Sintesi e caratterizzazione di inibitori delle topoisomerasi I e II

The present work deals with the synthesis of topoisomerase I and II inhibitors. The aim of our work was, in the first attempt, to synthetize a series of simplified derivatives of the campthotecin nucleus that were still able to interact with the topoisomerase I-CPT cleavable complex according to a molecular modelling study based on the crystallographic data. According to the citotoxicity of the natural compound alkannin/shikonin and of some derivatives bearing a nitrogroup in the side chain, we then decided to synthetize a series of compounds bearind a nitrophenilic or a naphtoquinonic ring subsituted in the 2 position with a nitroalcolic chain. We obtained the compounds 12-16 and some derivatives that show an peculiar citotoxicity in S.cerevisiae coltures that is still to be fully investigated. The compounds 33-46 were synthetised to investigate the ipothesis of conjugating the active mojeties of mitoxantrone and amsacrine. Their main structural features are: an anthracene-9,10-dione as base chromophore, two identical side chains in positions 1 and 4 of the anthraquinone nucleus as in mitoxantrone and the 4-methanesulphonamidoaniline substituent linked in position 6. Hence the new compounds mix structural features of both the parent compounds and should interact with DNA positioning the two chains within the major groove and the 4-methanesulphonamidoaniline substituent in the minor groove. The two chains in the 1,4 positions of the derivatives were selected according to literature data. The compounds 33-46 were tested for their biochemical behaviour. The compounds 35 and 36 show intercalating properties, capacity of inhibition toward the enzyme topoisomerase II and cytotoxic properties similar to the parent compounds, but more about their biological behaviour is to be investigated. The preliminary data show that there is a strict spatial relationship with the activity of the derivatives.

Il presente lavoro tratta la sintesi di inibitori delle topoisomerasi I e II. La prima parte del progetto tratta la sintesi di anelli triciclici semplificati rispetto alla molecola della camptotecina derivanti da uno studio di molecular modelling sui dati cristallografici disponibili in letteratura. La seconda parte del progetto nasce dalla sorprendente attività biologica rilevata per alcuni derivati sintetici, analoghi della alkannina/shikonina, contenenti una funzione nitroalcolica nella catena laterale. la terza parte, infine, riguarda a sintesi di molecole contenenti i farmacofori di mitoxantrone e amsacrina. I derivati si mostrano con un anello antrachinonico coniugato alla funzione metansolfonilanilica dell'amsacrina e con catene laterali alle posizioni 1 e 4. Tali catene, scelte a aprtire da dati di letteratura, sono caratterizzate da lunghezza, numero e tipo di sostituenti diversi.