Novel anthracycline-spacer-beta-glucuronide,-beta-glucoside, and -beta-galactoside prodrugs for application in selective chemotherapy.
A series of anthracycline prodrugs containing an immolative spacer was synthesized for application in selective chemotherapy. The prodrugs having the general structure anthracycline-spacer-beta-glycoside were designed to be activated by beta-glucuronidase or beta-galactosidase. Prodrugs with -chloro, -bromo or -n-hexyl substituents on the spacer were synthesized as well as prodrugs containing a -beta-glucuronyl, -beta-glucosyl or -beta-galactosyl carbamate specifier. The key step in the synthesis of all prodrugs is the highly beta-diastereoselective addition reaction of the anomeric hydroxyl of a glycosyl donor to a spacer isocyanate resulting in the respective beta-glycosyl carbamate pro-moieties. The resulting protected pro-moieties were coupled to an anthracycline. Prodrugs were evaluated with respect to activation rate by the appropriate enzyme and additionally, their IC50 values were determined. Optimal prodrugs in this study were at least 100- to 200-fold less toxic than their corresponding drug in vitro and were activated to the parent drug in a half-life time of approximately 2 h.
Leenders
R G
RG
Department of Organic Chemistry, NSR-Center for Molecular Structure, Design and Synthesis, University of Nijmegen, Toernooiveld, The Netherlands.
Damen
E W
EW
Bijsterveld
E J
EJ
Scheeren
H W
HW
Houba
P H
PH
van der Meulen-Muileman
I H
IH
Boven
E
E
Haisma
H J
HJ
D000903:Antibiotics, Antineoplastic / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D001711:Biotransformation; D002455:Cell Division / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D005697:Galactosides / Q000737:chemistry; D005960:Glucosides / Q000737:chemistry; D020719:Glucuronides / Q000737:chemistry; D006207:Half-Life; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D014407:Tumor Cells, Cultured
D000903:Antibiotics, Antineoplastic; D005697:Galactosides; D005960:Glucosides; D020719:Glucuronides; D011355:Prodrugs