Multifunctional Indomethacin Conjugates for the Development of Nanosystems Targeting Cancer Treatment.

Purpose: It is well known that the nonsteroidal anti-inflammatory drug (NSAID) indomethacin (IND) exhibits significant anticancer potential reported not only by in vitro and in vivo studies, but also in clinical trials. Despite promising results, IND is not widely used as an adjunctive agent in cancer therapy due to the occurrence of several gastrointestinal side effects, primarily after oral administration. Therefore, this study aimed to develop a nanosystem with reduced toxicity and risk of side effects for the delivery of IND for cancer treatment.

New Hydroxylactones and Chloro-Hydroxylactones Obtained by Biotransformation of Bicyclic Halolactones and Their Antibacterial Activity.

The aim of this study was to obtain new halolactones with a gem-dimethyl group in the cyclohexane ring (at the C-3 or C-5 carbon) and a methyl group in the lactone ring and then subject them to biotransformations using filamentous fungi. Halolactones in the form of mixtures of two diasteroisomers were subjected to screening biotransformations, which showed that only compounds with a gem-dimethyl group located at the C-5 carbon were transformed. Strains from the genus carried out hydrolytic dehalogenation, while strains from the genus carried out hydroxylation of the C-7 carbon.

Lysophosphatidylcholines Enriched with and Palmitoleic Acid Regulate Insulin Secretion via GPR119 Receptor.

Among lipids, lysophosphatidylcholines (LPCs) with various fatty acyl chains have been identified as potential agonists of G protein-coupled receptors (GPCRs). Recently, targeting GPCRs has been switched to diabetes and obesity. Concomitantly, our last findings indicate the insulin secretagogue properties of and palmitoleic acid (16:1, n-7) resulting from GPCR activation, however, associated with different signaling pathways.

Conjugates of 1,3- and 1,2-Acylglycerols with Stigmasterol: Synthesis, NMR Characterization, and Impact on Lipid Bilayers.

The main aim of research was synthesis and spectroscopic characterization of new conjugates in which stigmasterol was linked via carbonate or succinyl linker with 1,3- and 1,2-acylglycerols of palmitic and oleic acid. Acylglycerols containing stigmasterol residue at internal position have been synthesized from 2-benzyloxypropane-1,3-diol or dihydroxyacetone. Their asymmetric counterparts containing stigmasterol residue attached to sn-3 position have been obtained from (S)-solketal.

Divergent Synthesis of Functionalized Indenopyridin-2-ones and 2-Pyridones via Benzyl Group Transfer: Two Cases of Aza-semipinacol-Type Rearrangement.

The synthesis of bromo-substituted indeno[1,2-]pyridin-2-ones and 3-iodo-5-benzyl-substituted 2-pyridones, starting from easily available 6-benzyl-3,6-dihydropyridin-2(1)-ones, triggered by NBS and NIS, respectively, is described. In both syntheses, a transfer of a benzyl group from the C6 to C5 lactam position occurred, indicating a novel aza-semipinacol-type rearrangement. Identification of intermediate compounds in both transformations supported the proposed reaction mechanisms.

Thermo-oxidative stability of asymmetric distigmasterol-modified acylglycerols as novel derivatives of plant sterols.

The study investigated the thermo-oxidative stability of distigmasterol-modified acylglycerols as a new structured acylglycerols. Samples were heated at 60 and 180 °C for 8 h. Their percentage degradation and products formed during heating were compared with free stigmasterol and stigmasteryl esters.

Distigmasterol-Modified Acylglycerols as New Structured Lipids-Synthesis, Identification and Cytotoxicity.

Plant sterols, also referred as phytosterols, have been known as bioactive compounds which have cholesterol-lowering properties in human blood. It has been established that a diet rich in plant sterols or their esters alleviates cardiovascular diseases (CVD), and also may inhibit breast, colon and lung carcinogenesis. Phytosterols, in their free and esterified forms, are prone to thermo-oxidative degradation, where time and temperature affect the level of degradation.

Synthesis and Anticancer Activity of Mitotic-Specific 3,4-Dihydropyridine-2(1)-thiones.

Most anticancer drugs target mitosis as the most crucial and fragile period of rapidly dividing cancer cells. However the limitations of classical chemotherapeutics drive the search for new more effective and selective compounds. For this purpose structural modifications of the previously characterized pyridine aalog () were incorporated aiming to obtain an antimitotic inhibitor of satisfactory and specific anticancer activity.

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.

Antimicrobial chloro-hydroxylactones derived from the biotransformation of bicyclic halolactones by cultures of Pleurotus ostreatus.

