Synthesis and evaluation of water-soluble docetaxel prodrugs-docetaxel esters of malic acid

• Published in: Bioorganic & medicinal chemistry Vol. 15; no. 18; pp. 6323 - 6330
• Main Authors: Du, Wenting, Hong, Lan, Yao, Tongwei, Yang, Xiaochun, He, Qiaojun, Yang, Bo, Hu, Yongzhou
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 15.09.2007; Elsevier Science
• Subjects: Animals; Antineoplastic agents; Antineoplastic Agents, Phytogenic - chemical synthesis; Antineoplastic Agents, Phytogenic - chemistry; Antineoplastic Agents, Phytogenic - pharmacology; Biological and medical sciences; Cell Proliferation - drug effects; Docetaxel; Drug Screening Assays, Antitumor; Esters - chemistry; General aspects; Humans; Liver Neoplasms, Experimental - drug therapy; Liver Neoplasms, Experimental - pathology; Magnetic Resonance Spectroscopy; Malates - chemistry; Male; Malic acid; Mass Spectrometry; Medical sciences; Mice; Mice, Inbred ICR; Paclitaxel; Pharmacology. Drug treatments; Plasma - metabolism; Prodrug; Prodrugs - chemical synthesis; Prodrugs - chemistry; Prodrugs - pharmacology; Solubility; Taxoids - chemical synthesis; Taxoids - chemistry; Taxoids - pharmacology; Tumor Cells, Cultured; Water; Water-soluble; Malic acid; Prodrug; Water-soluble; Docetaxel; Paclitaxel; Antineoplastic agent; Liver; Leukemia; Lung; Blood plasma; Ester; Racemic; Tissue; Taxane derivatives; Water solubility; Mammary gland; Chemical synthesis; Tumor cell; Human; Terpenoid; Stability; Taxol; Rodentia; Epidermis; Malignant tumor; In vitro; Biological activity; Water soluble compound; In vivo; Vertebrata; Mammalia; Cell line; Mouse; Animal; KB cell line; Diterpene; Physicochemical properties; Cancer
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2007.04.002

The synthesis and evaluation of docetaxel esters of malic acid is reported. 2′-Malyl docetaxel and their sodium salts behave as prodrugs, and compound 3a demonstrated enhanced antitumor activity in vitro when compared to docetaxel and showed the inhibitory effect on tumor growth in vivo. The synthesis of docetaxel esters of malic acid is described. These compounds were found to have greatly improved water solubility and are stable in solution at neutral pH. The C2′ modified compounds 2a– c and 3a– c behave as prodrugs, that is, docetaxel is generated upon exposure to human plasma, whereas the C7 and C2′,7,10- l modified derivatives do not. 2′- dl-Malyl docetaxel sodium salt demonstrated enhanced antitumor activity in vitro when compared to docetaxel and showed the inhibitory effect on tumor growth in vivo.