The Studies On The Synthesis And Antitumor Mechanism Of Benzoxanthene Derivatives

Cancer is one of the leading causes of morbidity and mortality in the world.Pharmacotherapy,as the main means of cancer treatment,has carried out for decades.But as it kills the tumor cells,it brings poisonous effects to normal cells of hunman.As a result,cancer survivors suffer pains and agonies extremely.Thus,the hunting of the high targeting chemical therapeutic drugs with high efficiency and low toxicity becomes an urgent matter.Xanthone has been used as a chemical fluorescence dyestuff initially.And then,being founding out possessing with properties of favourable pharmacological activity,it provided with fuctions of anti-inflammatory,anti-oxidant,anti-viral and anti-tumor.In this paper,three series of dibenzoxanthenes and one series of benzoxanthones were synthesized,and the molecular structure of the compounds have been determined by means of mass spectrometry,nuclear magnetic resonance and X-ray single crystal diffraction.In addition,we have investigated their antitumor activities and effective mechanisms.The main contents include:(1)Using dinaphthol as raw material,six dibenzoxanthene compounds with different substituents at the 13 c position were synthesized and their structures were characterized.In addition,we found that four of these compounds have good antitumor effects under light conditions and can be used for photodynamic therapy.Through AO/EB staining,comet assay,ROS detection,JC-1 detection,Western Blot and other experiments,we found that they increased ROS content in cells,caused oxidative stress reactions and induced apoptosis.(2)Using 6-bromo-2-naphthol and 6-methoxyformyl-2-naphthol as raw materials,three 1-oxo-5-bromo-11-methoxyformyl-13c-substituted-1,13c-dihydroxyl-dibe nzo [a,kl] xanthene compounds were synthesized and their structures were characterized.They all showed excellent anti-proliferative activity against SGC-7901 cells,and it was found in mechanism studies that they affected the cell cycle by damaging DNA and tubulin and induced mitochondria to release cytochrome C and eventually lead to apoptosis.(3)A novel polycyclic bridged-ring xanthene was synthesized by nucleophilic substitution followed by Michael addition reaction between 1-oxo-13c-methoxy-1,13c-dihydroxyl-dibenzo [a,kl] xanthene and acetylacetone.Its structure was characterized by various analysis methods and its antitumor mechanism was studied.(4)Four novel benzoxanthones were synthesized according to the ring-opening reaction of dibenzoxanthenes and their structures were characterized.In vitro cytotoxicity experiments,it was found that the compound with cyano group exhibited better cytotoxicity compared with others.Moreover,it also caused apoptosis through the mitochondria pathway.In conclusion,we synthesized 14 benzoxanthene derivatives and determined their molecular structures.Most of these compounds have favorable cytotoxicity and selectivity under specific conditions.Mechanism studies have shown that they all induce apoptosis through the ROS-mitochondrial pathway.