Synthesis And In Vitro Anti-breast Cancer Activity Of Icaritin And Icariside Ⅱ Analogs

It is still a difficult task to control and cure malignant tumors.Chemotherapy using small molecules is currently one of the main treatments for metastatic tumors.Natural drugs are ideal scaffolds for research into drug discovery.Therefore,screening of lead compounds for tumor treatment from natural molecules has always been a mainstream and feasible way to discover new drugs.Icaritin and icariside Ⅱ are natural flavonoids feature an isopentenyl group,and they show antitumor potential against breast cancer.In order to obtain icaritin and icariside Ⅱ analogs with more potent anti-breast cancer activity to provide candidate molecules for the research and development of anti-breast cancer drugs,as well as to investigate the structure-activity relationship of icaritin and icariside Ⅱ,structure modifications were carried out using icaritin and icariside Ⅱ as scaffolds.The structures of the analogs were determined by spectral analysis.The CCK-8 kit was used to evaluate the anti-proliferation effect of icaritin and icariside Ⅱ analogs against human breast cancer cell line MCF-7.The correlations between in vitro anti-breast cancer activity of the synthesized analogs and their corresponding structures were analyzed to study the structure-activity relationship of icaritin and icariside Ⅱ.Starting from icaritin,16 icaritin analogs were synthesized;starting from icariside Ⅱ,27 icariside Ⅱ analogs were synthesized.The icariside Ⅱ analog S27,in which all the 5 hydroxyls were acetylated,showed the best inhibitory potency against MCF-7,which was 10 times of it’s precursor icariside Ⅱ.The icariside Ⅱ analog S11,in which an alkylamine moiety was introduced at 7-OH,showed potent selectivity between normal cells and cancer cells.The structure-activity(anti-breast cancer in vitro)relationship of icartin was summarized as follows: 8-isoprenyl is not essential for its anti-proliferation activity;7-OH is key to the anti-tumor activity;substitution of 6-H by Mannich bases is beneficial for its potency;acetylation of 7-OH,5-OH and 3-OH significantly increases its cytotoxicity;the substituent at 3-OH plays an important role in the anticancer activity,and minor changes of the substituent may have a significant impact on the anti-proliferation effect.The structure-activity(anti-breast cancer in vitro)relationship of icariside Ⅱ was summarized as follows: The substituent at 7-OH has an important impact on its anti-proliferation activity,as the introduction of small alkylamine groups or small rigid groups improves the potency,whereas the introduction of large rigid groups significantly reduces its anti-breast cancer activity;replacement of 6-H by Mannich bases reduces its cytotoxicity;acetylation of 7-OH,5-OH and the hydroxyl groups in the 3-O-rhamnosyl moiety is beneficial to improve the anti-proliferation effect.This study enriched the library of anti-tumor flavonoids,furthermore,it laid a material and theoretical basis for the development of icaritin,icariside Ⅱ and their analogs as lead compounds for anti-tumor agents.