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

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 synth...

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Main Authors:	Li-Xin Sheng, Jiang-Yu Zhang, Li Li, Xiao Xie, Xiao-An Wen, Ke-Guang Cheng
Format:	Article
Language:	English
Published:	MDPI AG 2020-01-01
Series:	Biomolecules
Subjects:	2-methoxyestradiol anti-tumor activity intrinsic apoptosis pathway
Online Access:	https://www.mdpi.com/2218-273X/10/1/123

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spelling	doaj-b76015df2f964887925fbda8bf787da62020-11-25T02:05:53ZengMDPI AGBiomolecules2218-273X2020-01-0110112310.3390/biom10010123biom10010123Design, Synthesis, and Evaluation of Novel 2-Methoxyestradiol Derivatives as Apoptotic Inducers through an Intrinsic Apoptosis PathwayLi-Xin Sheng0Jiang-Yu Zhang1Li Li2Xiao Xie3Xiao-An Wen4Ke-Guang Cheng5State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmacy of Guangxi Normal University, Guilin 541004, ChinaState Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmacy of Guangxi Normal University, Guilin 541004, ChinaState Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmacy of Guangxi Normal University, Guilin 541004, ChinaUnité 1177 (Drugs and Molecules for Living Systems)—Inserm, Université Lille 2, Institut Pasteur de Lille, F-59000 Lille, FranceJiangsu 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, ChinaState Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmacy of Guangxi Normal University, Guilin 541004, ChinaIn 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 17<i>β</i>-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 (<b>21b</b>) of thymine possessed good anti-proliferative activity (half maximal inhibitory concentration ≈ 25 µM). Among them, the uridine derivative <b>11</b> and the single-access derivative of uracil <b>12a</b> possessed good anti-proliferative selectivity against tested tumor cells. Furthermore, basic mechanism studies revealed that hybrids <b>11</b> and <b>12a</b> 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 <b>11</b> and <b>12a</b> could specifically bind to estradiol receptor alpha in a dose-dependent manner.https://www.mdpi.com/2218-273X/10/1/1232-methoxyestradiolanti-tumor activityintrinsic apoptosis pathway
collection	DOAJ
language	English
format	Article
sources	DOAJ
author	Li-Xin Sheng Jiang-Yu Zhang Li Li Xiao Xie Xiao-An Wen Ke-Guang Cheng
spellingShingle	Li-Xin Sheng Jiang-Yu Zhang Li Li Xiao Xie Xiao-An Wen Ke-Guang Cheng Design, Synthesis, and Evaluation of Novel 2-Methoxyestradiol Derivatives as Apoptotic Inducers through an Intrinsic Apoptosis Pathway Biomolecules 2-methoxyestradiol anti-tumor activity intrinsic apoptosis pathway
author_facet	Li-Xin Sheng Jiang-Yu Zhang Li Li Xiao Xie Xiao-An Wen Ke-Guang Cheng
author_sort	Li-Xin Sheng
title	Design, Synthesis, and Evaluation of Novel 2-Methoxyestradiol Derivatives as Apoptotic Inducers through an Intrinsic Apoptosis Pathway
title_short	Design, Synthesis, and Evaluation of Novel 2-Methoxyestradiol Derivatives as Apoptotic Inducers through an Intrinsic Apoptosis Pathway
title_full	Design, Synthesis, and Evaluation of Novel 2-Methoxyestradiol Derivatives as Apoptotic Inducers through an Intrinsic Apoptosis Pathway
title_fullStr	Design, Synthesis, and Evaluation of Novel 2-Methoxyestradiol Derivatives as Apoptotic Inducers through an Intrinsic Apoptosis Pathway
title_full_unstemmed	Design, Synthesis, and Evaluation of Novel 2-Methoxyestradiol Derivatives as Apoptotic Inducers through an Intrinsic Apoptosis Pathway
title_sort	design, synthesis, and evaluation of novel 2-methoxyestradiol derivatives as apoptotic inducers through an intrinsic apoptosis pathway
publisher	MDPI AG
series	Biomolecules
issn	2218-273X
publishDate	2020-01-01
description	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 17<i>β</i>-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 (<b>21b</b>) of thymine possessed good anti-proliferative activity (half maximal inhibitory concentration ≈ 25 µM). Among them, the uridine derivative <b>11</b> and the single-access derivative of uracil <b>12a</b> possessed good anti-proliferative selectivity against tested tumor cells. Furthermore, basic mechanism studies revealed that hybrids <b>11</b> and <b>12a</b> 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 <b>11</b> and <b>12a</b> could specifically bind to estradiol receptor alpha in a dose-dependent manner.
topic	2-methoxyestradiol anti-tumor activity intrinsic apoptosis pathway
url	https://www.mdpi.com/2218-273X/10/1/123
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Design, Synthesis, and Evaluation of Novel 2-Methoxyestradiol Derivatives as Apoptotic Inducers through an Intrinsic Apoptosis Pathway

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