Design, synthesis, and evaluation of water-soluble morpholino-decorated paclitaxel prodrugs with remarkably decreased toxicity.
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.
State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology & Toxicology, Beijing 100850, China.
Siliang
S
Feng
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.
Kuncheng
K
Chen
State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology & Toxicology, Beijing 100850, China.
Chenhong
C
Wang
State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology & Toxicology, Beijing 100850, China.
Xifeng
X
Jiang
State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology & Toxicology, Beijing 100850, China.
Huajin
H
Dong
State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology & Toxicology, Beijing 100850, China.
Zehui
Z
Gong
State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology & Toxicology, Beijing 100850, China. Electronic address: keliangliu55@126.com.
Keliang
K
Liu
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006367:HeLa Cells; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D015394:Molecular Structure; D060172:Morpholinos / Q000737:chemistry / Q000494:pharmacology*; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D017239:Paclitaxel / Q000737:chemistry / Q000494:pharmacology*; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D012995:Solubility; D013329:Structure-Activity Relationship; D014867:Water / Q000737:chemistry
D000972:Antineoplastic Agents, Phytogenic; D060172:Morpholinos; D011355:Prodrugs; D014867:Water; D017239:Paclitaxel
Anticancer; Morpholino group; Paclitaxel prodrugs; Water-soluble derivatives