Synthesis And Antitumor Activity Of Sophocarpine 13 Addition Derivatives

Objective:In the field of chemistry,especially in the field of organic chemistry,the active principle of natural medicine has always been a hot spot for scientists.To date,natural medicine components still occupy the dominant position among the clinically applied drugs.However,since the amount of natural products extracted is far from satisfying human needs,artificial synthesis is an effective means of drug development and utilization.The synthesis of natural products has always been an important study of our scholars,especially alkaloids.At present,domestic and foreign chemists have made more and more research on alkaloids,alkaloids extraction and separation,content determination,biological activity target tracking and other aspects have made a major breakthrough,more and more novel structures,pharmacological activity of alkaloids structure be found.The known alkaloids are still limited in practical application by the drawbacks brought by the peculiar structure.So the structural modification of natural products is another important part of the chemical field.The main purpose of chemical structure modification are the following:increase drug bioavailability;improve drug selectivity;reduce drug toxicity;prolong drug action time;improve drug solubility and so on.It has been reported that a large number of alkaloids with anti-tumor activity were extracted from Sophora flavescens and Sophora alopecurosides,with matrine and sophocarpine as the representatives,which are still the hot spots both at home and abroad.In this paper,one of the main components of Sophora flavescens Sophocarpine as the lead compound,according to the principle of pharmacophore combination structure of sophocarpine 13structure modification,resulting in a series of new anti-tumor activity of Sophora flavescens Base Derivatives.Aims to provide a reference and direction for the design and development of new antitumor drugs.Methods:Sophocarpine and matrine have good anti-tumor activity.More and more scholars pay attention to the development of antineoplastic drugs of sophocarpine and matrine.So far,many reports on the effects of sophocarpine and matrine on anti-tumor,anti-arrhythmia,anti-inflammatory and anti-virus Have different degrees of effect.Sophocarpine is a class of molecular structure containing quinolizidine structure of alkaloids,and the structure of matrine similar to the difference is that the 13-position of sophocarpineα,βunsaturated double bonds,can occur Classic Michael addition reaction.Therefore,we can refer to all kinds of examples of Michael addition of sophocarpine alkaline structural modification experimental study.Sophocarpine molecules in the presence of four ring structure（Figure 1）,and which ring A and B belong to Quinolizidine structure,it is easy to see through the literature,A,B,C ring Sophora Alkaloids and matrine mother ring,on the anti-tumor activity has a very important impact,coupled with the rigid skeleton is not easy to modify,so the mother does not as a structural reform considerations,so retained.The D ring is a lactone ring structure.Compared with matrine and sophocarpine,if D ring is destroyed anti-tumor activity will be greatly reduced.Therefore,in this experimental scheme,taking the retention of the D loop,evidence obtained by consulting a large number of literatures suggests that the 13-position of sophocarpine should be structurally modified to be a matrine derivative and its in vitro antitumor activity be measured.The experimental program to weak alkaline environment for the reaction conditions,first of all,the construction of ethanolamine structure on the double bond,through the introduction of hydroxyl can increase the water-soluble compounds.Then introduced in the secondary amine may enhance the anti-cancer activity of the group,such as:benzyl bromide,sulfonyl chloride and so on.Get the corresponding Sophocarpine 13-bit addition derivatives.MTT assay was used to test the antitumor activity of the 13-position derivative of sophocarpine in vitro.Results:In this paper,31 novel derivatives of sophocarpine 13 were synthesized and their structures were characterized by ¹H-NMR,¹³C-NMR and LC-MS.MTT assay was used to test anti-tumor activity in vitro and the new 13-position derivative of sophocarpine was tested.The results showed that for the Hep G-2 cells,the compounds SP-6,SP-7 and SP-10 SP-14,SP-17 and SP-18 showed stronger antitumor activity than matrine and sophocarpine.For the Hela,cervical cancer cell lines SP-1,SP-SP-9,SP-10,SP-14,SP-17 and SP-18 showed stronger antitumor activity than matrine and sophocarpine.Compounds SP-6,SP-7,SP-14and SP-17 showed good inhibitory activity on both tumor cells.Conclusion:In this paper,31 novel derivatives of sophocarpine13-position were successfully synthesized.The antitumor activity of the13-position derivative of sophocarpine was also investigated by MTT assay.The results showed that compound SP-6,SP-7,SP-14 and SP-17showed good inhibitory activity on both of the tumor cells tested,and the activity was superior to matrine and sophocarpine.This provides a new development idea for the design and synthesis of new anti-tumor drugs in the future,and has certain reference significance.