Year

2013

Degree Name

Master of Science - Research

Department

School of Chemistry

Abstract

Cancer is a leading cause of disease and death around the world, and is thought to be the largest challenge to human beings in the 21st century due to the lack of efficient treatments. A promising strategy for discovering anti-cancer drug candidates is to develop novel sialyltransferase transition-state analogue inhibitors as potential anti-metastasis drugs, to control cancer cell metastasis, and to prevent primary tumours turning into deadly secondary tumours. This thesis describes work towards the synthesis of sialyltransferase transition-state analogue inhibitors 15a-i, and in particular, three key fragments: α-hydroxyphosphonate derivatives, the protected cytidine component and the key phosphoryl linkage.

The α-hydroxyphosphonate derivatives were prepared as both key components of the sialyltransferase transition-state analogue inhibitors and also as bioactive molecules themselves. Nine diethyl α-hydroxyphosphonate derivatives 16a-i, nine dibenzyl α- hydroxyphosphonate derivatives 17a-i and one hydroxyphosphonic acid (29), were prepared in an efficient, inexpensive and readily accessible manner. Six of the compounds were novel, while another two were novel at the commencement of the project, but were described in the literature during the course of the project. Biological evaluation of the α-hydroxyphosphonate derivatives showed that selected examples exhibited promising protein kinase A inhibitory activity of 85-100% when tested at 100 μg/ml.

A large scale (overall more than 10 g) of the tri-N/O-acetylated cytidine (18) was obtained as the key precursor for the phosphoramidite coupling step in a highest overall yield of 64%. The two intermediate products, the silyl protected cytidine (31) and silyl protected tri-N/O-acetylated cytidine (32), were fully characterised and their reaction conditions optimised to give excellent yields of product (>90%). Moreover, the successful synthesis of the 2’, 3’-O-isopropylidene-cytidine (33) in 78% yield provided a simplified, one-step method for preparation of an alternative protected cytidine for coupling to the α- hydroxyphosphonates.

Two different approaches (the phosphoramidite approach and the phosphotriester approach) were investigated to introduce the key phosphoryl linkage that links the α- hydroxyphosphonate derivatives 16a-i and 17a-i with the protected cytidine component (18). In the phosphoramidite approach for preparing the sialyltransferase transition-state analogue inhibitors, 5-ethyl-thio-1-H-tetrazole (SET) was explored as an activator, as the most commonly used activator 1H-tetrazole is unavailable in Australia. The key 5’-amidite (21) intermediate was successfully prepared under modified conditions, accompanied with a byproduct (48) that was characterised and its formation explained. In addition, a phosphotriester approach was investigated as a new and potentially more efficient way to generate the desired sialyltransferase transition-state analogue inhibitors.

FoR codes (2008)

030499 Medicinal and Biomolecular Chemistry not elsewhere classified

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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.