The aim of this research was to test the ability of cultures of edible fungi to biotransform three bicyclic halolactones. The substrates (2-chloro-, 2-bromo- and 2-iodo-4,4,6,7-tetramethyl-9-oxabicyclo[4.3.

Production of feruloylated lysophospholipids via a one-step enzymatic interesterification.

Incorporation of ferulic acid (FA) into egg-yolk phosphatidylcholine (PC) in a lipase-catalyzed acidolysis and interesterification process was studied using four commercially available immobilized lipases as catalysts and two acyl donors: ferulic acid (FA) and ethyl ferulate (EF). Novozym 435 and a binary solvent system of toluene/chloroform 9:1 (v/v) were found to be the most suitable biocatalyst and medium, respectively, and significantly increased the incorporation of FA into the phospholipid fraction. Subsequently response surface methodology (RSM) and Box-Behnken design were employed to evaluate the effects of substrate molar ratio, enzyme loading and time of the reaction on the process of interesterification.

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

Starting from 1-acetyl-1-cyclohexene, three enantiomeric pairs (ee ≥99%) of bicyclic δ-halo-γ-lactones with cyclohexane ring were obtained in five-step synthesis. The key stereochemical steps were lipase-catalyzed kinetic resolution of racemic 1-(cyclohex-1-en-1-yl) ethanol followed by transfer of chirality to ethyl 2-(2-ethylidenecyclohexyl) acetate in the Johnson-Claisen rearrangement. Synthesized halolactones exhibited antiproliferative activity towards canine B-cell leukemia cells (GL-1) and canine B-cell chronic leukemia cells (CLB70) and the most potent (IC 18.

Synthesis and Antimicrobial Activity of Methoxy- Substituted γ-Oxa-ε-lactones Derived from Flavanones.

Six γ-oxa-ε-lactones, 4-phenyl-3,4-dihydro-2-1,5-benzodioxepin-2-one () and its five derivatives with methoxy groups in different positions of A and B rings (-), were synthesized from corresponding flavanones. Three of the obtained lactones (,,) have not been previously described in the literature. Structures of all synthesized compounds were confirmed by complete spectroscopic analysis with the assignments of signals on H and C-NMR spectra to the corresponding atoms.

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

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 ( AM10, AM296, AM536).

Syntheses and cytotoxicity of phosphatidylcholines containing ibuprofen or naproxen moieties.

In this study, novel phosphatidylcholines containing ibuprofen or naproxen moieties were synthesized in good yields and high purities. Under the given synthesis conditions, the attached drug moieties racemized, which resulted in the formation of phospholipid diastereomers. The comperative studies of the cytotoxicity of ibuprofen, naproxen and their phosphatidylcholine derivatives against human promyelocytic leukemia HL-60, human colon carcinoma Caco-2, and porcine epithelial intestinal IPEC-J2 cells were carried out.

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

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 ()-3-(2',5'-dimethylphenyl)hex-4-enoic acids () by kinetically controlled bromolactonization with -bromosuccinimide (NBS). γ-Bromo-δ-lactones () were isolated as the major products. Absolute configurations of stereogenic centers of γ-bromo-δ-lactones () were assigned based on X-ray analysis; configurations of δ-bromo-γ-lactones () and δ-bromo-γ-lactones () were determined based on mechanism of bromolactonization.

Synthesis and biological evaluation of phosphatidylcholines with cinnamic and 3-methoxycinnamic acids with potent antiproliferative activity.

A series of eight novel phosphatidylcholines containing cinnamic or 3-methoxycinnamic acids (3a-b, 5a-b, 9a-b, 10a-b) at -1 and/or -2 positions were synthesized and tested for their antiproliferative activity in an model against representative six human cancer cell lines (MV4-11, A549, MCF-7, LoVo, LoVo/DX, HepG2) and a normal cell line BALB/3T3. The structures of the new compounds were confirmed by spectral analysis. Biological evaluation revealed that all the tested conjugates exhibited higher antitumor activity than the corresponding free aromatic acids.

Synthesis, Characterization, and In Vitro Cancer Cell Growth Inhibition Evaluation of Novel Phosphatidylcholines with Anisic and Veratric Acids.

Phenolic acids and its methoxy derivatives are known to induce caspase-mediated apoptosis activity and exhibit cytotoxic effect towards various cancer cell lines. However, their low stability and poor bioavailability in the human organism extensively restrict the utility of this group of compounds as anticancer and health-promoting agents. In this report, a series of eight novel phosphatidylcholines (, , , ) containing anisic or veratric acids () at -1 and/or -2 positions were synthesized.

