Novel prodrugs of decitabine with greater metabolic stability and less toxicity
Novel prodrugs of decitabine with greater metabolic stability and less toxicity
复制标题
DOI：
10.1186/s13148-019-0709-y
复制
发表时间：
2019-08-01
影响因子：
5.7
通讯作者：
Ushijima, Toshikazu
中科院分区：
文献类型：
--
作者：
Hattori, Naoko;Sako, Magoichi;Ushijima, Toshikazu
背景：DNA去甲基化治疗现已用于血液肿瘤的治疗，并正在开发用于实体肿瘤的治疗。然而，现有的DNA去甲基化药物氮杂替丁(AZA)和地西他滨(DAC)由于在体内被胞苷脱氨酶快速脱氨，且存在自发的水解性裂解，很难实现稳定的药代动力学。结果：合成了35个5‘-O-三烷基硅烷基氮杂环硅烷基化氮杂环己烷/双环己烷基偶氮烷基偶氮化合物。其中，11个化合物表现出与DAC和愈创木他滨相似的脱甲基化活性，并具有良好的水相溶解性。小鼠体内药代动力学分析表明，OR-2003具有最高的血药浓度和曲线下面积，而OR-2100对胞苷脱氨酶表现出较高的稳定性。用OR-2003和OR-2100处理细胞后，DNA甲基转移酶1完全耗尽，并诱导基因特异性和全基因组去甲基化。该疗法抑制了多种类型癌细胞的生长，并诱导了肿瘤抑制基因的重新表达。OR-2003和OR-2100的抗肿瘤作用和DNA去甲基化作用与DAC相当，而体内不良反应较少。结论：我们开发的两种新型DAC前药具有更好的稳定性、相当的DNA去甲基化活性和较低的毒性。这些化合物有望克服在患者体内实现稳定药代动力学的困难，导致最大的DNA去甲基化活性和最小的不良影响。
Background: DNA demethylation therapy is now used in practice for hematological tumors and is being developed for solid tumors. Nevertheless, it is difficult to achieve stable pharmacokinetics with the current DNA-demethylating agents, azacitidine (AZA) and decitabine (DAC), because of their rapid deamination by cytidine deaminase in vivo and spontaneous hydrolytic cleavage. Here, we aimed to develop metabolically stable prodrugs of AZA and DAC as novel DNA-demethylating agents.Results: Thirty-five 5'-O-trialkylsilylated AZAs/DACs were synthesized with potential resistance to deamination. Out of these, 11 compounds exhibited demethylating activity similar to that of DAC and guadecitabine, and a suitable aqueous solubility. Pharmacokinetic analysis in mice showed that OR-2003 displayed the highest serum concentration and the area under the curve in an intraperitoneal experiment, whereas OR-2100 exhibited high stability to cytidine deaminase. Treatment of cells with OR-2003 and OR-2100 depleted DNA methyltransferase 1 completely and induced both gene-specific and genome-wide demethylation. The treatment suppressed the growth of multiple types of cancer cells and induced re-expression of tumor suppressor genes. The anti-tumor effect and DNA demethylation effect of OR-2003 and OR-2100 were comparable to that of DAC with fewer adverse effects in vivo.Conclusions: We developed two novel prodrugs of DAC that exhibited greater stability, comparable DNA demethylation activity, and less toxicity. These compounds are expected to overcome the difficulty in achieving stable pharmacokinetics in patients, leading to maximum DNA demethylation activity with minimum adverse effects.