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).
Antimicrobial drugs are highly popular in the treatment of infectious diseases and particularly nosocomial infections. However, excessive microbial exposure to drugs has become the most important factor triggering the emergence and spread of multidrug resistance (MDR) of microorganisms (1). This phenomenon has become a pressing global problem for two reasons. Firstly, it increases morbidity and mortality rates and treatment costs. Secondly, it limits the effectiveness of existing drugs and enhances the number of treatment failures (2). Furthermore, in the last few decades, cancer has become one of the most fiercely combated diseases around the world (3). Synthetic drugs are often the only option for cancer chemotherapy (4). However, most of them kill not only tumor cells but also the normal ones (5). Therefore, there is an urgent need for new treatments with few side effects. The use of medicinal plants and especially their secondary metabolites, essential oils (EOs), may pose a viable alternative. Thymus vulgaris L., known as common thyme (Lamiaceae family), is a perennial herb indigenous to the Mediterranean region, Asia, Southern Europe and North Africa (6). It is widely used in folk medicine and also in the food industry as a spice and natural preservative. Its oil is among the top 10 EOs exhibiting various biological activities (7) mainly due to phenols, e.g. thymol and carvacrol (8). This considerable potential of thyme oil encouraged us to analyze its chemical structure by GC-FID and GC-MS and verify its antimicrobial activity against seven reference strains responsible for nosocomial infections. We also assessed its cyto
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