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Synthesis of oxazole ring systems for use as inhibitors of telomerase function

Charalambidou, E.; (2008) Synthesis of oxazole ring systems for use as inhibitors of telomerase function. Masters thesis , UCL (University College London).

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The existence of G-quadruplex structures in telomeres of Stylonchia macronuclei in human cells has validated secondary DNA structures as potential targets for drug design. Specific biological effects of these drugs have been associated with selective interaction with intermolecular or intramolecular G-quadruplex structures formed in telomeres. Telomestatin is a natural product isolated from Streptomyces anulatus 3533-SV4, and has been shown to be a potent telomerase inhibitor through intramolecular interaction with G-quadruplex structure with a 70-fold selectivity over duplex DNA. Telomestatin is a macrocycle comprised of seven oxazole rings and one thiazoline ring, each linked in 2,4-manner to form an annulus. This thesis presents, first, an introduction to the biological background of inhibition of telomerase function through the binding of small molecules to G-quadruplex structures. The work is also placed in context by brief discussion of a representative selection of anti-cancer targets and drugs. A background to oxazole-containing natural products, and an outline of oxazole ring construction then follows. Chapter two describes an approach to the construction polyxazoles suitable as intermediates in a total synthesis of telomestatin. Several routes to 2,4-disubstituted oxazoles were examined, including (convergent) Hantzsch type condensations, but those were unsatisfactory. However assembly of protected serine derivates via BOP-HOBt coupling was effective, and subsequent cyclodehydration, using the William procedure of diethylamino sulfur trifluoride followed by bromotrichloromethane and a base, led to a successful iterative synthesis of 2,4-linked bis-oxazoles based on and then 2,4';2,4''-tris-oxazoles, useful key intermediates that establish a viable route to polyoxazole formation.

Type: Thesis (Masters)
Title: Synthesis of oxazole ring systems for use as inhibitors of telomerase function
Language: English
Additional information: Authorisation for digitisation not received
UCL classification: UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences > Dept of Chemistry
URI: https://discovery.ucl.ac.uk/id/eprint/16753
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