title: A Palladium-Catalyzed Carbonylation Approach to Eight-Membered Lactam Derivatives with Antitumor Activity.
abstract: The reactivity of 2-(2-alkynylphenoxy)anilines under PdI2 /KI-catalyzed oxidative carbonylation conditions has been studied. Although a different reaction pathway could have been operating, N-palladation followed by CO insertion was the favored pathway with all substrates tested, including those containing an internal or terminal triple bond. This led to the formation of a carbamoylpalladium species, the fate of which, as predicted by theoretical calculations, strongly depended on the nature of the substituent on the triple bond. In particular, 8-endo-dig cyclization preferentially occurred when the triple bond was terminal, leading to the formation of carbonylated ζ-lactam derivatives, the structures of which have been confirmed by XRD analysis. These novel medium-sized heterocyclic compounds showed antitumor activity against both estrogen receptor-positive (MCF-7) and triple negative (MDA-MB-231) breast cancer cell lines. In particular, ζ-lactam 3 j' may represent a novel and promising antitumor agent because biological tests clearly demonstrate that this compound significantly reduces cell viability and motility in both MCF-7 and MDA-MB-231 breast cancer cell lines, without affecting normal breast epithelial cell viability.
authors.affiliation: Laboratory of Industrial and Synthetic Organic Chemistry (LISOC), Department of Chemistry and Chemical Technologies, University of Calabria, Via Pietro Bucci, 12/C, 87036, Arcavacata di Rende (CS), Italy. raffaella.mancuso@unical.it.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Mancuso
authors.affiliation: Laboratory of Industrial and Synthetic Organic Chemistry (LISOC), Department of Chemistry and Chemical Technologies, University of Calabria, Via Pietro Bucci, 12/C, 87036, Arcavacata di Rende (CS), Italy.
authors.forename: Dnyaneshwar S
authors.initials: DS
authors.lastname: Raut
authors.affiliation: Department of Chemistry and Chemical Technologies, University of Calabria, Via Pietro Bucci, 14/C, 87036, Arcavacata di Rende (CS), Italy.
authors.forename: Nadia
authors.initials: N
authors.lastname: Marino
authors.affiliation: Institute on Membrane Technology, National Research Council, Via Pietro Bucci, 17/C, 87036, Arcavacata di Rende (CS), Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: De Luca
authors.affiliation: Health Center and Department of Pharmacy, and Health and Nutritional Science, University of Calabria, 87036, Arcavacata di Rende (CS), Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Giordano
authors.affiliation: Health Center and Department of Pharmacy, and Health and Nutritional Science, University of Calabria, 87036, Arcavacata di Rende (CS), Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Catalano
authors.affiliation: Health Center and Department of Pharmacy, and Health and Nutritional Science, University of Calabria, 87036, Arcavacata di Rende (CS), Italy.
authors.forename: Ines
authors.initials: I
authors.lastname: Barone
authors.affiliation: Health Center and Department of Pharmacy, and Health and Nutritional Science, University of Calabria, 87036, Arcavacata di Rende (CS), Italy.
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Andò
authors.affiliation: Laboratory of Industrial and Synthetic Organic Chemistry (LISOC), Department of Chemistry and Chemical Technologies, University of Calabria, Via Pietro Bucci, 12/C, 87036, Arcavacata di Rende (CS), Italy. bartolo.gabriele@unical.it.
authors.forename: Bartolo
authors.identifier: http://orcid.org/0000-0003-4582-1489
authors.initials: B
authors.lastname: Gabriele
mesh_terms: D000814:Aniline Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002384:Catalysis; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003500:Cyclization; D006801:Humans; D007769:Lactams; D010084:Oxidation-Reduction; D010165:Palladium / Q000737:chemistry*
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; D007769:Lactams; D010165:Palladium
keywords: antitumor agents; carbonylation; heterocycles; palladium; reaction mechanisms