Design, Synthesis And Antitumor Activity Study Of Nitrogen-Containing Curcumin And Flavonoid Derivatives

Cancer causes significant morbidity and mortality and is a major public health problem worldwide.The research of new antitumor drugs is of great significance since most of the currently available drugs had the disadvantages of high toxicity,low effection and multidrug resistance against subset of solid tumors.Structure modification of natural products is an old process but give a new hope for antitumor drug discovery.Curcumin and flavonoids are two kinds of natural products with antitumor activity and have been paid more attention for recent years.Based on SAR of curcuminoids and the previous work of our group,a series of novel curcumin analogues were designed and synthesized according to pharmacophore and scaffold hopping principle.Structurally,the new analogues are 1,5-diarylpentadienones which possess one nitrogen-containing substitution at the position 5 on one of the aromatic ring.24 new compounds were synthesized.All of them were screened for antiproliferation activity against two human tumor cell lines in vitro,and the result showed that most of the new analogues exhibit more antiproliferation activity than that of curcumin,with IC₅₀ values below 10μg/mL.The 'drug-like' properties of them were analyzed by Discovery Studio 2.0.The results suggest that most of them may be well absorbed by intestine and have good bioavailability.Another part work of this dissertation is a research of novel flavonoid derivatives.2,4-diarylchromane[4,3-d]-(?)^1,9b-1,2,3-thiadiazolines had been synthesized and found as antiproliferative compounds in our previous work.As a continuation of our study,according to the bioisosteric principle,the similar compounds,4-aryl-3,4-dihydrochromeno[3,4-d][1,2,3]diazaphosphole,2,4-diaryl-2, 3,3a,4-tetrabydro-chromeno[3,4-d][1,2,3]diazaphospholes and 4-phenyl-4H-chromeno [4,3-d][1,2,3]selenadiazoles were designed and synthesized.The pharmacological research showed a number of these analogues had significant antitumor activity against five human tumor cell lines in vitro.The highly potent derivative 3-5n,exhibits antiproliferative activity against all the tested human tumor cell lines with IC₅₀ values below 10μg/mL.The ADME properties were analyzed by Discovery Studio 2.0.The results suggest most of the above compounds may be well absorbed by intestine and have good bioavailability except 2,4-diaryl-2,3,3 a,4-tetraby dro chromeno[3,4-d][1,2,3]di azapho spholes.A novel method was found for synthesis of 4-aryl-3,4-dihydro-and 2,4-diaryl-2,3,3 a,4-tetrabydrochromeno[3,4-d][1,2,3]diazaphospholes,by the reaction of chromone-4-hydrazones with POCl₃-SOCl₂ and ethanol(or methnol) in turn.The optimization procedures were also reported in detail.In addition,we also found a new method for synthesis of 1,3,5-triarylpyrozoles or 3,5-diarylpyrozoles by one-pot reaction of flavonones,PO(OCH₃)₃ with arylhydrazines or alkylhydrazines,respectively.This method provided a facile and efficient approach for preparation of 3,5-diarylpyrozole derivatives.