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Open AccessArticle

Design, Synthesis, and Evaluation of Novel 2-Methoxyestradiol Derivatives as Apoptotic Inducers through an Intrinsic Apoptosis Pathway

State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmacy of Guangxi Normal University, Guilin 541004, China
Unité 1177 (Drugs and Molecules for Living Systems)—Inserm, Université Lille 2, Institut Pasteur de Lille, F-59000 Lille, France
Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases and State Key Laboratory of Natural Medicines, Center of Drug Discovery, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing 210009, China
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Biomolecules 2020, 10(1), 123;
Received: 12 December 2019 / Revised: 6 January 2020 / Accepted: 8 January 2020 / Published: 10 January 2020
(This article belongs to the Section Chemical Biology)
In order to discover novel derivatives in the anti-tumor field, reported anti-tumor pharmacophores (uridine, uracil, and thymine) were combined with 2-methoxyestradiol, which has been characterized as having excellent biological properties in terms of anti-tumor activity. Thus, 20 hybrids were synthesized through etherification at the 17β-OH or 3-phenolic hydroxyl group of 2-methoxyestradiol, and evaluated for their biological activities against the human breast adenocarcinoma MCF-7 cell lines, human breast cancer MDA-MB-231 cell lines, and the normal human liver L-O2 cell lines. As a result, all the uridine derivatives and single-access derivatives of uracil/thymine possessed good anti-proliferative activity against tested tumor cells (half maximal inhibitory concentration values from 3.89 to 19.32 µM), while only one dual-access derivative (21b) of thymine possessed good anti-proliferative activity (half maximal inhibitory concentration ≈ 25 µM). Among them, the uridine derivative 11 and the single-access derivative of uracil 12a possessed good anti-proliferative selectivity against tested tumor cells. Furthermore, basic mechanism studies revealed that hybrids 11 and 12a could induce apoptosis in MCF-7 cells through mitochondrial pathway. These hybrids induced morphological changes in MCF-7 cells, causing mitochondrial depolarization. These two hybrids also had the following effects: arrest of the cell cycle at the G2 phase; up regulation of Apaf-1, Bax, and cytochrome c; down regulation of Bcl-2 and Bcl-xL for both mRNA and protein; and increase of the expression for caspase-8 and -9. Finally, apoptotic effector caspase-3 was increased, which eventually caused nuclear apoptosis at least through an intrinsic pathway in the mitochondria. Additionally, hybrids 11 and 12a could specifically bind to estradiol receptor alpha in a dose-dependent manner. View Full-Text
Keywords: 2-methoxyestradiol; anti-tumor activity; intrinsic apoptosis pathway 2-methoxyestradiol; anti-tumor activity; intrinsic apoptosis pathway
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MDPI and ACS Style

Sheng, L.-X.; Zhang, J.-Y.; Li, L.; Xie, X.; Wen, X.-A.; Cheng, K.-G. Design, Synthesis, and Evaluation of Novel 2-Methoxyestradiol Derivatives as Apoptotic Inducers through an Intrinsic Apoptosis Pathway. Biomolecules 2020, 10, 123.

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