Microbial Asymmetric Functionalization of β-Cyclocitral-Derived Tetramethyl-Substituted γ-Lactone

Abstract

Searching for the new anticancer compounds we prepared three new β-cyclocitral-derived hydroxyl-γ-lactones by microbial hydroxylation of tetramethyl-substituted bicyclic γ-lactone. The substrate was transformed by the enzymatic system of filamentous fungi. Three out of fifteen strains were selected as effective biocatalysts (Fusarium culmorum AM10, Armillaria mellea AM296, Trametes versicolor AM536). The hydroxylation processes were not only regioselective but also stereoselective. The hydroxylation products of each secondary carbon atom in the cyclohexane ring were obtained by the application of the selected fungal strains. The Fusarium culmorum AM10 introduced the hydroxy function at C-3 and C-4, Armillaria mellea AM296 incorporated the hydroxy function at C-3 and C-5 and Trametes versicolor AM536 transformed the substrate to the mixture of C-3, C-4 and C-5 hydroxylactones. The hydroxylactones obtained were enantiomericaly enriched (ee values in the range 17–99%). The in vitro antiproliferative activities of the functionalization products were also evaluated. Regardless of the hydroxy substituent location all tested lactones exhibited similar, significant activity towards selected cancer cell lines (IC50 in the range 22.8–33.9 µg/mL).

Chemoenzymatic Synthesis of Enantiomeric, Bicyclic δ-Halo-γ-lactones with a Cyclohexane Ring, Their Biological Activity and Interaction with Biological Membranes

“…Overall, there were no significant differences in lactone activity regardless of halogen type and configuration of stereogenic centers. It is worth to point that the activity of tested compounds was comparable with the control and was much higher than antiproliferative activity of bicyclic lactones with the cyclohexane system reported earlier [20,41]. Figure 1.…”

“…The method has been described previously by Pruchnik et al [29]. The hemolytic activity of the lactones was tested as DMSO solutions (10,20,40,60,80, and 100 µM concentrations). The control contained only DMSO in the same volume as the tested samples.…”

“…The antyproliferative activity of lactone enantiomers was tested on two canine cell lines CLB70 and GL-1 ( Table 2). The choice of these specific cell lines was due to the possibility of comparing the results to previous experiments [18][19][20]. All tested substances exhibited significant activity.…”

“…An important element of the structure of these compounds, affecting their activity, was the presence of a halogen atom. Recently, we have also reported that some bicyclic γ-lactones with a cyclohexane system exhibited cytotoxicity against selected cancer cell lines [20]. Assuming that the introduction of a halogen atom can potentially increase the cytotoxic effect exhibited by this group of compounds, we designed the synthesis in order to obtain a series of new halogen derivatives of γ-lactones with a cyclohexane ring (6)(7)(8), containing iodine, bromine and chlorine atoms in the lactone structure.…”

New Bromo- and Iodo-Hydroxylactones with Two Methyl Groups Obtained by Biotransformation of Bicyclic Halolactones

“…These are usually lactones containing in their structure, apart from methyl groups, halogen atoms, or double bond. The most common products of such reactions are hydroxyl derivatives of lactones [6][7][8][9][10][11][12].…”