Synthesis of novel 8-(het)aryl-6H-pyrano[4′,3′:4,5]thieno[3,2-b]pyridines by 6-endo-dig cyclization of Sonogashira products and halolactonizations with Cu salts/NXS. Preliminary antitumor evaluation

• Published in: Tetrahedron Vol. 75; no. 10; pp. 1387 - 1397
• Main Authors: Rodrigues, Juliana M., Buisson, Pierre, Pereira, Joana M., Pinheiro, Inês M., Fernández-Marcelo, Tamara, Vasconcelos, M. Helena, Berteina-Raboin, Sabine, Queiroz, Maria-João R.P.
• Format: Journal Article
• Language: English
• Published: Elsevier Ltd 08-03-2019
• Subjects: 6-endo-dig lactonization; Antitumor compounds; Fused 2-pyranones; Sonogashira coupling; Thieno[3,2-b]pyridines; Sonogashira coupling; Fused 2-pyranones; Thieno[3,2-b]pyridines; 6-endo-dig lactonization; Antitumor compounds
• ISSN: 0040-4020; 1464-5416
• DOI: 10.1016/j.tet.2019.01.054

Novel 8-(het)aryl-6H-pyrano[4′,3′:4,5]thieno[3,2-b]pyridines were prepared in good to high yields by a tandem one-pot procedure of Sonogashira coupling and 6-endo-dig lactonization from 3-bromothieno[3,2-b]pyridine-2-carboxylic acid and (het)arylalkynes. Sonogashira coupling products were also prepared from the corresponding methyl ester giving in the same reaction the corresponding 6-endo-dig compounds as minor products. The Sonogashira phenyl ester product gave cyclization with electrophiles only in low to moderate yields. Nevertheless, halolactonizations using Cu(I) or (II) salts/N-halosuccinimides (NXS) from either the phenyl ester or the carboxylic acid derivatives occurred in good to high yields. The growth inhibition potential of the compounds was evaluated using human tumor cell lines, HCT-15 (colorectal adenocarcinoma) and NCI-H460 (non-small cell lung cancer) and studies of apoptosis induction were performed for the three most promising compounds in HCT-15 cells. Two of them caused almost 40% of cell death by apoptosis when tested at their 1.5 × GI50 concentrations. The tricyclic lactone with a F atom in the meta position showed to be the most promising one.
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