Tomasz Janecki

Natural and synthetic α-methylenelactones and α-methylenelactams with anticancer potential.

α-Methylene-γ- and δ-lactones, as well as α-methylene-γ- and δ-lactams, are plant-derived compounds often used in traditional medicine for the treatment of inflammatory diseases. In recent years, the anticancer properties of these compounds and the molecular mechanisms of their action have been studied extensively. In the search for modern anticancer drugs, various synthetic analogs of α-methylene-γ- and δ-lactones and lactams have been synthesized and tested for their cytotoxic activity. In this review, we give a brief description of the occurrence and biological activity of such compounds isolated from plants and their diverse synthetic analogs.

Enzymatic degradation studies of endomorphin-2 and its analogs containing N-methylated amino acids

In this paper, we describe the synthesis of novel endomorphin-2 analogs, containing N-methylated amino acids, consecutively in each position. The receptor-binding profile of the new analogs and their stability against enzymatic cleavage by commercially available peptidases, carboxypeptidase Y and aminopeptidase M, and a rat brain homogenate are reported. The best analog of this series, [Sar2]endomorphin-2, was almost equipotent with the parent peptide in the mu-receptor-binding assay and was also highly resistant to enzymatic degradation. This analog may be a suitable candidate for the in vivo antinociceptive studies.

Synthesis and biological evaluation of α-methylidene-δ-lactones with 3,4-dihydrocoumarin skeleton

A series of new 3-methylidenechroman-2-ones bearing various aromatic moieties and various substituents at position 4 were synthesized in a three step reaction sequence. Friedel-Crafts alkylation of phenols or naphthols using ethyl 3-methoxy-2-diethoxyphosphorylacrylate in the presence of trifluoromethanesulphonic acid gave 3-diethoxyphosphorylchromen-2-ones. These compounds were employed as Michael acceptors in the reaction with Grignard reagents to give adducts which were finally used as Horner-Wadsworth-Emmons reagents for the olefination of formaldehyde. All obtained 3-methylidenechroman-2-ones were tested against two human leukemia cell lines NALM-6 and HL-60 as well as MCF-7 breast cancer and HT-29 colon cancer adenocarcinomas. Several obtained methylidenechromanones displayed high cytotoxic activity with IC(50) values below 1 μM, mainly against leukemia and MCF-7 cell lines. Investigation of structure-activity relationships revealed that the presence of additional, ortho-fused benzene ring and n-butyl or i-propyl group in position 4 enhances the activity. Selected methylidenechromanones were also tested on normal human umbilical vein endothelial cells (HUVEC) and chromanone 14o was found to be eightfold more toxic against MCF-7 than normal cells. Furthermore, antimicrobial assays revealed that chromanone 14n is highly active and bactericidal at concentration equal to MIC or 2MIC against nosocomial and community-associated staphylococci (MRSA) which are resistant to most or all available therapeutic classes of antimicrobial drugs.

A convenient synthesis and cytotoxic evaluation of β-aryl-α-methylidene-γ-lactones and β-aryl-α-methylidene-γ-lactams

3-Aryl-2-diethoxyphosphoryl-4-nitrohexanoates 8, obtained by Michael addition of ethyl diethoxyphosphorylacetate 6 to 1-aryl-2-nitro-1-butenes 7, were utilized as convenient common intermediates in the synthesis of β-aryl-γ-ethyl-α-methylidene-γ-lactones 17 and β-aryl-γ-ethyl-α-methylidene-γ-lactams 21. Transformation of the nitro functionality in 8 into a hydroxyl or amino group and cyclization yielded lactones 16 or lactams 19, which were used in Horner–Wadsworth–Emmons olefination of formaldehyde to give target compounds in good yields. Cytotoxicity of these compounds was evaluated in vitro against mouse leukemia cell line L-1210 and two human leukemia cell lines, HL-60 and NALM-6. Two of the obtained compounds 17b,c with 4-bromophenyl and 4-methylphenyl substituents in the β position proved to be very potent against all three cell lines with IC50 values lower than 6 μM.

Synthesis and cytotoxic evaluation of β-alkyl or β-aryl-δ-methyl-α-methylene-δ-lactones. Comparison with the corresponding γ-lactones

We present a simple and general strategy for the synthesis of beta,delta-disubstituted-alpha-methylene-delta-lactones starting from easily available tert-butyl 2-(diethoxyphosphoryl)alk-2-enoates. The elaborated synthetic protocol includes pyrrolidine-catalyzed Michael addition of acetone, diastereoselective reduction of the carbonyl group, lactonization and finally the Horner-Wadsworth-Emmons reaction with formaldehyde. All alpha-methylene-delta-lactones were evaluated in vitro against mouse leukemia cell line L-1210 and two human leukemia cell lines HL-60 and NALM-6. Comparison of cytotoxic activity with corresponding alpha-methylene-gamma-lactones is also discussed.

