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).
Highlights
Cytotoxic activity against different cancer cell lines is one of the most characteristic biological activities of lactones possessing an aromatic ring in their structures
2,5-dimethylbenzaldehyde, in this work we report a synthesis of their chiral bromo analogs and evaluation of their activity against panel of canine cancer lines
The results showed an increase in values of generalized polarization (GP) for enantiomer 4R,5R,6S of cis γ-lactone γ-lactone 6 from concentration 40 μM
Summary
Cytotoxic activity against different cancer cell lines is one of the most characteristic biological activities of lactones possessing an aromatic ring in their structures. Among this diverse group of compounds many reports concern antiproliferative activity of natural lactones i.a. coumarin [1], campthotecin [2],. (−)-cleistenolide [3], (+)-crassalactones [4,5], or styryl lactones [6], including goniothalamin [7] or. Compounds bearing a β-aryl-γ-lactone or β-aryl-δ-lactone core derived from aromatic aldehydes exhibited cytotoxic effects on different cancer lines. Significant activity against human promyelocytic leukemia (HL-60) line was shown for racemic β-aryl-δ-iodo-γ-lactones obtained in five-steps synthesis in which the first step was Doebner condensation of aromatic aldehydes with monomethyl malonate [22]
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