具有显著降低毒性的水溶性吗啉修饰紫杉醇前药的设计、合成与评价

Design, synthesis, and evaluation of water-soluble morpholino-decorated paclitaxel prodrugs with remarkably decreased toxicity.

作者信息

Feng Siliang, Chen Kuncheng, Wang Chenhong, Jiang Xifeng, Dong Huajin, Gong Zehui, Liu Keliang

机构信息

State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology & Toxicology, Beijing 100850, China.

State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology & Toxicology, Beijing 100850, China; School of Pharmaceutical Sciences, Central South University, 172 Tongzipo Road, Changsha 410013, China.

出版信息

Bioorg Med Chem Lett. 2016 Aug 1;26(15):3598-602. doi: 10.1016/j.bmcl.2016.06.012. Epub 2016 Jun 6.

DOI:10.1016/j.bmcl.2016.06.012

PMID:27311893

Abstract

Novel water-soluble paclitaxel prodrugs were designed and synthesized by introducing morpholino groups through different linkers. These derivatives showed 400-20,000-times greater water solubility than paclitaxel as well as comparable activity in MCF-7 and HeLa cell lines. The prodrug PM4 was tested in the S-180 tumor mouse model, with paclitaxel as the positive control. The results showed that PM4 had comparable antitumor activity as paclitaxel, with tumor inhibition of 54% versus 56%, and remarkably decreased toxicity. The survival rate of treated mice was 8/8 in the PM4 group, compared to 3/8 in the paclitaxel group.

摘要

通过不同的连接基引入吗啉代基团，设计并合成了新型水溶性紫杉醇前药。这些衍生物的水溶性比紫杉醇高400 - 20000倍，并且在MCF - 7和HeLa细胞系中具有相当的活性。以紫杉醇作为阳性对照，在前药PM4在S - 180肿瘤小鼠模型中进行了测试。结果表明，PM4具有与紫杉醇相当的抗肿瘤活性，肿瘤抑制率分别为54%和56%，且毒性显著降低。PM4组治疗小鼠的存活率为8/8，而紫杉醇组为3/8。