Synthesis And Cytotoxic Activity Of Some B-norchoiesterol Aromatic Heterocyclic Compounds

Steroidal compounds as a kind of natural organic compounds,which widely exist in animals and plants,such as cholesterol,stigmasterol,testosterone,bile acid etc.Steroidal compounds which exist in the marine animals and plants have good medicinal values,and the researchers have found many novel steroidal compounds with good biological activities from marine animals and plants.In recent years,a lot of compounds with aromatic heterocyclic or aromatic ring are widely used in pesticide and medicine fields due to their good biological activities.After introduced with a heterocyclic or an aromatic heterocyclic,steroidal compounds would show different biological activity,the products obtained have generally good antitumor activity.Taking the cholesterol as a starting material,B-norcholesteryl-6-aldehyde possessing a structure of [6,5,6,5] fused ring was obtained by protection of 3-hydroxyl,ozonation reaction,dimethyl sulfide open-loop and intramolecular condensation.And then,using B-norcholesteryl-6-aldehyde as a precursor,some novel B-norcholesteryl benzimidazole and benzothiazole derivatives were synthesized by reacting with various o-phenylendiamine derivatives.Through above reaction,we had synthesized 16 steroidal heterocyclic compounds with the structures of benzimidazole,benzothiazole or enamine.In addition,using B-norcholesteryl-6-aldehyde as a precursor,18 steroidal compounds possessing a structure B-norcholesteryl thiazole were produced through reaction of 6-aldehyde group with various substituted thiosemicarbazone,and then reacting with different substituted bromoacetophenones.Similarly using B-norcholesteryl-6-aldehyde as a precursor,8 steroidal compounds with B-norcholesteryl-?-aminophosphate ester were synthesized by a pot reaction of phosphorous acid diethyl ester with different substituted heterocyclic amines.Finally,using B-norcholesteryl-6-aldehyde as a precursor,we hope to synthesized some steroidal hydrazone derivatives connected with aromatic heterocyclic compounds by reacting with hydrazine hydrate,and then with various aromatic aldehydes,but the target compounds weren't obtained.This topic had synthesized 48 compounds pessessing different structure feature of B-norcholesteryl aromatic heterocyclics,in which 42 compounds hadn't been reported before.The structures of all compounds were characterized by IR,1H NMR,13 C NMR and HREIMS Using MTT test method,their cytotoxicity was determined in vitro against human cervical cancer cells(HeLa),lung cancer cells(A549),liver cancer cells(HEPG2)and normal human kidney epithelial cells(HEK293T).The results showed that that most of the synthetic compounds could well inhibit the growth of the cell and some B-norcholesteryl benzimidazole compounds exhibited an excellent antiproliferative activity.Especially,compound 6a(4.2 ?mol/L),7a(3.6 ?mol/L),8a(4.9? mol/L),8b(4.7 ?mol/L)and 9b(2.2 ?mol/L)against human cervical cancer cell lines(HeLa)displayed a very good inhibitory activity,but almost inactive to normal kidney epithelial cells(HEK293T).In addition,to further disclose the molecular mechanism by which the compounds inhibit cancer cell proliferation,the HeLa cells were treated with compounds,and Annexin V assay was performed.The results showed that the compounds were able to effectively induce cancer cell apoptosis.However,synthesized B-norcholesteryl thiazol derivatives and B-norcholesteryl-?-aminophosphate ester derivatives were almost inactive to above cells.We synthesized some novel B-norcholesteryl derivatives and determined their antiproliferative activity against human cervical carcinoma(HeLa),human lung carcinoma(A549),human liver carcinoma cells(HEPG2)and normal kidney epithelial cells(HEK293T).The results showed that some B-norcholesteryl benzimidazole compounds exhibited an excellent antiproliferative activity and almost inactive to normal kidney epithelial cells(HEK293T),and were able to effectively induce tumor cells apoptotic.The results suggest that B-norcholesteryl derivatives based on benzimidazole group may constitute a novel class of antiproliferative agents,which deserve further study.The research provided a theoretical reference for the exploration of new anti-cancer agents and may be useful for the design of novel chemotherapeutic drugs.