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Ferrocenylmethylation of estrone and estradiol: Structure, electrochemistry, and antiproliferative activity of new ferrocene–steroid conjugates
Applied Organometallic Chemistry ( IF 3.9 ) Pub Date : 2020-07-06 , DOI: 10.1002/aoc.5889 Vidak Raičević 1 , Niko Radulović 2 , Ljiljana Jovanović 1 , Marko Rodić 1 , Ivana Kuzminac 1 , Dimitar Jakimov 3 , Tanja Wrodnigg 4 , Tim‐Oliver Knedel 5 , Christoph Janiak 5 , Marija Sakač 1
Applied Organometallic Chemistry ( IF 3.9 ) Pub Date : 2020-07-06 , DOI: 10.1002/aoc.5889 Vidak Raičević 1 , Niko Radulović 2 , Ljiljana Jovanović 1 , Marko Rodić 1 , Ivana Kuzminac 1 , Dimitar Jakimov 3 , Tanja Wrodnigg 4 , Tim‐Oliver Knedel 5 , Christoph Janiak 5 , Marija Sakač 1
Affiliation
Conjugates of ferrocene with steroidal estrogens as selective antiproliferative agents against hormone‐dependent breast cancer cells are believed to be limited by the inherent estrogenicity of the conjugates. Motivated by a significant cytotoxicity of the ester of ferrocenecarboxylic acid and the phenolic group of estradiol toward such a cell line, we decided to explore other a‐ring‐tethered ferrocene–estra‐1,3,5(10)‐triene conjugates; in this study, ferrocenylmethylation of estradiol and estrone with (ferrocenylmethyl)trimethylammonium iodide in the presence of potassium carbonate yielded five new compounds (1–5). In dimethylformamide, only O‐alkylated products formed (1 and 3), while a mixture of O‐ and C‐alkylated products was obtained when methanol was used (2, 4, and 5 in addition to 1 and 3). All compounds were characterized using 1D and 2D NMR, IR, UV–Vis, and high‐resolution mass spectrometry. Two of the conjugates, a 3‐O‐ and a 4‐C‐alkylated derivative of estrone (3 and 4, respectively), were also analyzed using single‐crystal X‐ray diffraction. A cyclic voltammetric investigation of the electrochemical properties of 1–5 was performed. While some of the compounds were shown to have a slight‐to‐moderate antiproliferative activity against at least one of the six tested human tumor cell lines and were nontoxic to (the noncancerous) fetal human fibroblasts, compound 2 (4‐(ferrocenylmethyl)estra‐1,3,5(10)‐triene‐3,17β‐diol) with an IC50 value of 0.34 μM was found to be more active against the hormone‐dependent breast cancer cell line MCF‐7 than doxorubicin. These results suggest that a‐ring substitution of steroidal estrogens is a plausible strategy for preparing other ferrocene–steroid conjugates acting against tumor cells.
中文翻译:
雌酮和雌二醇的二茂铁基甲基化:新型二茂铁-类固醇共轭物的结构,电化学和抗增殖活性
二茂铁与甾体雌激素的共轭物作为针对激素依赖性乳腺癌细胞的选择性抗增殖剂,被认为受到共轭物固有的雌激素性的限制。通过二茂铁甲酸和朝向这种细胞系中的雌二醇的酚基的酯的显著细胞毒性的启发,我们决定研究其它一-环-拴系的二茂铁-雌-1,3,5(10) -三烯的缀合物; 在这项研究中,雌二醇ferrocenylmethylation和雌酮与(二茂铁)三甲基碘化铵在碳酸钾的存在下,得到了五个新的化合物(1 - 5)。在二甲基甲酰胺中,仅形成O烷基化产物(1和3),而混合物ö -和C ^烷基化产物,得到当使用甲醇(2,4,和5除了1和3)。使用1D和2D NMR,IR,UV-Vis和高分辨率质谱对所有化合物进行了表征。还使用单晶X射线衍射分析了两种共轭物,即雌酮的3 O和4 C烷基化衍生物(分别为3和4)。的电化学特性的循环伏安调查1 - 5被执行了。尽管某些化合物对六种受试人类肿瘤细胞系中的至少一种具有轻微至中度的抗增殖活性,并且对(非癌性)胎儿人类成纤维细胞无毒,但化合物2(4-(二茂铁基甲基)发现IC 50值为0.34μM的-1,3,5(10)-三烯-3,17β-二醇比阿霉素对激素依赖性乳腺癌细胞MCF-7的活性更高。这些结果表明,甾环类雌激素的环取代是制备其他对肿瘤细胞起作用的二茂铁-类固醇结合物的可行策略。
更新日期:2020-09-14
中文翻译:
雌酮和雌二醇的二茂铁基甲基化:新型二茂铁-类固醇共轭物的结构,电化学和抗增殖活性
二茂铁与甾体雌激素的共轭物作为针对激素依赖性乳腺癌细胞的选择性抗增殖剂,被认为受到共轭物固有的雌激素性的限制。通过二茂铁甲酸和朝向这种细胞系中的雌二醇的酚基的酯的显著细胞毒性的启发,我们决定研究其它一-环-拴系的二茂铁-雌-1,3,5(10) -三烯的缀合物; 在这项研究中,雌二醇ferrocenylmethylation和雌酮与(二茂铁)三甲基碘化铵在碳酸钾的存在下,得到了五个新的化合物(1 - 5)。在二甲基甲酰胺中,仅形成O烷基化产物(1和3),而混合物ö -和C ^烷基化产物,得到当使用甲醇(2,4,和5除了1和3)。使用1D和2D NMR,IR,UV-Vis和高分辨率质谱对所有化合物进行了表征。还使用单晶X射线衍射分析了两种共轭物,即雌酮的3 O和4 C烷基化衍生物(分别为3和4)。的电化学特性的循环伏安调查1 - 5被执行了。尽管某些化合物对六种受试人类肿瘤细胞系中的至少一种具有轻微至中度的抗增殖活性,并且对(非癌性)胎儿人类成纤维细胞无毒,但化合物2(4-(二茂铁基甲基)发现IC 50值为0.34μM的-1,3,5(10)-三烯-3,17β-二醇比阿霉素对激素依赖性乳腺癌细胞MCF-7的活性更高。这些结果表明,甾环类雌激素的环取代是制备其他对肿瘤细胞起作用的二茂铁-类固醇结合物的可行策略。