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Alternative synthetic approaches to biologically active indeno[1,2-c]isoquinoline-5,11-diones
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1  Université Lille Nord de France – USTLille 1, LCOP, EA CMF 4478 - Bâtiment C3(2), F-59655 Villeneuve d'Ascq, France
2  Université Lille Nord de France – USTLille 1, LCOP, UMR 8181 'UCCS' - Bâtiment C3(2), F-59655 Villeneuve d'Ascq, France

Abstract: Indenoisoquinolinediones, as exemplified by lead compounds indotecan and indimitecan, are a class of non-camptothecin topoisomerase I poisons that display marked cytotoxic properties and for some of them antitumor activities in xenograft models. We have developed two alternative and dramatically different synthetic approaches to a variety of highly fused and diversely substituted models that differ from the elaboration of key precursors, i.e. arylated 2,3-dihydroisoquinolones. The first one is based upon a Suzuki-Miyaura cross-coupling reaction involving enol phosphates combined with a ring-closing metathesis (RCM) reaction to ensure the creation of the six-membered lactam unit. The second approach hinges upon the photoinduced electrocyclization of the 6π electron aromatic enamides. The presence of phenolic methoxy groups precluded an additional mandatory and problematic oxidation step to generate the unsaturated lactam ring. Intramolecular carbocationic annulation reaction and ultimate oxidation of the latent hydroxyl functionality completed the synthesis of the targeted title compounds.
Keywords: Indenoisoquinolinediones, enol phosphate, Suzuki-Miyaura coupling, ring-closing metathesis, photocyclization
Comments on this paper
Mark Penick
Ring C
Ring C is formally antiaromatic, which is a very unusual feature
to find in a drug.  Is attack on ring C a critical part of the 
anticancer activity?