Synthesis And Antitumor Activity Of Bile Acid-naphthalimide Derivatives Containing1,2,3-triazole Ring

Triazole is a class of heterocyclic with a wide range of biological activity, many pharmaceuticalchemistry workers and biochemistry workers all over the world have done a large amount of researches ofthese compounds.1,2,3-triazole derivatives are a class of heterocyclic compounds, and they have broadapplication in many prospects, mainly in terms of drugs, pesticides, and functional materials. In drugdevelopment field,1,2,3-triazole are often used to substitute amino to reduce the resistance of certainanti-cancer drugs, and so enhance anticancer activity. Research shows that click chemistry has become oneof the most attractive methods in organic synthesis. Monovalent copper-catalyzed azide-alkynecycloaddition reactions has been considered as the most typical reaction. This reaction can quicklysynthesize1,4-disubstituted1,2,3-triazole compounds, and the yield is very high, and the structure is moreselectively.1,8-naphthalimide compounds as DNA intercalator are often considered as an important classof anticancer drugs. Such molecules have a rigid naphthalene ring plane. And the structure helps them toembed in the DNA base more efficiently. So, these compounds exhibit a strong cutting ability of DNA andanti-tumor activity.As drug targeting carrier, bile acids has a significant advantage in the treatment of liver tumors.Scientists have synthesized a large number of acid chelated anticancer drugs, and tested their activity andachieved good research.Firstly, the application research progress of bile acid anti-tumor compounds and the click chemistryresearch status, and the pharmacological activity of triazole molecules are summarized in this article. And then the monovalent copper-catalyzed Husigen cycloaddition reaction have been applied to structuralmodification of bile acid molecules under the conditions of ultrasonic assistance. By this method, a seriesof bile acid derivatives containing1,2,3-triazole pharmacophore have been synthesized. Finally, theaphthalimide compounds having antitumor activity have connected to the2,4-carboxyl group of bile acidby amide formation reaction. A total of32new compounds were synthesized in this paper. And theanti-tumor activity of the target compounds have been measured by MTT assay method.1、A series of compounds4A-4H were synthesized using Click chemistry, and the reaction conditionswere optimized. We found that the best catalyst system is CuSO4·5H2O/NaAsc situ generated Cu (I), thebest response solvent system is H2O/THF. The effect of ultrasound power to the reaction rate and the yieldhave been investigated through eight group of experiments. The results showed that ultrasonic waves havesignificantly accelerated the click reaction rate, and with the increase of ultrasound power, the reaction timerapidly shortened. However, the yield almost unchanged. As the amount of the catalyst CuSO4·5H2O,NaAsc are equivalent, the yields up to the highest. And then all the reaction conditions have beenoptimized.2、By the optimized reaction conditions from4A, we have synthesized two series (acid series anddeoxycholate series) of eight cholic acid methyl ester derivatives containing1,2,3-triazole ring. Againthrough hydrolysis reaction to get eight cholic acid derivatives containing1,2,3-triazole ring.16compounds were new compounds and the structure of all the compounds were characterized by IR,ESI-MS, NMR.3、16bile acid-containing triazole ring Naphthalimide derivatives were synthesized by the amideformation reaction with CDI as catalyst. And the reaction conditions have been optimized. The structure of these16new compounds were identified by infrared spectroscopy (IR), nuclear magnetic resonance (NMR)and mass spectrometry (MS).4、The anti-tumor activity of target bile acid derivatives have been measured by MTT assaymethod.And we have made a comparison about antitumor activity of target bile acid derivatives with bileacid naphthalene imide derivatives and amonafide. It is concluded that the fluoride compound6B,6F,6J,6N show higher anti-tumor activity than amonafide.