Microbial Hydrolysis of Racemic β-Aryl-γ-ethylidene-γ-lactones and Antifeedant Activity of the Products against Panzer.

Hydrolysis of (±)-β-aryl-γ-ethylidene-γ-lactones by fungal strain AM370 afforded (−)-()-γ-ethylidene-γ-lactones ⁻ and (+)-()-γ-ketoacids ⁻. Enantiomeric purity of the unreacted lactones was strictly related to a size of an aryl substituent at C-4 of γ-lactone ring, with the highest (77%) obtained for the (−)-()-γ-ethylidene-γ-lactone possessing unsubstituted benzene ring () and the lowest one (15%) determined for the (−)-()-γ-ethylidene-γ-lactone with bulky 1,3-benzodioxole system (). Lactones ⁻, both racemic and enantiomerically enriched, as well as products of their hydrolysis showed varying degrees of feeding deterrent activity against lesser mealworm, Panzer, which depended on the structure of the compound and the developmental stage of the lesser mealworm.

Synthesis of Polycyclic δ-Lactams with Bridged Benzomorphan Skeleton: Selectivity and Diversity Driven by Substituents.

An efficient synthesis of bromofunctionalized 2,6-methano- and 1,5-methano-benzomorphanones, starting from easily available 6-benzyl-3,6-dihydropyridin-2(1H)-ones, is described. Furthermore, the synthesis of bridged benzomorphanones with hitherto not known polycyclic systems containing 2- or 3-azabicyclo[4.1.

Regio- and enantioselective microbial hydroxylation and evaluation of cytotoxic activity of β-cyclocitral-derived halolactones.

Three β-cyclocitral-derived halolactones, which exhibit antifeedant activity towards storage product pests, were subjected to microbial transformation processes. Among the thirty tested strains of filamentous fungi and yeast, the most effective biocatalysts were Absidia cylindrospora AM336, Mortierella isabellina AM212 and Mortierella vinaceae AM149. As a result of regio- and enantioselective hydroxylation four new oxygenated derivatives were obtained.

Influence of structure of lactones with the methylcyclohexene and dimethylcyclohexene ring on their biotransformation and antimicrobial activity.

The aim of this article is influence of the structure of lactones with the methylcyclohexene and dimethylcyclohexene ring on their biotransformation and antimicrobial activity. This work was based on the general remark that even the smallest change in the structure of a compound can affect its biological properties. The results of the biotransformation of four bicyclic unsaturated lactones with one or two methyl groups in the cyclohexene ring was tested using fifteen fungal strains (Fusarium species, Penicillium species, Absidia species, Cunninghamella japonica, and Pleurotus ostreatus) and five yeast strains (Yarrowia lipolytica, Rhodorula marina, Rhodorula rubra, Candida viswanathii, and Saccharomyces cerevisiae).

Synthesis and Biotransformation of Bicyclic Unsaturated Lactones with Three or Four Methyl Groups.

The aim of this study was to obtain new unsaturated lactones by chemical synthesis and their microbial transformations using fungal strains. Some of these strains were able to transform unsaturated lactones into different hydroxy or epoxy derivatives. Strains of and gave products with a hydroxy group introduced into a tertiary carbon, while the strain hydroxylated primary carbons.

Syntheses and antiproliferative activities of novel phosphatidylcholines containing dehydroepiandrosterone moieties.

Dehydroepiandrosterone (DHEA) is a natural hormone with many beneficial properties including an anticancer activity. Unfortunately, DHEA is unstable in the body and exhibits cytotoxicity against healthy cells. In this study, a series of new phosphocholines containing DHEA at sn-1 and/or sn-2 positions were prepared.

Chemoenzymatic Synthesis of trans-β-Aryl-δ-hydroxy-γ-lactones and Enzymatic Kinetic Resolution of Their Racemic Mixtures.

Two novel and convenient routes to obtain enantiomerically enriched -β-aryl-δ-hydroxy-γ-lactones - with potential antifeedant and anticancer activity were developed. In the first method starting from corresponding enantiomers of γ,δ-unsaturated esters - derived from enzymatically resolved allyl alcohols -, both enantiomers of hydroxylactones - were synthesized with high enantiomeric excesses (73%-97%). Configurations of the stereogenic centers of the synthesized compounds were assigned based on the mechanism of acidic lactonization of esters - in the presence of -chloroperbenzoic acid (-CPBA).