The aim of my thesis is twofold: the first research line consists in the synthesis of quinolizidine derivatives endowed with antiparasitic and anticholinesterase activity; the second study concerns the design and synthesis of benzotriazole derivatives with antitumor activity. I focused my attention on quinolizidine alkaloids, particularly lupinine and cytisine, for the preparation of compounds endowed with potential therapeutic interest, and particularly antiparasitic against Leishmania tropica and Leishmania infantum, and anticholinesterase activity; the quinolizidine nucleus, indeed, is a chemical moiety that has been widely used to synthesize new molecules (as described in literature), due to its well known biological activities; quinolizidine alkaloids are also very suitable for the linkage to other chemical moiety, such as carbo- and heterocyclic systems. I synthesized new N-alkyl and N-alkylarylcytisine derivatives, new basic molecules and some corresponding quaternary ammonium salts. All these compounds showed a weak antiparasitic activity but a very good anticholinesterasic and antibutyrrilcholinesterasic activities. I also synthesized new lupinine, aminolupinane and thiolupinine derivatives of xanthene-9-carboxylic acid and new cytisine derivatives of 1,4-naphthoquinone and anthraquinone. In parallel with this research line, I also developed an interest towards benzotriazolic derivatives: the benzotriazole nucleus is largely explored due to its broad spectrum of biological activities including antiviral, antimicrobial and anticancer properties. In addition, in our laboratory we recently synthesized benzotriazole-3,4,5-trimethoxybenzoate esters endowed with interesting antiproliferative activity (IC50 submicromolar). On this basis I synthesized two small series of 1-substituted benzoylbenzotriazoles (eight compounds) and of benzoic esters of 1-(2,3-hydroxyalkyl) benzotriazoles (28 compounds). Moreover, I also focused on another alkaloid, colchicine, well known for its antimitotic activity and its antitumoral potential (not yet exploited because of its disadvantages in therapy such as a very high toxicity). I synthesized a series of eight novel colchicine derivatives characterized by substituted 1,2,3-benzotriazoles moieties. Since colchicine exerts its activity by binding to a site localized in β-tubulin and thus achieving a conformational change in the tubulin dimer, I carried out docking simulations on the synthesized compounds, in order to predict their linkage to the β-tubulin. In comparison with the x-ray structure of colchicine bound to tubulin, the new synthesized compounds showed a different orientation in the binding sites but the calculated Ki values appeared to be in the nanomolar or subnanomolar concentration range, and one of them in particular was endowed with a lower Ki value than colchicine.
|Titolo della tesi:||Synthesis of quinolizisine and benzoazole derivatives with potential pharmacological activity|
|Data di discussione:||15-mar-2018|
|Appare nelle tipologie:||Tesi di dottorato|