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

  • Bioorg Med Chem Lett. 2016 Aug 1;26(15):3598-602. doi: 10.1016/j.bmcl.2016.06.012.
Siliang Feng  1 ,  Kuncheng Chen  2 ,  Chenhong Wang  1 ,  Xifeng Jiang  1 ,  Huajin Dong  1 ,  Zehui Gong  1 ,  Keliang Liu  3
Affiliations
  • 1. State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology & Toxicology, Beijing 100850, China.
  • 2. 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.
  • 3. State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology & Toxicology, Beijing 100850, China. Electronic address: [email protected].
PMID: 27311893 DOI: 10.1016/j.bmcl.2016.06.012
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.

Keywords
Anticancer; Morpholino group; Paclitaxel prodrugs; Water-soluble derivatives.