Novel Lipid-Based Carriers of Provitamin D: Synthesis and Spectroscopic Characterization of Acylglycerol Conjugated with 7-Dehydrocholesterol Residue and Its Glycerophospholipid Analogue.

The aim of this research was to design and synthesize new lipid conjugates of 7-DHC that could serve as a new storage form of esterified provitamin D, increasing the reservoir of this biomolecule in the epidermis and enabling controlled production of vitamin D even during periods of sunlight deficiency. Acylglycerol and glycerophospholipid containing succinate-linked provitamin D at the -2 position of the glycerol backbone were synthesized from dihydroxyacetone (DHA) and -glycerophosphocholine (GPC), respectively. The three-step synthesis of 1,3-dipalmitoyl-2-(7-dehydrocholesterylsuccinoyl)glycerol involved the esterification of DHA with palmitic acid, reduction of the carbonyl group, and conjugation of the resulting 1,3-dipalmitoylglycerol with 7-dehydrocholesterol hemisuccinate (7-DHC HS).

Heating and storage of structured acylglycerols with succinyl-linked stigmasterol residue does not cause negative chemical or biological changes.

Four structured acylglycerols with stigmasterol bonded by a succinyl linker were investigated and their stability were analyzed. Samples were heated to 60 °C and kept at that temperature to simulate storage, and to 180 °C to simulate frying conditions. The degradation of the synthesized compounds and formed derivatives was determined, and their cytotoxicity and genotoxicity on normal human cells from the digestive system was determined.

Chalcone-Derived Lactones: Synthesis, Whole-Cell Biotransformation, and Evaluation of Their Antibacterial and Antifungal Activity.

Four compounds with lactone moiety were synthesized from chalcone in three- or four-step synthesis. γ-Bromo-δ-lactone was the only product of bromolactonization of acid whereas bromolactonization of ester , apart from lactone also afforded its isomer and two diastereoisomeric δ-hydroxy-γ-lactones and . Lactone was also obtained in 88% yield as a product of simultaneous dehalogenation and translactonization of γ-bromo-δ-lactone by AM 359.

Thermo-oxidative stability and safety of new acylglycerols with stigmasterol residue: Effects of fatty acids saturation and position in the glycerol backbone.

The safety and thermoxidative stability of new diacyl-stigmasterylcarbonoyl-sn-glycerols (DAStGs) with two molecules of palmitic or oleic acids and one molecule of stigmasterol at the sn-2 or sn-3 position were studied. After heating to 60 °C, the compounds with stigmasterol at the sn-2 position were more stable than those with stigmasterol at the sn-3 position. The lowest level of degradation of stigmasterol after heating to 180 °C was detected for both compounds with oleic acid, followed by the samples with palmitic acid.

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.

Lipase-mediated Baeyer-Villiger oxidation of benzylcyclopentanones in ester solvents and deep eutectic solvents.

This work presents the chemo-enzymatic Baeyer-Villiger oxidation of α-benzylcyclopentanones in ester solvents as well as deep eutectic solvents (DES). In the first part of the work the effect of selected reaction conditions on the reaction rate was determined. The oxidation process was most effective in ethyl acetate at 55 °C, with the use of lipase B from Candida antarctica immobilized on acrylic resin and UHP as oxidant.

Acylglycerols of Myristic Acid as New Candidates for Effective Stigmasterol Delivery-Design, Synthesis, and the Influence on Physicochemical Properties of Liposomes.

New carriers of phytosterols; acylglycerols containing natural myristic acid at -1 and -3 positions and stigmasterol residue linked to -2 position by carbonate and succinate linker have been designed and synthesized in three-step synthesis from dihydroxyacetone (DHA). The synthetic pathway involved Steglich esterification of DHA with myristic acid; reduction of carbonyl group of 1,3-dimyristoylpropanone and esterification of 1,3-dimyristoylglicerol with stigmasterol chloroformate or stigmasterol hemisuccinate. The structure of the obtained hybrids was established by the spectroscopic methods (NMR; IR; HRMS).

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.

Methoxy-Substituted γ-Oxa-ε-Lactones Derived from Flavanones-Comparison of Their Anti-Tumor Activity In Vitro.

Background: The study investigated four flavanone-derived γ-oxa-ε-lactones: a parent unsubstituted compound and its three derivatives with the methoxy group in positions 2', 4' and 8. Our objective was to find out if the introduction of the methoxy group into the aromatic ring affects in vitro anti-tumor potency of the investigated lactones.

Methods: Cytotoxic and pro-apoptotic effects were assessed with cytometric tests with propidium iodide, annexin V, and Western blot techniques.

