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

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.

In vitro, in vivo and in silico Antihyperglycemic Activity of Some Semi-synthetic Phytol Derivatives.

Background: Due to the prevalence of type-2 diabetes across the globe, there is unmet need to explore new molecular targets for the development of cost-effective and safer antihyperglycemic agents. Objective: Structural modification of phytol and evaluation of in vitro, in vivo and in silico antihyperglycemic activity of derivatives establishing the preliminary structure activity relationship (SAR). Methods: The semi-synthetic derivatives of phytol were prepared following previously described methods. The antihyperglycemic potential was measured in vitro in terms of increase in 2-deoxyglucose (2-DG) uptake by L-6 rat skeletal muscle cells as well as in vivo in sucrose-loaded (SLM) and streptozotocin (STZ)-induced diabetic rat models. The blood glucose profile was measured at 30, 60, 90, 120, 180, 240, 300 and 1440 min post administration of sucrose in rats. The in silico docking was performed on peroxisome proliferator-activated receptor gamma (PPARγ) as anti-diabetic target along with absorption, distribution, metabolism, excretion and toxicity (ADMET) studies. Results: Nine semi-synthetic ester derivatives: acetyl (1), lauroyl (2), palmitoyl (3), pivaloyl (4), trans-crotonyl (5), benzoyl (6), m-anisoyl (7), 3,4,5-trimethoxy benzoyl (8) cinnamoyl (9) along with bromo derivative (10) of phytol were prepared. The derivatives 9, 8 and 2 caused 4.5, 3.2 and 2.7 times more in vitro uptake of 2-DG respectively than rosiglitazone (ROSI). The derivatives showed significant improvement on oral glucose tolerance both in SLM (29.6-21%) as well as STZ-induced diabetic (30.8-19.0%) rats. The in silico ADMET, docking studies showed non-toxicity and high binding affinity with PPARγ. Conclusion: The potent antihyperglycemic activity with favorable pharmacokinetics supports phytol derivatives as suitable antidiabetic lead.