Paclitaxel esters of malic acid as prodrugs with improved water solubility.
The synthesis of paclitaxel esters of malic acid is described. These compounds were found to have improved water solubility and are stable in solution at neutral pH. The C2' modified compounds behave as prodrugs, that is, paclitaxel is generated upon exposure to human plasma, whereas the C7 modified derivatives do not. 2'-Malyl paclitaxel sodium salt demonstrated enhanced antitumour activity and less toxicity in a P388 murine leukaemia in vivo model when compared to paclitaxel.
Damen
E W
EW
Department of Organic Chemistry, NSR Center for Molecular Structure, Design and Synthesis, University of Nijmegen, Toernooiveld, The Netherlands.
Wiegerinck
P H
PH
Braamer
L
L
Sperling
D
D
de Vos
D
D
Scheeren
H W
HW
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000494:pharmacology*; D004952:Esters; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008293:Malates / Q000737:chemistry*; D051379:Mice; D017239:Paclitaxel / Q000737:chemistry / Q000494:pharmacology*; D011355:Prodrugs / Q000737:chemistry / Q000494:pharmacology*; D012995:Solubility; D016339:Spectrometry, Mass, Fast Atom Bombardment; D014867:Water
D000972:Antineoplastic Agents, Phytogenic; D004952:Esters; D008293:Malates; D011355:Prodrugs; D014867:Water; C030298:malic acid; D017239:Paclitaxel