Synthesis of telomerase inhibitors based on polyoxazoles

• Main Author: Saadi, Mona
• Published: University College London (University of London) 2007
• Subjects: 547.59
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.498507

This thesis focuses on the synthesis of compounds expected to inhibit telomerase and provide potential for the treatment of cancer. Telomerase is a reverse transcriptase enzyme, which codes for telomeres and define the ends of chromosomes. Abnormal telomerase activity occurs in 85% of cancer cells and consequently has gained considerable interest as a target for cancer therapy. A natural product known as telomestatin can target G-quadruplexes and is shown to be very potent with activity at 5 nM. The aim of this thesis was to synthesise analogues of Telomestatin which contain a polyoxazole macrocycle. Chapter 1 discusses the enzyme telomerase and describes compounds which are able to inhibit its activity a literature survey on 2, 4-disubstituted oxazole chemistry is also described. Chapter 2 describes the attempted synthesis of a dipyridyltrisoxazole and a dipyridyl macrocycle. The synthetic approach involved the Hantzsch method to form oxazoles from amides and bromoketone. The Hantzsch method proved largely ineffective for obtaining the required oxazoles. A second approach involving the Willams-Wipf reaction was carried out to synthesise oxazoles. The procedure involved the cyclisation of L-serine methylester derived compounds with diethylaminosulfur trifluoride, followed by an oxidation reaction with 1,8- diazabicyclo 5.4.0 undec-7-ene and bromotrichloromethane. The Williams-Wipf approach helped to synthesise the half fragment required for the macrocycle. Chapter 3 involved the synthesis of a tetraoxazolylbipyridyl system. The Williams-Wipf approach was successful in delivering the half fragment of the desired system. However, the palladium cross coupling was ineffective in forming the tetraoxazolylbipyridyl system. Chapter 4 the aim was to synthesise a symmetrical octaoxazole ring system. The Willams-Wipf approach helped to develop the core structure to telomestatin which consists of five consecutive oxazole rings. A novel hepta oxazolyl ring system was also synthesised however, owing to insolubility of key intermediates the desired target could not be made.