Anticancer potential of novel α,β-unsaturated γ-lactam derivatives targeting the PI3K/AKT signaling pathway.
Abstract Six recently synthesized alkyl (Z)-2-(2-oxopyrrolidin-3-ylidene)acetates were evaluated for their potential as cytotoxic and anticancer agents. All compounds were tested in the ERα positive MCF-7, triple negative MDA-MB-231, and Her2+ SKBR-3 breast cancer cell lines. The most lipophilic derivatives, bearing the 4-isopropylphenyl (2) or 4-tert-butylphenyl (3) group at the γ-lactam nitrogen, proved to be cytotoxic against all the cancer cell lines tested (IC50 values ranging from 18 to 63 μM), exerting their greatest activity in SKBR-3 cells, with IC50 values of 33 and 18 μM, respectively. Biological studies showed that the cytotoxic effects of 2 and 3 are accompanied by apoptotic de…
Heterogenizing palladium tetraiodide catalyst for carbonylation reactions
We report the first example of successful heterogenization of the classical PdI42- carbonylation catalyst, achieved in two simple steps from ionic liquid-functionalized multi-walled carbon nanotubes (MWCNTs). The newly developed materials (PdI4@MWCNT-imi-X, X = Br, I) present the PdI42- anion supported on an imidazolium network (imi) grown on MWCNTs and have been fully characterized. The activity of PdI4@MWCNT-imi-X has been successfully tested in a paradigmatic carbonylation reaction, the oxidative monoaminocarbonylation of 1-alkynes with amines to give high value added 2-ynamides (obtained in good yields, 50–84%, starting from various substrates). The heterogeneous catalyst could be easil…
Iodolactonization of 3-Alkynylthiophene-2-Carboxylic and 3-Alkynylpicolinic Acids for the Synthesis of Fused Heterocycles
The iodolactonization of 3-alkynylthiophene-2-carboxylic acids and 3-alkynylpicolinic acids has been investigated. Using I2 as the iodine source and NaHCO3 as the base in MeCN, the process took place smoothly to afford thienopyranones and pyranopyridinones, respectively, from 6-endo-dig cyclization. The method also worked nicely for the transformation of 2-(phenylethynyl)thiophene-3-carboxylic acid and 3-(phenylethynyl) isonicotinic acid into 7-iodo-6-phenyl-4H-thieno[3,2-c]- pyran-4-one and 4-iodo-3-phenyl-1H-pyrano[4,3-c]pyridin-1- one, respectively. Although with some 3-alkynylpicolinic acids the process led to a mixture of the 6-endo-dig and 5-exo-dig products, it could be still made se…
Catalytic Carbonylative Double Cyclization of 2-(3-Hydroxy-1-yn-1-yl)phenols in Ionic Liquids Leading to Furobenzofuranone Derivatives
A catalytic carbonylative double cyclization method for the synthesis of furo[3,4-b]benzofuran-1(3H)-ones is reported. It is based on the reaction between readily available 2-(3-hydroxy-1-yn-1-yl)phenols, CO, and oxygen carried out in the presence of catalytic amounts of PdI2 (1 mol %) in conjunction with KI (20 mol %) and 2 equiv of diisopropylethylamine at 80 degrees C for 24 h under 30 atm of a 1:4 mixture of CO-air. Interestingly, the process was not selective when carried out in classical organic non-nucleophilic solvents (such as MeCN or DME), leading to a mixture of the benzofurofuranone derivative and the benzofuran ensuing from simple cycloisomerization, whereas it turned out chemo…
Dimethyl 2,2′-[Carbonylbis(azanediyl)](2S,2′S)-bis[3-(4-hydroxyphenyl)propanoate]
The thus‐far unknown ureic derivative dimethyl 2,2′‐[carbonylbis(azanediyl)](2S,2′S)‐ bis[3‐(4‐hydroxyphenyl)propanoate] has been efficiently synthesized by enantiospecific oxidative carbonylation of readily available L‐tyrosine methyl ester, using a very simple catalytic system (PdI2 in conjunction with KI) under relatively mild conditions (100 °C for 5 h in DME as the solvent and under 20 atm of a 4:1 mixture CO‐air).
Multicomponent Synthesis of Benzothiophen-2-acetic Esters by a Palladium Iodide Catalyzed S-cyclization – Alkoxycarbonylation Sequence
A catalytic carbonylative approach to the multicomponent synthesis of benzothiophene derivatives from simple building blocks [1-(2-(methylthio)phenyl)prop-2-yn-1-ols, carbon monoxide, and an alcohol)] is presented. It is based on an S-cyclization-demethylation-alkoxycarbonylation-reduction sequence promoted by the PdI2/KI catalytic system, occurring under relatively mild conditions (40 atm, 80 °C, 15 h). Benzothiophene-2-acetic esters are obtained in moderate to good yields (35–70%) starting from variously substituted substrates in combination with different alcohols as external nucleophiles (17 examples). (Figure presented.).
Iodocyclization of 2-Methylthiophenylacetylenes to 3-Iodobenzothiophenes and their coupling Reactions under More Sustainable Conditions
We report the first example of iodocyclization of readily available 2-methylthiophenylacetylenes in a deep eutectic solvent (ChCl/urea 1/2, mol/mol) as recyclable and more sustainable solvent with respect to the classical VOCs employed so far. The process successfully afforded a variety of 3-iodobenzothiophenes in good to high yields starting from differently substituted substrates, with the possibility to recycle the DES several times without appreciable lowering of the product yield. The 3-iodothiophenes thus synthesized are known to be important precursors of biologically active molecules and functionalized heterocycles, and were successfully employed for performing representative Sonoga…
Synthesis, computational evaluation and pharmacological assessment of acetylsalicylic esters as anti-inflammatory agents
A convenient approach to the synthesis of alkyl esters of aspirin (ASA-OR) has been developed. The synthesis of ASA-OR has been realized in two steps: (1) direct esterification of salicylic acid with alcohols in the presence of dicyclohexylcarbodiimide to give alkyl salicylates (SAL-OR); (2) acetylation of SAL-OR with acetyl chloride to yield ASA-OR. Molecular mechanics simulations, performed to calculate the kinetic radii of several ASA-OR, indicated that the pentyl and hexyl acetylsalicylates possess the best properties to cross cell membranes. The in vitro biological tests demonstrate their anti-inflammatory activity, superimposable to that of aspirin. The results of our study suggest th…