Synthesis Of11-aniline/cyclamine Substituted Cryptolepine Derivatives And Interaction Study As DNA Intercalators

DNA is a classical target for many anticancer agents in clinical use. In general, the bioactivities of these drugs are related to their interactions with the DNA molecule, which affect the replication, expression, transcription and other physiological functions. Therefore, exploration on the interaction of small molecule with DNA has important significance for design of high efficient and low-toxicity anti-cancer drug, drug screening and mechanism study.Cryptolepine is a naturally occurring indoloquinoline alkaloid isolated from antimalarial herb, which have been used in Western Africa for centuries. This compound and its derivatives possess interesting biological properties. Further mechanistic investigation at the molecular level demonstrated that cryptolepine could interact with DNA through intercalation and consequently interfere with the catalytic activity of topoisomerase Ⅱ. Amsacrin, a9-aniline substituted acridine derivative, is a synthetic DNA intercalator, which widely clinical used for acute leukemia and malignant lymphoma treatment. Cryptolepine and acridine share the motif of quinoline structure. Therefore, inspired form the modification strategy of amsacrin, a series of Cryptolepine serivatives were designed. First, based on the isostere theory and from the structure of alkaloid crytolepine,5-N-methylbenzofuro[3,2-b]quinoline scaffold was designed. Second, aniline subsituents were introduced on the11-position of5-N-methylbenzofuro[3,2-b]quinoline derivatives and11-aniline-substituted5-N-methylbenzofuro[3,2-b]quinoline derivatives4a-w were designed. Third, in order to change the spatial structure and steric size of substituents, alicyclic cyclamine were used to replace aromatic amine and developed11-cyclamine derivatives5a-k. The main works in the thesis are shown as follows:(1) A series of11-aniline substituted cryptolepine analogues4a-w were designed and synthesized;(2) A series of11-cyclamine substituted cryptolepine analogues5a-k were designed and synthesized;(3) The binding between11-aniline substituted cryptolepine analogues4a-w and CT DNA were studied by UV spectroscopic method;(4) The binding between11-cyclamine substituted cryptolepine analogues5a-k and CT DNA were studied by UV spectroscopic method;(5) The Surflex-dock studies on11-aniline substituted cryptolepine analogues as DNA intercalators;(6) The Surflex-dock studies on11-cyclamine substituted cryptolepine analogues as DNA intercalators.The results from UV and docking studies indicate that:①11-substituted Cryptolepine derivatives is likely to interact with DNA by the intercalative binding. Through π-π stacking and electrostatic interaction. And the interaction capability of the derivatives with DNA is higher than amsacrin.②The interaction capability of11-aniline substituted derivatives4a-w with DNA is stronger than11-cyclamine derivative5a-k.③The type and position of substituents are the important factors for influencing the interaction capability of these derivatives with DNA. The interaction capability of4a-w indicate that:4-aniline derivatives>2-aniline derivatives; electronic donating substituents> electronic withdrawing substituents; When aniline contains more than one substituent.2-substituted derivatives has weaker interaction.④For the piperazine derivatives, the branch chain with larger steric hindrance will make the interaction of compounds with DNA weaker.⑤The UV results and the docking results are basically consistent, and complementary each other.