Synthesis And Anti-tumor Activities Of Novel Flavone Acetic Acid Andbenzofur An Derivatives

Cancer,as the second leading cause of death after cardiovascular diseases,has seriously threatened public health nowadays.However,most clinically effective anticancer agents are subjected to low efficacy,high cytotoxicity and multidrug resistance against solid tumors.Therefore,it has been a hot topic in the field of anticancer drug discovery to develop antitumor drugs with high efficacy,low cytotoxicity and minimum side effects.Flavonoids are a class of small molecule organic compounds that are widely distributed in diverse groups of plants.They have been used as drugs because of their widespread biological activities and fewer side effects.In this paper,we describe the design,synthesis and anti-tumor activities of two types of potential anti-tumor flavonoids,including(1)novel flavone acetic acid derivatives and(2)2-aroylbenzofuran-3-ols.Part ?.Synthesis and anti-tumor activities of novel flavone acetic acidsThe vasculatures of solid tumors are fundamentally different from normal vasculatures,and thus offer a unique target for anti-cancer therapy.At present,the inhibitors which targeted tumor vascular are divided into tumor angiogenesis agents(AIs)and tumor-vascular disrupting agents(VDAs),and the mode of action of these two agents is essentially different.Tumor-vascular disrupting agents(Tumor-VD As)are capable of selectively destroying tumor vasculatures,shutting down blood supply to solid tumors and causing extensive tumor cell necrosis,thus they become a very potential anti-tumor agents.Flavonoid-based small molecule cytokines inducers as one class of the tumor vascular-disrupting agents,function by activating the immune system and inducing the release of tumor necrosis factor(TNF-a)to destruct tumor vasculars.In order to obtain potent flavonoid-based VDAs having the induction of appoptoiss in endothelial cells within tumor bood vessels,in this paper we synthesized a series of novel flavone acetic acid derivatives,by using flavone-8-acetic acid(FAA)and 5,6-dimethylxanthenone-4-acetic acid(DMXAA)as lead compounds.Firstly,to obtain the potent anti-tumor flavonoid-based agents,we designed thirteen 3-phenyl-flavone-8-acetic acid derivatives AFAA01-13 by combining cis-stilbene,a pharmacophore of both tubulin depolymerization agents and Cyclooxygenase-2(COX-2)inhibitors,with the pharmacophore of flavonoid-based vascular-disrupting agents.These AFAA derivatives were synthesized in six steps,starting from 2-methyl resorcinol and substituted phenylacetic acids.Their antiproliferative activities toward colon cancer cells(HT29)and lung cancer cells(A549)were evaluated.The preliminary results suggested that the antiproliferative activities of AFAA compounds toward colon cancer cells(HT29)were higher than those toward lung cancer cells(A549).Besides,maintaining the aryl groups at the 2-position and introducing the aryl groups at the 3-position of flavones-8-acetic acid derivatives can improve theirs activitities toward HT29.For example,the antiproliferative activities of compounds AFAA02(IC50 = 236.6 ?M),AFAA04(IC50=170.0?M),AFAA09(IC50=70.3 ?M)and AFAA12(IC50=248.5 ?M)were 12.4,17.2,34.8 and 11.8-fold higher than that of FAA(IC50 = 2449 ?M).Among them,compounds AFAA04 and AFAA09 were 1.5 and 3.7-fold active than DMXAA(IC50=261.9 ?M)respectively.Compounds AFAA02 and AFAA12 were very similar with DMXAA.Secondly,in order to study the effect activities of the aryl groups at the 2-position of flavones-8-acetic acid derivatives,we synthesized three isoflavones-8-acetic acid derivatives(IFAA)in six steps,starting from 2-methyl resorcinol and substituted phenylacetic acids.Their antiproliferative activities toward HT29 and A549 were tested.The preliminary results suggested that comparing with FAA,IFAA did not show higher antiproliferative activities toward both the two tumor cells.Part II.Microwave-assisted synthesis and anti-tumor activities of 2-aroylbenzofuran-3-olsBenzofuran derivatives are widely distributed in nature,and have attracted considerable interests because of their multiple pharmacological properties and wide applications in drug discovery.For example,2-aroylbenzofuran-3-ols,as a class of typical benzofuran derivatives,do not only have unique antitumor and anti-inflammatory activities,but also are useful synthetic intermediates for many drugs.However,the synthetic methods have limited applications because of the poor availability of starting materials and low yields.Therefore,during the last few decades,major efforts have been made to develop a straightforward approach for the synthesis of 2-aroylbenzofuran-3-ols from readily available starting materials.Herein,we describe an efficient one-step synthesis of 2-aroylbenzofuran-3-ols BF6a-I from Dieckmann reaction of substituted methylsalicylates with 2-bromo-1-aroylethanones in alkaline aprotic solvent(acetone as a solvent,anhydrous potassium phosphate as a base)under microwave irradiation.This approach has the feature of short reaction time,high yields and efficiency.The antiproliferative activities of these 2-aroylbenzofuran-3-ols toward breast cancer cells(MCF7),gastric cancer cells(MKN45),hepatocellular carcinoma cells(HepG2)and lung cancer cells(A549)were tested.The results indicated that most of these compounds had moderate inhibitory activities toward the four tested cancer cells at a concentration of 100 ?M.However,compound BF6i(IC50 = 42 ?M)exhibited strong inhibition toward A549.