Doctor of Philosophy
School of Chemistry
Kirk, Nicholas, Synthetic and biological investigations into hypoxia-activated anti-tumour codrugs, Doctor of Philosophy thesis, School of Chemistry, University of Wollongong, 2015. https://ro.uow.edu.au/theses/4537
Tumour-selective, non-cytotoxic chemotherapeutics are much sought after in oncology. Two cancer-selective drug types are angiogenesis inhibitors, drugs which halt the growth of new blood vessels in tumours, and hypoxia-activated prodrugs, which are non-toxic agents that are activated into cytotoxins selectively within tumours. It is possible to conceive a dual-action prodrug (a.k.a. codrug) which releases both an angiogenesis inhibitor and a cytotoxin selectively within a tumour after bio-reductive activation. Specifically, prodrugs designed to release nitrogen mustard cytotoxins along with SU5416 from a 2-nitrophenylacetamide precursor were of particular interest.
A synthesis of the prototype hypoxia-activated anti-tumour codrug (Z)-1 was successfully achieved with an overall yield of 12% over 7 steps. A synthetically more convenient route through carboxylic acid intermediate (Z)-5 was unsuccessful, as ester/amide coupling conditions produced the cyclisation product 5,7-dimethyl-2-(2- nitrophenyl)-3H-pyrrolizin-3-one 14 in high yield. Instead, it was necessary to optimise a step-wise synthesis through N-(4-(bis(O-tert-butyldimethylsilyl-2- hydoxyethyl)amino)phenyl)-2-(2-nitrophenyl)acetamide 8, then perform a Knoevenagel condensation with N-protected pyrrole aldehyde 9 to form (Z)-7. After deprotection and chlorination of (Z)-7, prototype codrug (Z)-1 was obtained as an air-stable solid.