Natural ��-carboline Derivatives Synthesis And Activity

Malignant tumor (cancer) is the pathological changes. It causes serious harm to the health of the human being. The inhibitors of topoisomerase Ⅱplay an important role in the treatment of cancer. Recently, many studies are focusing on intercalators as a potent inhibitors of topoisomerase Ⅱ. Intercalating agents share a common planar polyaromatic system. These agents bind to DNA base pairs by insertion. The chromophores are linked to basic chains that might also play an important role in the affinity and selectivity of their action. γ-carboline derivatives are recently subjects to many investigations. They represent a class of anticancer drugs that are related to the natural product ellipticine by deletion of an aromatic ring. β-carboline structures are present in many naturals products. These compounds effect on DNA topoisomerases, but they don.t stabilize the cleavable complex mediated by topoisomerase. This is might be due to the lack of the basic side chains in this class of compounds. For this reason, we designed and synthesized a series of β-carbolines compounds bearing a basic side chain . Our chemical work consisted in the following routes: 1-(3-dimethylaminopropyl)amino-γ-carboline was obtained by using pyridine as starting material via an eight-step sequence, such as oxidation, nitration, rearrangement and amino-substitution. According to the reported methods, two derivatives of 1-amino-β-carboline were synthesized, using acrylonitrile and diethyl malonate as starting materials through an eight-step sequence, such as condensation, Raney Ni catalyst, rearrangement and DDQ oxidation. Tryptamine was synthesized by using 1-bromo-3-chloropropane and diethyl malonate as starting materials, via Japp-Klingemann reaction and Fischer indole rearrangement. The obtained tryptamine was condensed with aldehydes (formaldehyde, acetaldehyde, furfural, 5-(hydroxymethyl) furfural) to give tetrahydro- β-carboline. Protecting amine to amide, DDQ oxidation, then treated with hydrazine gave four series of 1-substituted 4-amino-β-carboline. In total, 17 derivatives of 4-amino-β-carbolines, 9 derivatives of 4-amino-1-methyl-β-carbolines, 4 derivatives of 4-amino-1-furanyl-β-carbolines and 2 derivatives of 4-amino-1- (5-hydroxymethylfuranyl)-β-carbolines were synthesized. 9 复旦大学博士论文 A synthetic route of 4-amin...