcystins with a favorable ratio of inhibition to transportability, making these derivatives potentially suitable for drug development.