First Total Synthesis And Structure Activity Relationship Of A New Flavonoid Natural Product

In recent years,hydroxyisopentenyl flavonoids have been reported in a number of studies.Most of these compounds have diverse biological activities.In 2016,Sanjuanolide was isolated from Dalea frutescens by Shaffer et al..Its novel structural characteristics and good anticancer activity attracted our attention.Sanjuanolide is a kind of typical hydroxyisopentenyl flavonoids,which has specialα,β-unsaturated structural unit,has relatively simple molecular structure and novel hydroxyisopentene functional group.In this work,a series of flavonoids with hydroxy isopentenyl structure were designed and synthesized on the basis of the synthesis of natural products,and their antitumor and antibacterial activities were studied.The specific work is as follows:（1）Based on the principle of combinatorial chemistry,a feasible synthetic route for natural products and analogues was designed through reasonable inverse synthetic analysis.（1）Based on the first synthetic of Sanjuanolide,eight analogues were synthesized by introducing electron withdrawing and electron donating groups on the modifiable sites of two aromatic rings to explore the effect of the change of electron cloud density on the activity of natural products.（2）Four 5’-hydroxy isopentenyl flavones,represented by Bartercin A,were synthesized.（3）On the premise of further study of structure-activity relationship,we designed the heterocyclic flavonoid analogues:retaining the 3’-hydroxyisopentenyl part,benzene ring（B ring）was replaced by heterocyclic aromatic hydrocarbons（pyridine,thiofuran,furan,pyrrole,etc.）or phenolic analogues（disubstituted）,a total of nineteen heterocyclic flavonoid analogues were designed,and ten of them were finished.The key intermediates and target products were characterized by¹H NMR,¹³C NMR,IR and HRMS.（2）The inhibitory activities of Sanjuanolide and its analogues on five cell lines,including PANC-1,A549,A375,PC-3 and MDA-MB-231,were studied by MTT assay.The results showed that the IC₅₀of Sanjuanolide on A375 and PC-3 were 13.1μM and17.5μM,the antitumor activity of 3d on A375 and PC-3 was better than that of natural product Sanjuanolide,with IC₅₀of 4.3μM and 5.1μM.（3）The antibacterial activities of four 5’-natural products and ten heterocyclic analogues against E.coli、P.eruginosa、S.aureus and B.subtilis were studied by dilution method.The results showed that the MIC of natural product Xanthohumol D against B.subtilis was 12.5μg/m L,and the MIC of analogue 8j and 9p against B.subtilis was 6.25μg/m L.In this work,we used combinatorial chemistry strategy,Claisen Schmidt condensation under alkaline conditions as the key reaction to construct chalcone skeleton structure,and Schenck ene reaction to construct hydroxyisopentenyl structure.A total of23 target compounds were synthesized,and their antitumor and antibacterial activities were studied.It was found that introducing electron withdrawing group（Cl）into C4position of natural products had a positive effect on antitumor activity;in addition,these compounds failed to fight Gram-negative bacteria,but they were successful against Gram-positive bacteria.