Abstract:
Natural products originate from the enzyme-catalysed transformation of common intermediates through one or more biosynthetic pathways. Two such biosynthetic pathways, the mevalonate and the recently discovered deoxyxylulose phosphate pathways give rise to isoprenoid natural products. Isoprenoid natural products are biosynthesised from isoprene (C5) units, with incorporation of fragments from other biosynthetic pathways affording structural diversity. The teak wood derived natural product, tecomaquinone I (2.53), was identified as a potent inhibitor of human FTase, exhibiting activity in the nanomolar range. The structurally-related cytotoxic natural product, tectol (2.55) exhibited moderate inhibitory activity against FTase and P. falciparum. Analogues of tecomaquinone I (2.53), altering the isoprenoid fragment, were synthesised and their bioactivity examined. Increasing the number of isoprene units on the side chain afforded 4-methylpent-3-enyl (2.71 A–D) and 4,8-dimethylnona-3,7-dien-1-yl (2.78 A–D) analogues, both of which were synthesised as four (racemic) diastereomers. The analogues were not as potent as 2.53 in the FTase inhibition assays, with the 4-methylpent-3-enyl tecomaquinone analogues (2.71 A–D) exhibiting the highest activity. Anti-plasmodial assays revealed a specific structural requirement, with only analogues of tectol (2.55) exhibiting activity. Marine meroterpenoids, thiaplidiaquinones A (3.1) and B (3.2) were shown to induce apoptosis in Jurkat cells. Analogues of thiaplidiaquinones A (3.1) and B (3.2) and their regioisomers 3.3 and 3.4, altering the isoprenoid fragments, were synthesised biomimetically. Varying the number of isoprene units afforded prenyl and farnesyl analogues. The prenyl analogues (3.33–3.36) exhibited a similar profile to 3.1–3.4, where the regioisomers were more active than the natural products, in the anti-plasmodial, cytotoxicity and FTase inhibition assays while no trends were observed for the farnesyl analogues (3.47–3.50). The sesquiterpenoid, onchidal (4.40) was isolated from the defensive secretion of a shell-less mollusc. The feeding deterrent activity exhibited by the mollusc has been associated with the reactive fragments of 4.40. Analogues, bearing the enol acetate and dialdehyde forms of the reactive warhead of onchidal (4.40) were synthesised. n-Hexyl (4.61–4.63), cyclohexylethyl (4.71–4.73) and hexyne (4.88 and 4.89) analogues were synthesised and reactivity studies conducted with model thiol and amine nucleophiles. All the analogues exhibited selectivity towards amine nucleophiles forming diaminated pyrrole adducts. Reactivity studies conducted on lysozyme, examined by ESIMS and SDS-PAGE, detected modifications consistent with pyrrole adducts as well as evidence of protein crosslinking. Model reactions incorporating fluorescent tags on the hexyne analogue were achieved with dansyl and lissamine rhodamine azides through a ‘click’ reaction.