Year

2019

Degree Name

Doctor of Philosophy

Department

School of Chemistry and Molecular Bioscience

Abstract

The effectiveness of current anticancer drugs such as nitrogen mustards, 5-fluorouracil and sunitinib is hampered by dose-limiting side effects. Targeted prodrugs designed to be selectively activated in hypoxic regions of solid tumours and locally deliver active cytotoxins are potentially very useful for improving the efficacy and side effect profiles of anticancer chemotherapeutics. This project investigated rationally designed hypoxiaactivated antitumour amide- and ester-linked kinase inhibitor–cytotoxin prodrug conjugates. These mutual prodrugs combined an angiogenesis inhibitor, semaxanib (SU5416), together with a cytotoxin into a single molecule, with the cytotoxin being either a 4-aminoaniline nitrogen mustard or floxuridine (an FDA-approved antimetabolite). The compounds contained an arylnitro triggering group designed to undergo bioreductive activation selectively in hypoxic regions of tumours to the aniline derivative. Formation of the aniline group then initiates a spontaneous intramolecular cyclisation reaction to simultaneously eject the two active anticancer drugs.

The first goal of the project was to devise and implement viable synthetic routes towards semaxanib|4-aminoaniline mutual prodrug 1 and semaxanib|floxuridine mutual prodrug 2. The synthesis of mutual prodrug 1 was optimised and scaled-up based on a previous small-scale synthesis completed by PhD student Nicholas Kirk. The synthesis of 1 was accomplished in 6 steps providing 190 mg of 1 prepared in pure form. The synthesis of mutual prodrug 2 was completed in 7 steps to give a total of 302 mg of pure 2.

Download

Share

COinS
 

Unless otherwise indicated, the views expressed in this thesis are those of the author and do not necessarily represent the views of the University of Wollongong.