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首页> 外文期刊>European Journal of Medicinal Chemistry: Chimie Therapeutique >Minor chemical modifications of the aminosteroid derivative RM-581 lead to major impact on its anticancer activity, metabolic stability and aqueous solubility
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Minor chemical modifications of the aminosteroid derivative RM-581 lead to major impact on its anticancer activity, metabolic stability and aqueous solubility

机译：氨基甾体衍生物RM-581的次要化学修饰导致对其抗癌活性，代谢稳定性和含水溶解度的重大影响

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摘要

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 (CH2) 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. (C) 2019 Elsevier Masson SAS. All rights reserved.
机译：将氨基甾体（AM）RM-581是围绕一个炔雌醇骨干，最近已经成为这个家庭的主角人选，在体外和体内效力在不同类型的癌症，包括高病死率胰腺癌显示。为了延长结构 - 活性关系（SAR）到其它雌烷类似物，我们合成了聚焦在位置C3或它的甾核的C2系列RM-581衍生物。这些新的AM衍生物第一上一个大的选择前列腺癌，乳腺癌，胰腺癌和卵巢癌细胞系的测试。对代谢稳定性（人肝微粒体）这些修饰的影响也被测量。一个SAR研究表明相关取代基的性质抗癌活性的细调。事实上，除了潜在的前药基团，如在酚对方的C3酯，氨基磺酸酯或磷酸酯（化合物8,9和10）的提供优于抗增殖活性RM-581在乳腺癌和胰腺癌细胞类型，同时保持其它癌症细胞活性线。此外，磷酸基团是在水中的溶解度非常有益的。然而，笨重氨基甲酸酯前药6（N，N-二甲基）和7（N，N-二乙基）活性较低。否则，碳同系化（CH 2）在C2（化合物33）是代谢稳定性有益的，并且在此期间，此AM保守相同抗癌活性作为RM-581。然而，更换被氢或乙酰（化合物17或21B）的羟基或甲氧基在C3的是有害的抗癌活性，指向该位置的芳族氧原子的一个至关重要的分子相互作用。总体而言，这项工作提供的结构要求有更好的认识，以保持RM-581的抗癌活性，也发现的一些小结构的改变同时增加代谢稳定性和水溶性，药理学发展的三个重要参数。 （c）2019年Elsevier Masson SAS。版权所有。

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