Laboratory of Medicinal Chemistry, Endocrinology and Nephrology Unit, CHU de Québec - Research Center (CHUL, T4), Québec, QC, G1V 4G2, Canada.
Laboratory of Medicinal Chemistry, Endocrinology and Nephrology Unit, CHU de Québec - Research Center (CHUL, T4), Québec, QC, G1V 4G2, Canada; Department of Molecular Medicine, Faculty of Medicine, Université Laval, Québec, QC, G1V 0A6, Canada.
Eur J Med Chem. 2020 Feb 15;188:111990. doi: 10.1016/j.ejmech.2019.111990. Epub 2019 Dec 23.
The aminosteroid (AM) RM-581 is built around a mestranol backbone and has recently emerged as this family's lead candidate, showing in vitro and in vivo potency over different types of cancer, including high fatality pancreatic cancer. To extend the structure-activity relationships (SAR) to other estrane analogs, we synthesized a focused series of RM-581 derivatives at position C3 or C2 of its steroidal core. These new AM derivatives were first tested on a large selection of prostate, breast, pancreatic and ovarian cancer cell lines. The impact of these modifications on metabolic stability (human liver microsomes) was also measured. A SAR study revealed a fine regulation of anticancer activity related to the nature of the substituent. Indeed, the addition of potential prodrug groups like acetate, sulfamate or phosphate (compounds 8, 9 and 10) at C3 of the phenolic counterpart provided better antiproliferative activities than RM-581 in breast and pancreatic cancer cell types while maintaining activity in other cancer cell lines. Also, the phosphate group was highly beneficial on water solubility. However, the bulkier carbamate prodrugs 6 (N,N-dimethyl) and 7 (N,N-diethyl) were less active. Otherwise, carbon homologation (CH) at C2 (compound 33) was beneficial to metabolic stability and, in the meantime, this AM conserved the same anticancer activity as RM-581. However, the replacement of the hydroxy or methoxy at C3 by a hydrogen or an acetyl (compound 17 or 21b) was detrimental for anticancer activity, pointing to a crucial molecular interaction of the aromatic oxygen atom at this position. Overall, this work provided a better knowledge of the structural requirements to maintain RM-581's anticancer activity, and also identified minor structural modifications to increase both metabolic stability and water solubility, three important parameters of pharmacological development.
氨基甾体（AM）RM-581 以美雌醇为骨架构建，最近成为该家族的主要候选药物，在不同类型的癌症（包括致命性高的胰腺癌）的体外和体内均显示出活性。为了将结构-活性关系（SAR）扩展到其他雌烷类似物，我们在 steroidal 核心的 C3 或 C2 位置合成了一系列聚焦的 RM-581 衍生物。这些新的 AM 衍生物首先在大量前列腺、乳腺、胰腺和卵巢癌细胞系上进行了测试。还测量了这些修饰对代谢稳定性（人肝微粒体）的影响。SAR 研究表明，与取代基的性质有关的抗癌活性得到了精细的调节。事实上，在酚类对应物的 C3 位置添加潜在的前药基团，如醋酸盐、磺酸盐或磷酸盐（化合物 8、9 和 10），可提供比 RM-581 更好的抗增殖活性，特别是在乳腺和胰腺癌细胞类型中，同时保持对其他癌细胞系的活性。此外，磷酸基团对水溶性非常有利。然而，更大体积的氨基甲酸酯前药 6（N，N-二甲基）和 7（N，N-二乙基）的活性较低。此外，C2 位的碳同系化（CH）（化合物 33）有利于代谢稳定性，同时，这种 AM 保留了与 RM-581 相同的抗癌活性。然而，C3 位的羟基或甲氧基被氢或乙酰基取代（化合物 17 或 21b）会损害抗癌活性，这表明该位置的芳香氧原子存在关键的分子相互作用。总的来说，这项工作提供了更好地了解维持 RM-581 抗癌活性的结构要求，并确定了一些较小的结构修饰，以提高代谢稳定性和水溶性，这是药理学发展的三个重要参数。