Antiproliferative, Antimicrobial and Antiviral Activity of β-Aryl-δ-iodo-γ-lactones, Their Effect on Cellular Oxidative Stress Markers and Biological Membranes.

The aim of this work was the examination of biological activity of three selected racemic cis-β-aryl-δ-iodo-γ-lactones. Tested iodolactones differed in the structure of the aromatic fragment of molecule, bearing isopropyl (), methyl (), or no substituent () on the position of the benzene ring. A broad spectrum of biological activity as antimicrobial, antiviral, antitumor, cytotoxic, antioxidant, and hemolytic activity was examined.

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

The influence of buffer type, co-solvent type, and acyl chain length was investigated for the enantioselective hydrolysis of racemic 4-arylbut-3-en-2-yl esters using Lecitase Ultra (LU). Immobilized preparations of the Lecitase Ultra enzyme had significantly higher activity and enantioselectivity than the free enzyme, particularly for 4-phenylbut-3-en-2-yl butyrate as the substrate. Moreover, the kinetic resolution with the immobilized enzyme was achieved in a much shorter time (24-48 h).

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).

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.

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.

Enantiomeric trans β-aryl-δ-iodo-γ-lactones derived from 2,5-dimethylbenzaldehyde induce apoptosis in canine lymphoma cell lines by downregulation of anti-apoptotic Bcl-2 family members Bcl-xL and Bcl-2.

For many years, studies focused on developing new natural or synthetic compounds with antineoplastic activity have attracted the attention of researchers. An interesting group of such compounds seem to be those with both lactone moiety and an aromatic ring which, in addition to antimicrobial or antiviral activity, also exhibit antitumor properties. The study shows antitumor activity of two enantiomeric trans isomers of 5-(1-iodoethyl)-4-(2',5'-dimethylphenyl)dihydrofuran-2-one.

Lipase-Catalyzed Transesterification of Egg-Yolk Phophatidylcholine with Concentrate of n-3 Polyunsaturated Fatty Acids from Cod Liver Oil.

Phospholipids containing PUFAs are important vehicles for their delivering to the targeted tissues. In our research project we established enzymatic methods for the enrichment of natural egg-yolk PC with PUFAs. Instead of synthetic PUFA ethyl esters, the new strategy was developed using polyunsaturated fatty acids enriched fraction (PUFA-EF) from cod liver oil as the natural acyl donors.

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.

Isoprenoid-phospholipid conjugates as potential therapeutic agents: Synthesis, characterization and antiproliferative studies.

The aim of this research was to extend application field of isoprenoid compounds by their introduction into phospholipid structure as the transport vehicle. The series of novel isoprenoid phospholipids were synthesized in high yields (24-97%), their structures were fully characterized and its anticancer activity was investigated in vitro towards several cell lines of different origin. Most of synthesized compounds showed a significantly higher antiproliferative effect on tested cell lines than free terpene acids.

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).

Optically active stereoisomers of 5-(1-iodoethyl)-4-(4'-isopropylphenyl)dihydrofuran-2-one: The effect of the configuration of stereocenters on apoptosis induction in canine cancer cell lines.

Four stereoisomers of δ-iodo-γ-lactones with p-isopropylphenyl substituent at β-position: cis-(4R,5R,6S)-1, cis-(4S,5S,6R)-2, trans-(4R,5S,6R)-3, trans-(4S,5R,6S)-4 with proved antiproliferative activity were subjected to in vitro tests for a better understanding of their anticancer activity. The subject of our interest was a possible relationship between a configuration of chiral centers of the studied lactones and their anticancer potency against a panel of canine cell lines representing hematopoietic (CLBL-1, GL-1, CL-1, CLB70) and mammary gland cancers (P114, CMT-U27, CMT-U309). To determine the anticancer activity of the tested compounds, cell viability and cell metabolic activity were checked using propidium iodide staining and the MTT test.

Synthesis and Biological Evaluation of Novel Phosphatidylcholine Analogues Containing Monoterpene Acids as Potent Antiproliferative Agents.

The synthesis of novel phosphatidylcholines with geranic and citronellic acids in sn-1 and sn-2 positions is described. The structured phospholipids were obtained in high yields (59-87%) and evaluated in vitro for their cytotoxic activity against several cancer cell lines of different origin: MV4-11, A-549, MCF-7, LOVO, LOVO/DX, HepG2 and also towards non-cancer cell line BALB/3T3 (normal mice fibroblasts). The phosphatidylcholines modified with monoterpene acid showed a significantly higher antiproliferative activity than free monoterpene acids.