Comparison of Anti‐Invasive Activity of Parthenolide and 3‐Isopropyl‐2‐Methyl‐4‐Methyleneisoxazolidin‐5‐One (MZ‐6) – A New Compound with α‐Methylene‐γ‐Lactone Motif – on Two Breast Cancer Cell Lines

The biological activities of parthenolide, a sesquiterpene lactone isolated from feverfew, have been attributed to the presence of the α‐methylene‐γ‐lactone skeleton. The lactone skeleton can react via the Michael type addition with sulfhydryl groups of enzymes and other functional proteins, interfering with key biological processes in the cell. In the present study, we describe an efficient method of preparation of 3‐isopropyl‐2‐methyl‐4‐methyleneisoxazolidin‐5‐one (MZ‐6), a synthetic compound with α‐methylene‐γ‐lactone ring, as in parthenolide, additionally modified by introduction of a nitrogen atom. Furthermore, we investigated the cytotoxic activity and anti‐metastatic potential of MZ‐6 in comparison with parthenolide. Both compounds showed considerable cytotoxicity against breast cancer MCF‐7 and MDA‐MB‐231 adenocarcinoma cells in vitro and were then evaluated for their anti‐metastatic potential. The experimental results showed that MZ‐6 and parthenolide suppressed, to a similar degree, migration of MCF‐7, but not more aggressive MDA‐MB‐231 cells. In both cell lines, tested compounds down‐regulated mRNA and protein levels of metalloproteinase‐9 and urokinase plasminogen activator, the key proteases involved in the degradation of extracellular matrix and dissemination of cancer cells. The obtained results indicate that simple analogs of α‐methylene‐γ‐lactones can be good substitutes for more complex structures isolated from plants.

Structure-activity Relationship, Conformation and Pharmacology Studies of Morphiceptin Analogues - Selective μ-Opioid Receptor Ligands

Morphiceptin (Tyr-Pro-Phe-Pro-NH(2)) is one of the most selective agonists for the mu-opioid receptor. In this review structure-activity relationships of morphiceptin analogues and studies resulting in defining low energy conformations are discussed. Finally, new developments in the control of tumour growth and cell proliferation by morphiceptin analogues are surveyed, which open future perspectives in the diagnosis and treatment of various cancers.

Horner-Wadsworth-Emmons olefination of nonstabilized phosphonates. A new synthetic approach to β,γ-unsaturated amides

Abstract Aminolysis of readily accessible β-diethoxyphosphonyl-γ-butyrolactones 5 and 22 provides a convenient entry to (E)-β,γ-unsaturated amides 8 and 24 respectively. The key step of the aminolysis involves elimination of diethoxyphosporic acid from the corresponding β-hydroxyalkylphosphonates 7 and 23. Stereochemistry of the amides 8 and 24 results from their consecutive base catalyzed isomerization.

New glutathione peroxidase mimetics-Insights into antioxidant and cytotoxic activity

A series of N-alkyl benzisoselenazol-3(2H)-ones has been obtained and transformed to corresponding diselenides by the reduction with sodium borohydride. Additionally, efficient methodology for the oxidative Se-N bond formation by potassium iodate has been presented, new conversion of diselenide to benzisoselenazolone was observed. The GPx-like activity of all synthetized derivatives has been evaluated by NMR. N-Allyl diselenide was up to five times better antioxidant than ebselen. Anticancer capacity towards MCF7 and DU145 cancer cells has been also tested. The highest antiproliferative activity was obtained for N-cyclohexyl benzisoselenazolone.

Stereocontrolled synthesis of 5-(1′-hydroxyalkyl)-3-methylidenetetrahydro-2-furanones

Abstract Diastereo- and enantioselective synthesis of 5-(1′-hydroxyalkyl)-3-methylidenetetrahydro-2-furanones from 2-diethoxyphosphoryl-4-alkenoic acids or 2-diethoxyphosphoryl-4-alkenoates was readily accomplished using novel methodology involving syn - or anti -dihydroxylation procedures combined with Horner–Wadsworth–Emmons olefination techniques.