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首页> 外文期刊>European Journal of Medicinal Chemistry: Chimie Therapeutique >Synthesis and in vitro antitumour activity of 4(R)-methyl-3-O-phosphonomethyl-alpha-L-threose nucleosides
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Synthesis and in vitro antitumour activity of 4(R)-methyl-3-O-phosphonomethyl-alpha-L-threose nucleosides

机译：4（R）-Methyl-3-O-膦酰甲基-α-L-促核苷的合成和体外抗肿瘤活性

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摘要

A series of novel alpha-L-threose nucleoside phosphonate analogs, 4(R)-methyl-3-O-phosphonomethyl-alpha-Lthreose nucleosides, were synthesized in multistep sequences starting from D-xylose. The synthetic sequence consisted of the following key stages: (i) the multistep synthesis of 1,2- O-isopropylidenyl-4(R)-methyl-3-O-phosphonomethyl-L-threose, (ii) the transformation of 1,2-O-isopropylidenyl sugar into suitable 1,2-di-O-acyl L-threose precursor, and (iii) the construction of target alpha-L-threose nucleoside phosphonate analogs by Vorbruggen glycosidation reaction, deprotection of acyl group, and hydrolysis of diethyl group on phosphonate. The target nucleoside phosphonates were evaluated for their antitumour activities in cell culture-based assays. Compound 8g, 2-fluroadenosine phosphonate, showed remarkable activity against human breast cancer cell lines (MCF-7 and MDA-MB-231) with IC50 values of 0.476 and 0.391 mu M, corresponding to 41- and 47-fold higher potency than the reference compound 5-FU, respectively. Subsequent investigations found that the compound 8g can inhibit the proliferation of breast cancer cells and cell cloning. The mechanistic studies indicated that compound 8g could cause DNA damage to breast cancer cells through the ATM-Chk1/Chk2-cdc25c pathway, leading to blockage of the G2/M phase cycle of breast cancer cells, which ultimately led to apoptosis. Moreover, 8g could inhibit the PI3K/AKT signaling pathway and induce apoptosis. These results indicate that compound 8g holds promising potential as an antitumour agent. (C) 2021 Elsevier Masson SAS. All rights reserved.
机译：从D-木糖开始，以多步序列合成了一系列新的α-L-苏氨酸核苷膦酸酯类似物4（R）-甲基-3-O-膦酰甲基-α-L-苏氨酸核苷。合成顺序包括以下关键阶段：（i）1,2-O-异亚丙基-4（R）-甲基-3-O-膦酰甲基-L-苏氨酸的多步合成，（ii）将1,2-O-异亚丙基糖转化为合适的1,2-二-O-酰基-L-苏氨酸前体，以及（iii）通过Vorbruggen糖苷化反应构建目标α-L-苏氨酸核苷膦酸类似物，酰基的脱保护和二乙基在膦酸盐上的水解。在基于细胞培养的检测中，对目标核苷膦酸盐的抗肿瘤活性进行了评估。化合物8g，2-氟鸟嘌呤膦酸酯，对人乳腺癌细胞系（MCF-7和MDA-MB-231）显示出显著的活性，IC50值分别为0.476和0.391μM，分别比参考化合物5-FU高41倍和47倍。随后的研究发现，化合物8g可以抑制乳腺癌细胞的增殖和细胞克隆。机理研究表明，化合物8g可通过ATM-Chk1/Chk2-cdc25c通路对乳腺癌细胞造成DNA损伤，导致乳腺癌细胞G2/M期周期阻滞，最终导致细胞凋亡。此外，8g还能抑制PI3K/AKT信号通路，诱导细胞凋亡。这些结果表明化合物8g作为一种抗肿瘤药物具有良好的应用前景。（c）2021爱思唯尔马松SAS。版权所有。

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  • 作者

    Liu Feng-Wu; Ji Shujie; Gao Yingying; Meng Yao; Xu Wenke; Wang Haixia; Yang Jing; Huang Hao; Herdewijn Piet; Wang Cong;

  • 作者单位

    Zhengzhou Univ Sch Pharmaceut Sci Key Lab Adv Drug Preparat Technol Minist Educ China Zhengzhou;

    Zhengzhou Univ Sch Pharmaceut Sci Key Lab Adv Drug Preparat Technol Minist Educ China Zhengzhou;

    Zhengzhou Univ Sch Pharmaceut Sci Key Lab Adv Drug Preparat Technol Minist Educ China Zhengzhou;

    Zhengzhou Univ Sch Pharmaceut Sci Key Lab Adv Drug Preparat Technol Minist Educ China Zhengzhou;

    Zhengzhou Univ Sch Pharmaceut Sci Key Lab Adv Drug Preparat Technol Minist Educ China Zhengzhou;

    Zhengzhou Univ Sch Pharmaceut Sci Key Lab Adv Drug Preparat Technol Minist Educ China Zhengzhou;

    Zhengzhou Univ Sch Pharmaceut Sci Key Lab Adv Drug Preparat Technol Minist Educ China Zhengzhou;

    Zhengzhou Univ Sch Pharmaceut Sci Key Lab Adv Drug Preparat Technol Minist Educ China Zhengzhou;

    Katholieke Univ Leuven Rega Inst Med Res Med Chem Herestr 49 B-3000 Leuven Belgium;

    Zhengzhou Univ Sch Pharmaceut Sci Key Lab Adv Drug Preparat Technol Minist Educ China Zhengzhou;

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  • 正文语种 eng
  • 中图分类 药学;
  • 关键词

    L-threose nucleoside phosphonate analogs; D-xylose; Antitumour activity; Mechanistic investigations;

    机译：L-苏氨酸核苷磷酸类似物;D-木糖;抗肿瘤活性;机械调查;

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