Design, Synthesis And Antitumor Activity Study Of Carboline Derivatives

Cancer remains a significant health concem,and has gradually been the first killer in the world instead of cardiovascular diseases.The most clinically effective anticancer agents are associated with problems of low efficacy against solid tumors,high toxicity, and development of multidrug resistance.Therefore,it remains a hotspot for medicinal chemist to develop novel antieancer agents with high efficacy and low toxicity.Antimitotic agent is one of the most successful classes of anticancer drugs,and microtubule is recognized as an important target for the development of potential antimitotic agents.Recent years,the colchicine binding site inhibitors(CSIs)have attracted a great deal of attention because of their simple structures and potent activities. Based on the common structural features of CSIs reported in the literature,and the finding that indole moiety presented in many CSIs,we utilized rational drug design principle,introduced carboline,an planar antitumor moiey,and an aromatic ring as two hydrophobic planes.Sulfonamide,carbonyl,or amide group which presented in many potent tubulin polymerization inhibitors were used as the linker.Thus,we constructed the basic structure of CSIs,and synthesized three series of novel carboline derivatives. The total 112 compounds were tested for their cytotoxic activities in vitro against several human tumor cell lines.Primary SAR study indicated that the efficacy of three carboline moieties on antitumor activity was:γ-carboline＞β-carboline＞α-carboline. Utilizing of sulfonamide or carbonyl group as the linker was more beneficial for the activities.In order to gain insight on the mechanisms of action of these compounds,we chose the potent cytotoxic and representative compounds for further assay.Tubulin polymerization inhibition assay showed that all the 14 tested compounds exhibited potential inhibitory effect against microtubule.DNA intercalation assay indicated that most of theγ-carboline derivatives(1-34,1-37,1-74,1-87,1-109)could not interact with DNA except for compounds 1-35.Besides,benzo[1,2-i]γ-carboline derivatives (1-115)and 3-basic group substituted-β-carboline derivatives(1-161)could also intercalate into DNA and reduce the fluorescence of EB-DNA complex.We also tested the effects ofγ-carbolines 1-34,1-74,1-87,1-109 on cell cycle of A549 cell line.It clearly demonstrated that all these compounds arrested the cell cycle on G₂/M phase. Based on the extensive biological activities of 1,2,3,4-tetrahydrocarbazole-1-ones, especially their antitumor activity,we utilized the molecular heterozygosity principle and synthesized a series of 2-substituted aminomethyl-9-alkyl-1,2,3,4-tetrahydrocarbazole -1-ones through mannich reaction.The total 17 1,2,3,4-tetrahydrocarbazole -1-one mannich bases were test for their cytotoxic activities in vitro against several human tumor cell lines.The results implied diethylaminomethyl or 4-methylpiperidin methyl moiety was the most suitable mannich base in this series of compounds,and the presence of isoprenyl group at N⁹ was beneficial for the activities. Primary mechanism research of compound 2-3 indicated it exhibited a potential inhibitory effect against microtubule.In the last part of my dissertation,we described the application of microwave irradiation in organic synthesis.We found a practical and simple microwave enhanced Bischler reaction for the synthesis of 2-phenyl-indoles or 1,2,3,4-tetrahydrocarbazoles, and a microwave enhanced Fischer reaction for the synthesis ofγ-carbolines.These new approaches provided simple,fast,and efficacy methods for the construction of these important pharmaceutical active structures,and extended the microwave irradiation utility in heterocyclic chemistry.