The Design,Synthesis And Anti-tumor Activities Study Of Dimethoxyl Naphthoquinoe Dioxime Derivatives

Lithospermum which is collected by Chinese Pharmacopoeia,is commonly used as chinese traditional medicine in clinical practice.Shikonin and alkannin,a pair of enantiomers,are the main effective components of Lithospermum.Though their significant antitumor effects have been demonstrated for a long period of time,none is used as antitumor drug because of severe side effects.Our research group has been working hard on the structural modifications of shikonin,alkannin and their derivatives,aiming to reduce the toxic effect and enhance antitumor selectivity.To our surprise,oximate modification to the mother nucleus of alkannin and shikonin was found to be an available approach to reduce the toxic effect,while still maintained their antitumor activity.Clearly,this new derivatives named DMSKO showed a totally different mechanism from shikonin.The structure of DMSKO of consists of three parts:5,8-dimethoxy-1,4-naphth-oquinone?DMO?which is the mother nucleus,isopentene side chain and a substituent at the?carbon of side chain.As far as we knew,the antitumor activities of DMO derivatives with different side chains were not reported yet,so we designed and synthesized several kinds of 6-substituted DMO to explore their structure activity relationships.We aimed to obtain DMO derivatives which has better antitumor activities and were easier for industrial production compared with DMSKO.Firstly,we designed and synthesized unsubstitued DMO and DMO derivatives with ester group on 6 position.It is disappointing that we failed to obtain compounds with good antitumor activities(IC₅₀>25?M against HCT-15).Then we designed and synthesized 6-alkyl DMOs with hydroxy/acetoxyl/isopentyloxy on the?site of alkyl chain.For the DMO derivatives which have the same substituent on the?site of alkyl chain,the antitumor activities increased with the length of the alkyl chain until the number of the carbon atoms of the side chain was upto certain value.For the DMO derivatives which have the same alkyl chain,those with isopentyloxy branch on the?carbon showed the best antitumor activities while those with hydroxy branch showed the worst.Among all the above compounds,6-?1-?isopentyloxy?nonane?DMO showed the best antitumor activety with the IC₅₀0 value of 0.4?M.Furthermore,we designed and synthesized 6-alkyl substituted DMO derivatives which had no subtituent on?site of the side chain.To our surprise,these compounds still showed strong antitumor activities.Based on the structure activity relationships mentioned above we speculated that the antitumor activity in vitro may related to the lipophilic property of side chain.The increased lipophilic properties may give rise to the higher antitumor activites in vitro.In addition,we found that the chiral center at the?carbon has no obvious influence on the antitumor activities.Neither R nor S isomers showed better activities than racemic ones.Finally,we obtained 4 amino acid esters of6-?1-?hydroxy?n-undecyl?DMO as water soluble prodrugs which also retained good antitumor activities.In summary,we designed and synthesized 64 DMO derivatives which were elucidated by ¹H NMR and ¹³C NMR.The antitumor activities of all the compounds against HCT-15 cancer cell line were determined by MTT assay in vitro.After studying SAR of DMO derivatives,we obtained DMO derivatives with satisfying antitumor activities.Finally,we sythesized amino acid esters of6-?1-?hydroxy?n-undecyl?DMO as water soluble prodrugs which might be used for the further in vivo antitumor activity studies.