An investigation into the asymmetric synthesis of novel benzopyrans for biological evaluation

Brawn, Peter (2012) An investigation into the asymmetric synthesis of novel benzopyrans for biological evaluation. (PhD thesis), Kingston University,


The aim of this project was to prepare a novel range of dicobalt hexacarbonyl-alkyne complexes for testing as anticancer agents and benzopyrans as antihypertensives. In addition an investigating into the stereoselectivity of the Nicholas reaction will be undetaken. Hypertension and cancer are two very different dieases that are becoming more prevalent in modern life. Interest in antiproliferatory compounds containing metallic substituents has intensified since the serendipitous discovery of cisplatin in 1969. More recently Co-ASS, a dicobalt hexacarbonyl alkyne complex derived from aspirin, was found to out perform Cisplatin in the inhibition of MCF-7 breast cancer cells. This has led to a number of cobalt-alkyne complexes being found to possess anticancer activity. The preparation of a range novel cobalt-alkyne complexes is herein described along with the testing of their efficacy against CaCo-2 cancer cells. This Study showed that the presence of aromatic ring substituents had a large detrimental effect on their activity with the unsubstituted counterpart eliciting an IC50 value of 16.02 µM relative to >100 µM for the substituted counterparts. The observed IC50 of 16.02 is similar to those found in the literature for the cobalt-alkyne complexes of propargyl amides Co-ASSAM and Co-Phthal giving values of 8.8 and 22.2 repectively on MCF-7 cells. Benzopyrans are known to relax smooth muscle by activating transmembrane potassium channels. Cromakalim, the bench mark potassium channel activator however is not used clinically due to undesirable side effects. This has led to a large amount of work into the preparation of novel benzopyrans that maintain this activity whilst eliminating these side effects. Although the novel benzopyrans prepared were shown to be less active, as vasorelaxants, compared to cromakalim, they do, show greater activity compared to compounds that had been previously prepared within the Tyrrell group. Finally we show the exclusive cis diastereoselective nature of our studied Nicholas reaction in the simultaneous formation of two chiral centres. The effect of chiral induction on the formation of these two centres is also investigated showing the ee of the Nicholas reaction to be >99% and a de of 68% in the most selective instance.

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