Elongated multiple electronic cascade and cyclization spacer systems in activatible anticancer prodrugs for enhanced drug release.
The design and synthesis of several novel elongated self-elimination spacer systems for application in prodrugs is described. These elongated spacer systems can be incorporated between a cleavable specifier and the parent drug. Naphthalene- and biphenyl-containing spacers were synthesized but did not eliminate. Prodrugs of the anticancer agents doxorubicin and paclitaxel are reported that contain two or three electronic cascade spacers. A novel catalytic application of HOBt was found for the synthesis of N-aryl carbamates through reacting a 4-nitrophenyl carbonate with an aniline derivative, to connect the 1,6-elimination spacers via a carbamate linkage. In addition, a double spacer-containing paclitaxel prodrug was synthesized, comprising a 1,6-elimination spacer and a bis-amine linker connected to paclitaxel via a 2'-carbamate linkage. Prodrugs in which the novel spacer systems were incorporated between a specific tripeptide specifier and the parent drug doxorubicin or paclitaxel proved to be significantly faster activated by plasmin in comparison with prodrugs containing conventional spacer systems. It is expected that the generally applicable novel spacer systems reported herein will contribute to future development of improved enzymatically activated prodrugs.
de Groot
F M
FM
Department of Organic Chemistry, NSR-Center for Molecular Structure, Design and Synthesis, University of Nijmegen, Toernooiveld 1, 6525 ED Nijmegen, The Netherlands.
Loos
W J
WJ
Koekkoek
R
R
van Berkom
L W
LW
Busscher
G F
GF
Seelen
A E
AE
Albrecht
C
C
de Bruijn
P
P
Scheeren
H W
HW
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002219:Carbamates / Q000737:chemistry; D003500:Cyclization; D004317:Doxorubicin / Q000008:administration & dosage / Q000737:chemistry; D004354:Drug Screening Assays, Antitumor; D004583:Electrons; D005341:Fibrinolysin / Q000737:chemistry; D006801:Humans; D006868:Hydrolysis; D007202:Indicators and Reagents; D007700:Kinetics; D009842:Oligopeptides / Q000737:chemistry; D017239:Paclitaxel / Q000008:administration & dosage / Q000737:chemistry; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D002219:Carbamates; D007202:Indicators and Reagents; D009842:Oligopeptides; D011355:Prodrugs; D004317:Doxorubicin; D005341:Fibrinolysin; D017239:Paclitaxel