Design And Synthesis Of Novel Sugar-conjugated Water-soluble CA-4antitumor Agents

Cancer,also known as malignant tumor,is caused by the disorder of the cell proliferation mechanism.In addition to growing out of control,cancer cells also invade the surrounding normal tissues and even transfer to the rest of the body via circulating system or the lymphatic system,causing emaciation,weakness,anemia,loss of appetite,fever and impairing the viscera function severely.Cancer is treated with surgery,radiation therapy,chemotherapy,hormone therapy or biological therapy.The choice of treatment depends on the type,location,stage of cancer,the patient’s age and general health,and other factors.Chemotherapy is one of the important means for the treatment of cancer.However,due to the poor selectivity on cancer cells and normal cells,the toxicity and side effects of the chemotherapy drugs are severe.Therefore,unremitting efforts have been made to seek novel anticancer drugs with high efficiency and low toxicity.Combretastatin A4(CA-4)was abstracted from Combreum caffrum,an African bush willow.CA-4,a vascular inhibitor,can target tubulin and inhibit tubulin polyme-rization,thus it can inhibit the tumor blood vessels and has antitumor effect.But it is insoluble in water and has low bioavailability.As an antitumor drug,a derivative of it,which is now known as CA-4P,is a strong inhibitor of tubulin assembly.CA-4P is now in clinical trial Ⅲ as a vascular-targeting agent.Three combretastatin-based glycoconjugates,namely Glu-CA4,Man-CA4,and Gal-CA4 with glucose,mannose,and galactose respectively,were synthesized and their in vitro and in vivo biological characteristics were evaluated.The starting materials were isovanillin and 3,4,5-trimethoxybenzaldehyde.Different sugars were chosen and each step of the reaction was optimized.In this paper,sugar-conjugated CA-4 were designed and synthesized,all intermediates and target compounds have been characterized by1 H NMR,13 C NMR,IR and MS.The glycoconjugates were found to have a superior safety profile with their maximum tolerated dose(MTD)values exhibiting a 16~34-fold increase compared to CA-4.Given the drawbacks of CA-4,the enhanced solubility and safety profiles of CA-4 glycoconjugates auger well for further investigation into these intriguing candidates’ in vivo efficacy.