Ricerc@Sapienza

Recently, Poly-ADP-Ribose Polymerase (PARP) inhibitors are one of the most intensively studied group of antiblastic agents for the management of recurrent ovarian cancer. Among this family, Olaparib was the first to be approved by European Medicines Agency as maintenance therapy post-response to platinum-based chemotherapy for recurrent ovarian cancer in women with deleterious BRCA1/2 mutation. Following that, the Food and Drug Administration (FDA) approved Olaparib monotherapy as fourth or later line of treatment in advanced ovarian cancer with deleterious germ-line BRCA1/2 mutation.

An efficient strategy for the synthesis of 6-unsubstituted indolo[1,2-c]quinazolines is described. The Pd-catalyzed reaction of o-(o-aminophenylethynyl) trifluoroacetanilides with Ar-B(OH)2 afforded 2-(o-aminophenyl)-3-arylindoles, that were converted to 12-arylindolo[1,2-c]quinazolines by adding dimethylformamide dimethyl acetal (DMFDMA) to the reaction mixture after extractive work-up.

A straightforward one-pot approach to the synthesis of challenging 12-arylindolo[1,2-c]quinazolin-6(5H)-ones is described. Starting from readily available o-(o-aminophenylethynyl)trifluoroacetanilides, palladium-catalyzed aminoarylation of the triple bond with ArI, ArBr, and ArN2 +BF4 – is followed by cyclization of the resulting N-trifluoro­acetyl-2-(o-aminophenyl)-3-aryl indole. This sequential reaction provides the title compounds by means of a rare elimination of trifluoromethane.

A straightforward approach to the synthesis of challenging 12-arylindolo[1,2-c]quinazolin-6(5H)-ones through the palladium-catalyzed direct arylation of N-benzyl and NH-free[1,2-c]quinazolin-6(5H)-ones with aryl bromides and chlorides is described.