Antoszczak Michal, Mielczarek-Puta Magdalena, Struga Marta, Huczynski Adam
Department of Medical Chemistry, Faculty of Chemistry, Adam Mickiewicz University, Uniwersytetu Poznańskiego 8, Poznań, 61-614, Poland.
Chair and Department of Biochemistry, Medical University of Warsaw, Banacha 1, Warszawa, 02-097, Poland.
Anticancer Agents Med Chem. 2025;25(5):330-338. doi: 10.2174/0118715206322603241002064435.
Since it was discovered that a natural polyether ionophore called salinomycin (SAL) selectively inhibits human cancer cells, the scientific world has been paying special attention to this compound. It has been studied for nearly 15 years.
Thus, a very interesting research direction is the chemical modification of SAL structure, which could give more biologically active agents.
We evaluated the anticancer activity of (thio)urea analogues class of C20-epi-aminosalinomycin (compound 3b). The studies covered the generation of reactive oxygen species (ROS), proapoptotic activity, cytotoxic activity, and lipid peroxidation .
Thioureas 5a-5d showed antiproliferative activity against selected human colon cancer cell lines greater than that of chemically unmodified SAL, with a 2~10-fold higher potency towards a metastatic variant of colon cancer cells (SW620). Mechanistically, SAL derivatives showed proapoptotic activity in primary colon cancer cells and induced the production of reactive oxygen species (ROS) in these cells. In SW620 cells, SAL derivatives increased lipid peroxidation with a weak effect on apoptosis and low ROS formation with cytotoxic effects followed by cytostatic ones, suggesting different modes of action of the compounds against primary and metastatic colon cancer cells.
The results of this study suggested that urea and thiourea derivatives of SAL provide promising leads for the rational development of new anticancer active agents.
自从发现一种名为沙利霉素（SAL）的天然聚醚离子载体可选择性抑制人类癌细胞以来，科学界就一直特别关注这种化合物。对其研究已近15年。
因此，一个非常有趣的研究方向是对SAL结构进行化学修饰，这可能会产生更多具有生物活性的药物。
我们评估了C20-表-氨基沙利霉素（化合物3b）的（硫）脲类似物类的抗癌活性。研究内容包括活性氧（ROS）的产生、促凋亡活性、细胞毒性活性和脂质过氧化作用。
硫脲类化合物5a-5d对所选人类结肠癌细胞系的抗增殖活性高于未化学修饰的SAL，对结肠癌细胞转移变体（SW620）的效力高2至10倍。从机制上讲，SAL衍生物在原发性结肠癌细胞中表现出促凋亡活性，并在这些细胞中诱导活性氧（ROS）的产生。在SW620细胞中，SAL衍生物增加了脂质过氧化，对细胞凋亡影响较弱，ROS形成较少，具有细胞毒性作用，随后是细胞生长抑制作用，表明这些化合物对原发性和转移性结肠癌细胞的作用方式不同。
本研究结果表明，SAL的脲和硫脲衍生物为合理开发新型抗癌活性剂提供了有前景的线索。
