Synthesis And Structural Characterization Of A Novel DNA Intercalators

DNA is the carrier of genetic information and plays an especially important role in the course of genetic, which is the main target molecule that exists in anticancer and antiviral therapies. Investigation on the interactions of DNA with small molecules is important to not only understanding the mechanism of anticancer and antivirus but also designing of novel anticancer drugs. Intercalative binding is one of the most important modes of these interactions, which is the mechanism of many anticancer drugs.In this dissertation, methods of the synthesis of DNA bisintercalators having N,N-1,2- Di-(β-D-glucuronamide) ethane as the linker and three classes of methyl (aryl tri-O-acetyl-glucopyranosidic)-uronates are studied. Four novel DNA bisintercalators having N,N-1,2-Di-(β-D- glucuronamide) ethane as the linker and quinoline, acridine, purine and indole as the intercalative groups are designed and synthesized in order to study the effet of this novel linker on the mode of action and the binding capability.of DNA bisintercalator.In all, twelve new compounds including four targets are synthesized. They are confirmed by 1H NMR, 13C NMR and ESI-MS, and screening of their bioactivities is underway. The bisintercalators are synthesized in three steps.1. Synthesis of glucuronosyl donorsMethyl esterification and acetylation of glucurono-6,3-lactone makes the methyl tetraacetyl glucopyranuronate. Glucuronosyl bromide, glucuronosylazide and glucuronosylamine are obtained respectively by the following bromization, azide substitution and reduction under H2.2. Synthesis of methyl (aryl glucopyranosidic)-uronatesReactions of suitable glucuronosyl donors with 8-hydroxyl quinoline, 9-β-hydroxylethyl acridine, 6- chloropurine and 2-(indole-3-yl) acetic acid make four methyl (aryl tri-O-acetyl-glucopyranosidic)-uronates, whose acetate protecting groups are removed by NaOMe/MeOH in the following reaction.3. Synthesis of the bisintercalatorsThe unprotected methyl (aryl glucopyranosidic)-uronates are reacted refluxing with 0.5eq. ethylendiamine in methanol and eventually four bisintercalators are obtained.