Synthesis of novel phytol-derived \u03b3-butyrolactones and evaluation of their biological activity

Anna Gliszczyńska,Katarzyna Dancewicz,Gabriela Maciejewska,Joanna Wietrzyk,Marta Świtalska,Beata Gabryś

doi:10.1038/s41598-021-83736-6

Abstract

The synthesis of phytol-derived γ-butyrolactones as well as their evaluation for deterrent activity towards peach-potato aphid Myzus persicae and antiproliferative activity against four selected cancer cell lines are reported. Products were obtained in good yields (19–96%) and their structures were fully characterized by spectroscopic data (NMR, HRMS). Four synthesized δ-halo-γ-lactones (4–7) are new and have not been previously described in the literature. In the choice test phytol (1) appeared deterrent to M. persicae, whereas modifications of its structure did not cause the avoidance of the treated leaves by the aphids. In contrast, aphids were attracted to the leaves treated with the new trans-δ-chloro-γ-lactone (6). Electrical Penetration Graph (EPG) technique applied to explore the aphid probing and feeding activity revealed that neither phytol nor lactone 6 affected aphid probing and the consumption of phloem sap, which means that both phytol and the lactone 6 might have acted as postingestive modifiers of aphid behavior. The results of in vitro antitumor assays showed that obtained phytol derivatives exhibit cytotoxic activity against studied cancer cell lines (leukemia, lung and colon carcinoma and its doxorubicin resistant subline). Halolactones 4–6 were identified as the compounds, which arrest cell cycle of leukemia cells mainly in G2/M and S phases.

Highlights

The synthesis of phytol-derived γ-butyrolactones as well as their evaluation for deterrent activity towards peach-potato aphid Myzus persicae and antiproliferative activity against four selected cancer cell lines are reported
Like for racemic δ-halo-γ-lactone synthesized from farnesol it was shown that γ-butyrolactones are able to inhibit the growth of cancer cell lines, A549 and HL-6016,23
A series of phytol-derived compounds were synthesized in good yields and their aphid behavior modifying activity and cytotoxic potency were evaluated

Summary

Introduction

The synthesis of phytol-derived γ-butyrolactones as well as their evaluation for deterrent activity towards peach-potato aphid Myzus persicae and antiproliferative activity against four selected cancer cell lines are reported. Among biological activities that γ-lactones show, to the fore comes extensively described in the literature their significant role which they play in the world of insects and the role of anticancer agents This type of molecules is responsible for effective sexual signaling as sex attractant pheromones between different species of insect, exhibits good antifeedant activity against insects and is well-known as strong antitumor, antibiotic, antifungal and antiviral agents. Valuable γ-butyrolactones are those which structure is based on the isoprenoid skeleton These lactones isolated from plants constitute one of the most numerous groups of antifeedants. Looking among isoprenoids for a biologically active natural carbon skeleton that could be the basis structure for developing its active lactone derivatives which can be useful as a new type of insecticides and cytostatic molecules we selected phytol (3,7,11,15-tetramethylhexadec-2-en-1-ol) (PYT) [1]. The calculated lethal doses ( LD50) of PYT for them are above 5 g and 10 g/kg, respectively

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