新型可诱导DNA甲基转移酶和组蛋白甲基转移酶抑制剂的设计合成,构效关系和活性研究

Recently more and more studies discovered that abnormal DNA methylation and histone methylation is closely correlative with many diseases. The methyltransferase inhibitors can inhibit tumor growth significantly and great progress has been made in this research field. However, these inhibitors are toxic to normal cells and have serious side effect because of the lack of specificity. These difficulties greatly decrease the clinic application of these inhibitors. Up to present, there is little report about the research of specific methyltransferase inhibitors. In this project, the introduction of the strategy of the inducibility into the design of methyltransferase inhibitor is proposed to increase the selectivity of drugs to the cancer cells, and will resolve the problem of low selectivity and high toxicity. The project intend to designe and synthesize analogues of cofactor of methyltransferase SAM containing aryl boronic acids or their esters as prodrugs. The ability of these prodrugs to inhibit different DNA methyltransferase and histone methyltransferase under inducing conditions will be measured. The interaction between inhibitors and methyltransferase, as well as structure-activity relationship of inhibitors with methyltransferase will be elucidated by the theoretical calculationand. In addition, the effect of these small molecules towards various tumor cells and normal cells will be measured. This study is useful to study the mechanism of methyltransferase and drug discovery. It is suggested that a potential therapeutic strategy for tumor may be developed.

近年来，越来越多的研究发现异常的DNA甲基化和组蛋白甲基化和肿瘤发生等多种疾病相关。甲基转移酶抑制剂可以显著抑制肿瘤生长，相关研究已经取得了许多进展。但是由于抑制剂缺乏特异性，抑制剂对正常的细胞组织具有较大的毒副作用，很大程度上限制了其临床应用。目前对特异性抑制剂的研究很少。本项目将药物诱导策略引入甲基转移酶抑制剂的设计中，为提高药物对癌细胞的选择性提供了条件。同时，也为解决药物的低效高毒问题提供了机会。本项目设计合成得到含有苯硼酸或苯硼酸酯结构的甲基转移酶辅助因子SAM的类似物作为前药，在诱导条件下检测上述药物分子在诱导条件下对各种DNA甲基转移酶和组蛋白甲基转移酶的抑制能力，运用计算机模拟技术研究小分子与甲基转移酶的相互作用和构效关系，并检测药物分子对各种肿瘤细胞和正常细胞的作用。本项目的实施，对研究甲基化抑制剂的作用机制和药物开发具有重要的战略意义，也为肿瘤的治疗工作开辟一条新途径。

DNA甲基化和肿瘤等多种疾病相关。甲基转移酶抑制剂可以显著抑制肿瘤生长，相关研究已经取得了许多进展。但是由于抑制剂缺乏特异性，抑制剂对正常的细胞组织具有较大的毒副作用，很大程度上限制了其临床应用。本项目将药物诱导策略引入甲基转移酶抑制剂的设计中，为提高药物对癌细胞的选择性提供了条件。. 本项目在前期合成小分子抑制剂及其活性测试的基础上，通过对分子结构深入的构效关系研究之后，新设计合成了基于5-氮杂脱氧胞嘧啶苯硼酸酯的小分子抑制剂。测试发现，该分子只在H2O2浓度较高的肿瘤细胞中诱导成为甲基化抑制剂5-氮杂脱氧胞嘧啶，从而导致肿瘤细胞衰老，而对H2O2浓度较低的正常细胞则影响较少，对肿瘤细胞中抑癌基因p16的进一步检测也表明，肿瘤细胞经过化合物治疗后确实使原先因为高度甲基化从而沉默的抑癌基因p16重新表达。该化合物有望成为肿瘤治疗的特异性药物。. 按研究计划，除了设计特异性的潜在抑制剂药物分子外，还要建立快速、灵敏检测甲基转移酶抑制剂生物活性的方法，因此需要有一种对DNA甲基化灵敏方便的检测方法。本项目开发出一种DNA甲基化多位点同步检测的新方法，该方法只用对5μg的细胞提取基因组进行一次PCR，能够对多个DNA甲基化位点，包括CpG和非CpG位点，实现同步检测，结果灵敏可靠。.

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