Versatile synthesis of functionalised dibenzothiophenes via Suzuki coupling and microwave-assisted ring closure

• Published in: Organic & biomolecular chemistry Vol. 9; no. 17; pp. 6066 - 6074
• Main Authors: Rodriguez-Aristegui, Sonsoles, Clapham, Kate M., Barrett, Lauren, Cano, Celine, Desage-El Murr, Marine, Griffin, Roger J., Hardcastle, Ian R., Payne, Sara L., Rennison, Tommy, Richardson, Caroline, Golding, Bernard T.
• Format: Journal Article
• Language: English
• Published: CAMBRIDGE Royal Soc Chemistry 07.09.2011
• Subjects: Chemistry; Chemistry, Organic; Cyclization; DNA-Activated Protein Kinase - antagonists & inhibitors; DNA-Activated Protein Kinase - metabolism; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Humans; Microwaves; Physical Sciences; Science & Technology; Thiophenes - chemical synthesis; Thiophenes - chemistry; Thiophenes - pharmacology; DIBENZOFURANS; DEPENDENT PROTEIN-KINASE; POTENT; CARBAZOLES; INHIBITOR
• ISSN: 1477-0520; 1477-0539
• DOI: 10.1039/c1ob05282a

Amino-substituted biphenyls were obtained by Suzuki cross-coupling of 2,6-dibromoaniline with a phenylboronic acid (substituted with Me, NO2, OH, OMe or Cl) preferably assisted by microwave irradiation. Conversion of the amino group into a thiol preceded a base-induced intramolecular substitution, also facilitated by microwave heating, to generate the second C-S bond of the target dibenzothiophene. The 1-, 2-, 3- or 4-substituted 6-halodibenzothiophenes obtained were subjected to a palladium-mediated coupling with 2-morpholin-4-yl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4H-chromen-4-one to give the respective 6-, 7-, 8- or 9-substituted dibenzothiophen-4-ylchromenones. These compounds were evaluated as inhibitors of DNA-dependent protein kinase (DNA-PK) and compared to the parent 8-(dibenzo[b,d]thiophen-4-yl)-2-morpholin-4-yl-4H-chromen-4-one. Notably, derivatives bearing hydroxy or methoxy substituents at C-8 or C-9 retained activity, whereas substitution at C-7 lowered activity. Substitution with chloro at C-6 was not detrimental to activity, but a chloro group at C-7 or C-8 reduced potency. The data indicate permissive elaboration of hydroxyl at C-8 or C-9, enabling the possibility of improved pharmaceutical properties, whilst retaining potency against DNA-PK.