Abstract
Ficifolidione, a natural insecticidal compound isolated from the essential oils of Myetaceae species, is a spiro phloroglucinol with an isobutyl group at the C-4 position. We found that ficifolidione showed cytotoxicity against cancer cells via apoptosis. Replacement of the isobutyl group by n-propyl group did not influence the potency, but the effect of the replacement of this group by a shorter or longer alkyl group on the biological activity remains unknown. In this study, ficifolidione derivatives with alkyl groups such as methyl, n-pentyl, and n-heptyl group—instead of the isobutyl group at the C-4 position—were synthesized to evaluate their cytotoxicity against the human promyelocytic leukaemia cell line HL60 and their insecticidal activity against mosquito larvae. The biological activities of their corresponding 4-epimers were also evaluated. As a result, the conversion of the isobutyl group to another alkyl group did not significantly influence the cytotoxicity or insecticidal activity. In HL60 cells treated with the n-heptyl-ficifolidione derivative, the activation of caspase 3/7 and the early stages of apoptosis were detected by using immunofluorescence and flow cytometric techniques, respectively, suggesting that the cytotoxicity should be induced by apoptosis even though the alkyl group was changed.
Highlights
IntroductionEssential oils extracted from various kinds of plants have attracted great interest because the oils show various interesting biological activities, such as pest insect repellent, anti-fungal, antioxidant and cytotoxic activities [1,2,3,4].Among these plants, the genus Eucalyptus are well-known as a source of various essential oils, including p-menthane-3,8-diol (repellent against mosquitoes from E. citriodora) [5] and ericifolione (insecticidal activity) [6].Ficifolidione, tetramethyltetrahydrochromenedione-spirobicyclo[3.1.1]cylcoheptane, was reportedly isolated from two Myetaceae species, Eucalyptus ficifolia and Kunzea ericoides, using hexane extraction in the course of exploring insecticidal substances against worms and mosquitoes [7].We were interested in analysing the structure-activity relationship (SAR) of ficifolidione, a unique spiro-compound with a phloroglucinol moiety, using a series of derivatives of this compound
We found that ficifolidione showed little insecticidal activity against the insects tested, whereas higher cell toxicity was observed against cancer cells compared with normal Vero cells
Ficifolidione was reportedly active against the larvae of Aedes aegypti and C. quinquefasciatus
Summary
Essential oils extracted from various kinds of plants have attracted great interest because the oils show various interesting biological activities, such as pest insect repellent, anti-fungal, antioxidant and cytotoxic activities [1,2,3,4].Among these plants, the genus Eucalyptus are well-known as a source of various essential oils, including p-menthane-3,8-diol (repellent against mosquitoes from E. citriodora) [5] and ericifolione (insecticidal activity) [6].Ficifolidione, tetramethyltetrahydrochromenedione-spirobicyclo[3.1.1]cylcoheptane, was reportedly isolated from two Myetaceae species, Eucalyptus ficifolia and Kunzea ericoides, using hexane extraction in the course of exploring insecticidal substances against worms and mosquitoes [7].We were interested in analysing the structure-activity relationship (SAR) of ficifolidione, a unique spiro-compound with a phloroglucinol moiety, using a series of derivatives of this compound. Essential oils extracted from various kinds of plants have attracted great interest because the oils show various interesting biological activities, such as pest insect repellent, anti-fungal, antioxidant and cytotoxic activities [1,2,3,4]. Among these plants, the genus Eucalyptus are well-known as a source of various essential oils, including p-menthane-3,8-diol (repellent against mosquitoes from E. citriodora) [5] and ericifolione (insecticidal activity) [6].
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