Preparation of Enantiomeric β-(2′,5′-Dimethylphenyl)Bromolactones, Their Antiproliferative Activity and Effect on Biological Membranes

Abstract

Three novel enantiomeric pairs of bromolactones possesing a 2,5-dimethylphenyl substituent at the β-position of the lactone ring have been synthesized from corresponding enantiomeric (E)-3-(2′,5′-dimethylphenyl)hex-4-enoic acids (4) by kinetically controlled bromolactonization with N-bromosuccinimide (NBS). γ-Bromo-δ-lactones (5) were isolated as the major products. Absolute configurations of stereogenic centers of γ-bromo-δ-lactones (5) were assigned based on X-ray analysis; configurations of cis δ-bromo-γ-lactones (6) and trans δ-bromo-γ-lactones (7) were determined based on mechanism of bromolactonization. Synthesized compounds exhibited significant antiproliferative activity towards the four canine cancer cell lines (D17, CLBL-1, CLB70, and GL-1) and one human cancer line (Jurkat). Classifying the compounds in terms of activity, the most active were enantiomers of trans δ-bromo-γ-lactones (7) followed by enantiomers of cis isomer (6) and enantiomeric γ-bromo-δ-lactones (5). Higher activity was observed for all stereoisomers with S configuration at C-4 in comparison with their enantiomers with 4R configuration. Synthesized compounds did not induce hemolysis of erythrocytes. The results of the interaction of bromolactones with red blood cell membranes suggest that these compounds incorporate into biological membranes, concentrating mainly in the hydrophilic part of the bilayer but have practically no influence on fluidity in the hydrophobic region. The differences in interactions with the membrane between particular enantiomers were observed only for γ-lactones: stronger interactions were found for enantiomer 4R,5R,6S of cis γ-lactone (6) and for enantiomer 4S,5R,6S of trans γ-lactone (7).

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

“…In this regard all tested compounds did not have a toxic effect on red blood cells (RBCs). These results are consistent with the results obtained for bromolactones with a 2,5-dimethylfenyl substituent [19].…”

“…The nucleophilic attack of an oxygen atom from carboxylate ion is highly stereospecific and goes from opposite sides of halonium ion. The steric consequences are the antiperiplanar orientations of C-X and C-O bonds [17,19,35,36] that determine configurations of two new stereogenic centers at C-1 and C-1' in the formed halolactones. The rigid structure of the cyclohexane ring as well as the presented lactonisation mechanisms allowed us to assign (1S,6S,1'R) configuration for halolactones 6a, 7a and 8a obtained from (S)-acid 5a (Scheme 4).…”

“…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.…”

“…In the last few years, our scientific interests have concentrated on the synthesis of biologically active lactones [7,8,16]. In our previous research on antiproliferative compounds, we developed a synthetic pathway to obtain highly active γ-lactones with a β-aryl substituent [17][18][19]. An important element of the structure of these compounds, affecting their activity, was the presence of a halogen atom.…”

Free and Immobilized Lecitase™ Ultra as the Biocatalyst in the Kinetic Resolution of (E)-4-Arylbut-3-en-2-yl Esters

“…However, since a large variety of chiral esters possess the stereogenic center in the nucleophilic part of molecule, to extend the substrate scope and increase the usability of this enzyme in the asymmetric synthesis, we employed Lecitase™ Ultra for the biocatalytic resolution of racemic 4-arylbut-3-en-2-ol esters. In our working group, these alcohols are the subject of special interest as chiral precursors of the optically active lactones with antiproliferative activity [56,57]. Likewise, they have been used in the production of chiral drugs [58,59].…”