3 - (3'-methoxy-4'-hydroxyphenyl) -4 - Hydroxyphenyl - Has -3 - Its Derivatives Synthesis And Biological Activity Study

Angiogenesis inhibitor can interdict the supply of oxygen and nutrition for tumor growth and transfer by inhibiting abnormal angiogenesis, which resulted in curing tumors. 2-Methoxyestradiol (2-ME), a novel angiogenesis inhibitor in its Phrase I-III clinical trials, is proved to be potent to various solid tumors, such as breast cancer, prostate cancer, multiple myeloma.Considering the special structure of 2-Methoxyestradiol, we designed and synthesized a non-steroid analog with similar structure to 2-ME --3-(p-Methoxyl-m-hydroxyphenyl) -m- hydroxyphenyl- 3- butylethylene (2), which was found as the metabolite of diethylstilbestrol by Gottschilch R. It was separated from Syria Golden Hamster given diethylstilbestrol and no related reports on synthesis or bio-activity to this compound.In the process of synthesizing 2, there occurred some unexpected chemical problems which were explored deeply to conclude relevant reasons and mechanism. For instance, the elimination of alcohols with 1, 2-diphenylethanol scaffold catalyzed by various acids afforded the unexpected alkenes respectively, which were not the products following Sayzteff s Rule. It was assumed that the steric effect of P-C in this structure was the very reason which caused such abnormal dehydration. Meanwhile, the chemoselectivity was observed during the demethylation of the two methoxyl groups, whose reactivities differed under various conditions, attached to the substituted benzene cycles. On the basis of the intermediate (29), 3-(p-Methoxyl-m-hydroxyphenyl) -m- hydroxyphenyl-butylethylane, several dehydrogenating conditions were tried and only to get an unexpected cyclized product (30). As for the special eliminating compound (28), halogen was attached to the double bond so as to carry out one more elimination, which resulted in our target structure (2) in the form of cistrans isomers.During the synthesis of 2, we also tried to synthesize a series of diphenylethene derivates (3) so as to find out the influence of different groups on position-11 to their bioactivities.The angiogenesis inhibitory activities of target compound and some intermediates were evaluated on human umbilical vein endothelial cells (HUVEC) and vascular endothelial growth factor (VEGF). The assay data indicated that parts of those tested samples with diphenylethene structures were potent to inhibit the testing modules, which proved that different groups substituted on the benzene cycle could significantly affect their inhibitory activities to HUVEC.In the thesis, we realized the synthesis of target compound and obtained 36 new compounds, some of which were tested on their antiangiogenesis activity. Such information provided clues and experiences for the further research in this field and the exploration on new types of neovascularization inhibitory agents in the future.