Laboratory of Medicinal Chemistry, Endocrinology and Nephrology Unit, CHU de Québec - Research Center (CHUL, T4), Quebec, QC G1V 4G2, Canada.
Laboratory of Medicinal Chemistry, Endocrinology and Nephrology Unit, CHU de Québec - Research Center (CHUL, T4), Quebec, QC G1V 4G2, Canada; Department of Molecular Medicine, Faculty of Medicine, Université Laval, Quebec, QC G1V 0A6, Canada.
Steroids. 2022 Oct;186:109064. doi: 10.1016/j.steroids.2022.109064. Epub 2022 Jun 14.
Cancer remains one of the leading causes of death, worldwide. In addition, the lack of efficacy and selectivity of chemotherapeutic agents for cancer cells is a challenge that needs to be addressed through the development of new drugs. Since aminosteroids are of interest in fighting cancer, our group previously reported antiproliferative activity on several cancer cell lines of two representatives, RM-133 and RM-581. To extend the structure-activity relationship study of aminosteroids, of which RM-133 (androstane) and RM-581 (estrane) are the main candidates, we performed the chemical synthesis and biological evaluation on lung (SHP-77), breast (T-47D) and prostate (DU-145, PC-3 and LAPC-4) cancer cells of four analogues of RM-581. We moved the functionalized side chain from position 2 of the androstane and estrane derivatives to incorporate it into a new chain located at position 17. Chemical synthesis took place in 2 steps from steroidal side-chain carboxylic acids, allowing to obtain 4 steroid derivatives with acceptable yields, which were fully characterized by nuclear magnetic resonance spectroscopy (H and C NMR). After the evaluation of compounds 12-15, lower antiproliferative activities varying from 12 to 54%, 0-33% and 0-63% were observed for SHP-77, DU-145 and PC-3 cell lines, respectively, while higher activities varying from 33 to 62% and 45-84% were observed for T-47D and LAPC-4 cell lines, respectively, when tested at 10 µM. Overall, it was observed that these aminosteroids have a lower cytotoxic activity than that of RM-581 and, that moving the side chain from steroid position C2 to C17 is clearly detrimental for antiproliferative activity. However, this work has enabled us to expand our knowledge of the structural requirements to maintain the anticancer activity of aminosteroid derivatives.
癌症仍然是全球范围内主要的死亡原因之一。此外，化疗药物对癌细胞的疗效和选择性不足，这是一个需要通过开发新药物来解决的挑战。由于氨基甾体在抗癌方面具有重要意义，我们的研究小组之前曾报道过两种代表性化合物 RM-133 和 RM-581 对几种癌细胞系的增殖抑制活性。为了扩展氨基甾体的构效关系研究，我们对 RM-581（雌甾烷）的四个类似物进行了化学合成和生物评价，这些类似物包括 RM-133（雄甾烷）和 RM-581（雌甾烷），它们是主要候选物。我们将功能化侧链从雄甾烷和雌甾烷衍生物的 2 位移动到 17 位，将其整合到新链中。化学合成分两步从甾体侧链羧酸进行，以获得 4 种具有可接受产率的甾体衍生物，它们均通过核磁共振波谱（H 和 C NMR）进行了充分表征。在对化合物 12-15 进行评价后，我们观察到它们对 SHP-77、DU-145 和 PC-3 细胞系的增殖抑制活性分别为 12-54%、0-33%和 0-63%，而对 T-47D 和 LAPC-4 细胞系的增殖抑制活性分别为 33-62%和 45-84%，测试浓度为 10 μM。总的来说，这些氨基甾体的细胞毒性活性低于 RM-581，并且将侧链从甾体 C2 位移动到 C17 位显然对增殖抑制活性有害。然而，这项工作使我们能够扩展对维持氨基甾体衍生物抗癌活性的结构要求的认识。
