Design,Synthesis And Antitumor Bioactivity Evaluation Of Sterol 5?,8?-Endoperoxides

Cancer is a leading cause of death worldwide.In the past decades,researchers from all over the world have tried their best to develop high efficiency and low toxicity anticancer drugs.Natural medicine has a long medical history,the active compound from natural medicine is one of the important sources of lead structure in drug discovery and research.According to reports,in 1981-2012,about 46%of the structure of the listed drugs derived from natural products,natural products derivatives and analogs.Due to the diversity and complexity stereoscopic structure of natural products,and a variety of physical and chemical properties,people have been interested in its full of a wide range of research.Based on the review of the development of natural peroxides and steroidal drugs,we took ergosterol peroxide as the guide structure for research,which was extracted from the most typical representative of Chinese herbal medicine ganoderma lucidum.Here,we designed and synthesized four series of sterol 5?,8?-endoperoxides with different structures by modifying C-3 and C-17 of sterol.All of the synthesized compounds were evaluated for antitumor bioactivity.Firstly,using natural ergosterol as the starting material,we synthesized ergosterol peroxide by photo oxidation reaction.After confrming the structure of ergosterol peroxide,we examined the biological functions of the synthetic ergosterol peroxide.The results showed that ergosterol peroxide induced cell death and inhibited cell migration and cell cycle progression.By inspiration of significant anticancer activity of our previously screened natural ergosterol peroxide?EP?,a series of novel ergosterol peroxide 3-carbamate derivatives?I-3a-h?were synthesized and characterized.The anti-proliferative activity of synthesized compounds against human hepatocellular carcinoma cells?HepG2,SK-Hep1?and human breast cancer cells?MCF-7,MDA-MB231?were investigated.Compound I-3d,I-3f and their hydrochloride exhibited significant in vitro anti-proliferative activity against the tested tumor cell lines,with IC₅₀ values ranging from0.85 to 4.62?M.Furthermore,fluorescence mitochondria-targeting images showed that the designed coumarin-I-3d conjugate?I-5?localized mainly in mitochondria,leading to enhanced anticancer activities over the parent structure?EP?.We hope to get valuable information for further design of novel steroidal anticancer agents.Herein,we designed and synthesized a series of novel steroidal5?,8?-endoperoxide derivatives that with C-17 aliphatic side chain?II-5a-d and II-14a-f?were designed,synthesized,and biologically evaluated for their in vitro anti-proliferative inhibitory and cytotoxic activity.The results revealed that most of these compounds showed moderate-to-excellent anti-proliferative effects against the tested cancer cell lines.Among them,compound II-5b and II-14d exhibited preferable inhibitory activities(IC₅₀ of II-5b and II-14d are 8.07 and 9.50?M against HepG2,respectively).The structure-activity relationships indicated that incorporation the peroxidic bridge to the steroid scaffolds at C-5 and C-8 positions together with the aliphatic side-chain at the C-17 position would provide synergistic effect for the bioactivity.It is well known that N,O,S-heterocycles are important structural units present in many drugs,natural and synthetic products with potent bioactivity profile.Here a series of novel 5?,8?-epidioxyandrostan-3?-ol-17-hydrazone derivatives?III-8a-h?possessing various aromatic heterocycle structures in 17-side chain of their steroidal nucleus were synthesized and characterized.The anti-proliferative activity of synthesized compounds against some cancer cells was investigated.The results have demonstrated that compound III-8b(IC₅₀=8.74?M to HepG2)with quinoline and III-8c(IC₅₀=9.38?M to SK-Hep1)with indole structure in side chain display excellent anti-proliferative activity in vitro against tested cancer cell lines.And then a of novel 5?,8?-epidioxyandrost-3?-ol-17-?O-phenylacetamide?oxime derivatives?IV-8a-p?were synthesized and characterized.The antiproliferative activity of synthesized compounds against human hepatocellular carcinoma cells and human breast cancer cells were investigated.Compound IV-8d and IV-8i displayed excellent antiproliferative activity(IC₅₀<15?M)in vitro and preferentially target cancer cells over normal cells,and thus represents a new lead for further optimization.The structure-activity relationships indicated that incorporation the peroxidic bridge to the steroid scaffolds at C-5 and C-8 positions together with the oxime-phenylacetamides side chain at the C-17 position would provide synergistic effect for the bioactivity.Finally,31 of the target compounds were chosen to do 3D-QSAR.The results would be very useful for designing new series of steroidal 5?,8?-endoperoxides.