Tucknott, Matthew L. (2013) The chemical synthesis of natural and novel [beta]-acid derivatives for biological evaluation as anticancer and antibacterial agents. (PhD thesis), Kingston University, .
Abstract
The Tyrrell group has, in recent years, developed a strong interest in the chemical synthesis and biological activity of the hop bitter acids lupulone 1, humulone 2 and their naturally occurring congeners, 1 a-d and 2a-d. Previous work focused on investigating the chemistry of the a-acid humulone 2, demonstrating the propensity of this compound to have a cytotoxic effect against the SK-MES lung cancer cell line and the MCF-7 breast cancer cell line. This thesis documents the recent research concerning the synthesis, the anticancer and antibacterial activity of the ß-acid lupulone 1, its naturally occurring congeners 1 a-d and further, novel, non-naturally occurring compounds. We resumed the group's previous collaboration with the Golston and Pirianov research group at St Georges, where the anticancer studies were performed. The synthesis centred on a Friedel-Crafts acylation of phloroglucinol 32, followed by a C-trialkenylation reaction between the acylphloroglucinol and an allyl bromide. We conducted experiments that focused upon the choice of base and solvent for the trialkenylation reaction, concluding that liquid ammonia as both the base and solvent offered the most efficient route to the ß-acids. It was shown that aliphatic allylic bromides lend themselves to the' reaction, . although some derivatives require purification by column chromatography in addition to recrystallisation. In contrast, aromatic allyl bromides did not participate in the alkenylation reaction. We further investigated an alternate G-alkenylation reaction involving the di¬lithiation of 1,3,5-trimethoxybenzene. We discovered that by including copper (I) iodide in the reaction, prenyl bromide 23 and allyl bromide 41 could be successfully coupled. VVe also discovered that our 2nd generation ß-acids 42a-g could participate in a ring-closing metathesis reaction, forming novel spirocyclic compounds 50a-b. Our antibacterial studies showed that ß-acids are effective against Gram-positive bacteria, but not Gram-negative bacteria in accordance with published observations. We took our investigations further and found that ß-acids are effective against mutlidrug-resistant 'Staphylococcus aureus', even where the commercially available ciprofloxacin 67 was not. Our anticancer studies showed that of the compounds tested, non-natural derivative 1g featuring a cyclopropyl ring was most effective against the MCF-7 and MDA-MB-231 breast cancer cell lines, and non-natural derivative 1j was most effective against the DU145 and PC3 prostate cancer cell lines.
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