Structural Modification Of Rotenone, Synthesis Of Analogues And Research On Biological Activity

Rotenone is a broad-spectrum insecticide and its derivatives show several biological activities including acaricide and antitumor. Based on the structure-activity relationship of rotenone derivatives and the research of antidepressant drugs and anticancer drugs, we designed and synthesized a series of novel rotenone derivatives, and evaluated their bioactivities in vitro. The main results of this thesis are described as followings:1. Twelve novel cyclopropane rotenone derivatives were designed and synthesized from rotenone by open-loop rearrangement with the dimethyloxo-sulphonium methylide in alkaline conditions, etherification and esterification to modify the structure of active sites. Five cycloprop rotenone oxime-ether derivatives were designed and synthesized by the principle of Substructure Link Way, introducing the oxime-ethers group with excellent bioacitivity into the compound3a. The novel compound7was obtained by Beckmann rearrangement reaction with chloride-catalyzed.The structures of new compounds were characterized by1H NMR and MS. For the key intermediates, we analysis the crystal structures of compound2and7by X-ray diffraction, which were consistent with the target compound. Owing to the attack of rotenone by dimethyloxosulphonium methylide from two directions, there are two conformations of cyclopropane structure in the molecule. X-ray diffraction shows that a pair of diastereoisomers exists in the crystal lattice of cycloprop rotenone.The bioassay indicated that some compounds show moderate insecticidal activity.2. Twelve pyrazole rotenone derivatives were designed and synthesized from rotenone via the open-loop rearrangement react with hydrazine hydrate to introduce an alkaline center of pyrazole ring as a dual inhibitors, the etherification of amine group and esterification of phenolic hydroxyl group. Twenty-eight N-acylpyrazole rotenone derivatives were designed and synthesized from the compound10d and10e by the nucleophilic substitution reaction to introduce different side chains of hetero atoms.The structures of newly compounds were confirmed by1H NMR,13C NMR and MS. We obtained the crystal structure of compound11a, which was consistent with the target compound by X-ray diffraction analysis. For the amino group of the hydrazine hydrate offensing rotenone molecule from two directions, there were two conformations of pyrazole structure present in the molecule. X-ray diffraction found that a pair of diastereoisomers existed in one crystal lattice of pyrazole rotenone.Through the high-throughput screening means of fluorescent substance ASP, the compounds were evaluated for their activity as5-HT inhibitor in vitro. Most of the compound exhibited potent inhibitory activity against5-HT.3. In order to establish a certain configuration between benzopyran and benzofuran, three series of twenty-eight compounds were designed and synthesized from the substituted phenol by nucleophilic substitution, cyclization, bromation, ketalization, rearrangement and hydrolysis reaction, then altered2-isopropenyl benzofuran group of rotenone with benzofuranol, which has preferred biological activity to commercialize, and finally altered dihydropyran group with amide group.The structures of novel compounds were determined by1H NMR and MS. The antitumor assay indicated that this series of compounds have a certain degree of antitumor activity against Hela cell line.