Design, Synthesis And Bioactivities Of New Polysubstituted Butneolides Derivatives

Butenolides are an important class of natural products or synthetic bioactive molecules, of whichγ-alkylidene butenolides widely present in natural products, also can be used as synthetic intermediates of natural products. For the significant physiological activity of such compounds, they have great prospects for the development and application in medicine and pesticide and so on. And in organic synthesis has a strong application value. The total synthesis of these compounds and their analogues long since have attracted researcher's attention.In this thesis, on the basis ofβandα,βsubstituted butenolides, we designed and synthesized series of newγ-butenolide:rupatadine derivatives, rofecoxib derivatives, losigamone and its analogues and other smallγ-butenolide moleculers. Their corresponding activities were evaluated. The corresponding work was described as follows:First, with antihistamines rupatadine as the lead compounds, replacement of the 5-methyl-3-pyridine of rupatadine byα,β-unsaturated-γ-alkylidenebutenolide, a series of derivatives were stereoselectively synthesized. The first time, tricyclic antihistamines and butenolides were combined by five-numbered lactone ring, which expanded the structural types of antihistamines. Twenty rupatadine analogues were synthesized, eighteen were new compounds. All compounds obtained were characterized by NMR, IR and HR MS spectras. Some of their anti-histamine activities were also evaluated. For the evaluation of H1 antihistamine activity, the in vitro histamine-induced contraction of the guinea-pig ileum assay (HC) was used. A preliminary structure-activity relationship was analysized. Their H1 antihistamine activities have shown a high dependence on the exact nature of the substituent in the lactone ring. Optimum structures 7,8a and 8g display potent activity inhibiting histamine-induced effects, which were better than the positive control loratadine.Second, rofecoxib (vioxx) is selective COX-2 (cyclooxygenase-2) inhibitors. However, the research finding of significant elevation of adverse cardiovascular events in people already at risk has triggered the withdrawal from use of one of the most widely used COX-2 inhibitors. Studies have shown that the facile oxidation of the conjugate base of rofecoxib is a possible contributor to chronic human toxicity. In order to avoid or reduce this side effect, fourty eight rofecoxib derivatives were stereoselectively synthesised, all of them were new compounds. All compounds obtained were characterized by NMR, IR and HR MS spectras. Some of their COX-2 inhibitory activities and cytotoxic activities were evaluated. The selective COX-2 inhibitory activity of candidate compoundsⅡ-3 was better than the control drug rofecoxib. The cytotoxic activity on prostate cancer cells showed that the IC50 values of compoundsⅡ-3,Ⅱ-6,Ⅱ-7,Ⅱ-11,Ⅱ-12,Ⅲ-3,Ⅲ-11 andⅢ-16 all less than 50μM. The IC50 value of optimum structuresⅡ-7 was about 12.5μM, but the positive control rofecoxib has no antiproliferative effect. It showed that rofecoxib and its analogues onγ-alkylidene butenolides derivatives is a very effective modification.Third, four series of newγ-alkylidene butenolide andγ-hydroxyalkyl butenolide were prepared. Their bioactivities such as antibacterial activity and cytotoxic activity were evaluated. Preliminary evaluation results showed that some of the compounds showed moderate to good antibacterial activity and cytotoxic activity, among them compound 1d exhibited good antibacterial activity against staphylococcus aureus with the MIC value was 40μg/mL.Compound 9'd showed good cytotoxic activity against Ec9706 cell, the IC50 value was 39.39μg/mL, which was comparative to the positive drug fluorouracil(IC50=37.74μg/mL).Finally, with losigamone as the lead compounds, a series of losigamone analogues were synthesized. Twelve losigamone analogues were synthesized, six were new compounds. The de value of crystalline losigamone was about 96%. The diastereoselective synthesis conditions were explored, the de value was about 50%, less than the original process'diastereoselectivity.In summary, more than 116 of novelγ-alkylidene butenolides derivatives were obtained.105 of them were new compounds. Some of their bioactivities and structure-bioactivity relationship were investigated. As candidates, a few compounds were valuable to further investigate for new drug development.