title: Versatile synthesis of functionalised dibenzothiophenes via Suzuki coupling and microwave-assisted ring closure.
abstract: Amino-substituted biphenyls were obtained by Suzuki cross-coupling of 2,6-dibromoaniline with a phenylboronic acid (substituted with Me, NO(2), 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.
authors: Newcastle Cancer Centre, Northern Institute for Cancer Research, School of Chemistry, Bedson Building, Newcastle University, Newcastle upon Tyne, United Kingdom NE1 7RU.
authors: Sonsoles
authors: S
authors: Rodriguez-Aristegui
authors: Kate M
authors: KM
authors: Clapham
authors: Lauren
authors: L
authors: Barrett
authors: Céline
authors: C
authors: Cano
authors: Marine
authors: M
authors: Desage-El Murr
authors: Roger J
authors: RJ
authors: Griffin
authors: Ian R
authors: IR
authors: Hardcastle
authors: Sara L
authors: SL
authors: Payne
authors: Tommy
authors: T
authors: Rennison
authors: Caroline
authors: C
authors: Richardson
authors: Bernard T
authors: BT
authors: Golding
mesh_terms: D003500:Cyclization; D051747:DNA-Activated Protein Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008872:Microwaves; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D013876:Thiophenes; D051747:DNA-Activated Protein Kinase; C016366:dibenzothiophene