Synthetic studies towards the human telomerase inhibitors - the rubromycins

Abstract

In recent years, a set of structurally related natural antibiotics were isolated from cultures of Streptomyces collinus. These compounds were known as the rubromycins and included B- and ?-rubromycin, as well as the related compounds known as purpuromycin, heliquinomycin and the griseorhodins. All of these compounds consist of a naphthazarin moiety linked to an isocoumarin ring through a bisbenzannulated 5,6-spiroketal system and exhibited some form of activity against human telomerase, an enzyme that builds telomere repeat units onto the terminals of each chromosome. This enzyme is generally present in human cancer cells, whereas it is not present in regular human somatic cells. a-Rubromycin, the ring-opened form of B-rubromycin, displays a markedly lower activity towards human telomerase. This suggests that the spiroketal moiety plays a crucial role in the inhibition of telomerase. Several model compounds were synthesised based on this spiroketal core unit. These compounds took the form of bisbenzannulated 6,6-spirodioxines, and were synthesised in a similar method to those synthesised by Brimble et al. in 2007.1 Catechol and 2,3-dihydroxy naphthalene were first converted to the monobenzylated equivalents, and were subsequently reacted with epichlorohydrin to form the epoxide intermediates. Alongside these epoxide intermediates, several 3-substituted 2-benzyloxyphenols were synthesised from 2-substituted phenols by first undergoing a magnesium mediated ortho-formylation, followed by conversion of the phenol to the benzyl ether, and finally Baeyer-Villiger oxidation to form the benzyloxyphenol. The benzyloxyphenols and the epoxide intermediates were coupled under basic conditions, followed by mild oxidation, and lastly hydrogenation and acid-catalyzed ring closing to form the 6,6-spirodioxines. Synthesis of an amine equivalent of the 6,6-spirodioxines was also accomplished in similar fashion, with the exception of using 2-benzyloxyaniline to react with the epoxide intermediate. Synthesis of sulphur containing equivalents was also attempted, however 2-benzyloxythiophenol could not be synthesised.

Date of Award	2014
Original language	English