Synthesis Of Oleandrin Derivatives And Evaluation Research Of Their Antitumor Activity

Cardiac glycoside compounds have the effect of enhancing myocardial contraction and are used clinically to treat arrhythmia and congestive heart failure.Modern pharmacological studies have shown that cardiac glycoside compounds can specifically bind sodium and potassium ATPase,not only have a cardiac effect,but also can selectively inhibit the proliferation of human tumor cells and induce apoptosis.Therefore,the development of sodium and potassium ATPase inhibitors has received widespread attention as an anti-tumor drug.There are more than 30 kinds of animals and plants containing cardiac glycoside compounds reported in our country,such as poisonia convolvulus,digitalis,sagebrush,yellow oleander,oleander and toad.Oleander is an ornamental plant,widely distributed in tropical and subtropical regions.It likes warm and cold,planted in all provinces of China,open cultivation in the south,indoor cultivation in the north.Oleander has many effects such as cardiotonic,diuretic,anti-tumor,analgesic,cough,and anti-inflammatory.Its main chemical components are cardiac glycosides,steranes,terpenes,flavonoids,etc.Oleandrin is the largest quantity,the most content and the most important active ingredient in oleander.Oleandrin is the strongest anti-tumor active monomer compound in oleander,but it has poor drug-like properties,low water solubility（<10μg/m L）and a narrow therapeutic window,which severely limits its development as an antitumor drug.Therefore,it is necessary for us to modify its structure and strive to find drug candidate molecules with strong antitumor activity,low toxicity and good drug-like properties.According to the literature research and laboratory research experience,we find that structural modification of the oleandrin C-4’hydroxyl group will have an important effect on antitumor activity.According to the design idea of the subject,first of all,we explore the configuration of the hydroxyl group and the necessity of the existence of the hydroxyl group at the C-4’position.We transform theβhydroxyl group at the C-4’position into a ketone and anαhydroxyl group and find the anti-tumor activity of the derivatives is lower than the prototype compounds,which indicates that theβconfiguration of the C-4’hydroxyl group must be retained and further derivatization continued.Secondly,in order to improve the water solubility of oleandrin while maintaining anti-tumor activity,we design and synthesize a series of amino acid ester derivatives.And we find that all amino acid ester derivatives maintain the anti-tumor activity of the prototype compounds,IC₅₀（A549）at 17.20-49.24 n M.Compounds 4a,4b,4e and 4f whose IC₅₀（A549,He La,NCI-H460,BEL-7402,PC-3）is between 17.20-52.48 n M,of which compound 4b has the most active that is twice that of the parent compound on A549 and He La.And 4b hydrochloride4b-HCl has a significant anti-tumor effect on tumor-bearing mice at a therapeutic dose of 6 mg/kg,with a tumor suppression rate of 96.4%.The toxicity of 4b is within our acceptable range,and the water solubility of 4b-HCl（2 mg/m L）is more than 200 times higher than oleandrin（<10μg/m L）.In summary,the amino acid ester derivatives designed and synthesized in this subject as a potential new antitumor drug can continue to be further researched.Secondly,we provide exemplary research for improving the drug-like properties of cardiac glycoside compounds and improving water solubility.The research work of this topic is an important exploration in the antitumor field of cardiac glycoside compounds.