Sesquiterpenoid unsaturated dialdehydes - Structural properties that affect reactivity and bioactivity

Sammanfattning: The natural unsaturated 1,4-dialdehydes warburganal (6), polygodial (14), isovelleral (55) and merulidial (56a) and their corresponding unconjugated aldehyde isomers (121), (15), (108) and (109a) were prepared, and their bioactivity and reactivity towards various nucleophiles were investigated. New synthetic routes to prepare (-)-6 and its isomer (+)-121 from (-)-14, and (+)-109a from (-)-56a, have been developed. The dialdehydes (-)-55 and (+)-108 were prepared by total synthesis. A natural adduct between (-)-56a and triacetic acid lactone (155) was isolated from the culture filtrate of the fungus Merulius tremellosus, and the same adduct was shown to be formed from the reaction between 56a and 155 in aqueous solutions as well as in organic solvents. The reactivity of the eight unsaturated 1,4-dialdehydes towards lactone 155, L-lysine, L-alanine and L-cysteine was investigated. The naturally occuring dialdehydes 6, 14, 55, 56a all react faster than their corresponding isomer 121, 15, 108 and 109a, which correlates with for instance their antibiotic activities. The drimane dialdehydes 6 and 14, are generally reactive towards various nucleophiles, while the marasmane 55 and its isomer 108 are specifically reactive towards thiols. The dialdehydes 6, 55 and 56a are easily autoxidised, while less bioactive derivatives are not, and the biological activities of the autoxidation products of 55 and 56a are of the same order as their parent compounds. Furthermore, 55 was found to oxidise cysteine to cystine in buffer at pH 7.4. The biological activities of the dialdehydes can only in part be correlated with their reactivity towards nucleophiles, and other molecular mechanisms, for example oxidative, for their action must be considered. A correlation between the hot taste of the dialdehydes to the human tongue and their affinity for the vanilloid receptor, which is the target for the pungent compounds capsaicin and resiniferatoxin, was found. The hot taste of the dialdehydes to the human tongue, as well as their interactions with the dopamine D1 receptor and their mutagenicity in Ames' test, were at least to some extent shown to be enantiospecific.