Synthesis Of Matrine-Triazole Derivatives And Evaluation Of Preliminary Antitumor Activity

In recent years,the incidence and mortality of malignant tumors have been increasing year by year,and it is our urgent need to find and develop new anti-tumor drugs.Matrine is a main active substance extracted and isolated from the roots of the leguminous plants Sophora flavescens,the broad bean root and the bitter bean.Matrine has extensive pharmacological effects,such as anti-tumor,anti-pulmonary fibrosis,anti-virus,anti-inflammatory,cardiovascular protection and neuroprotection.Especially in terms of antitumor activity,matrine can kill tumor cells through a variety of mechanisms,which has become one of the hotspots in matrine bioactivity research.In spite of matrine has a wide range of pharmacological effects,its bioavailability is low,and is of poor chemical stability and certain toxicity.For example,compound matrine injection can cause side effects such as central nerve paralysis and spasm.Triazolium heterocyclic structure is an indispensable active fragment in the field of drug design and synthesis,wherein benzotriazole,1,2,3-triazole,1,2,4-triazole and triazolopyrimidine are a very important class of nitrogen heterocyclic pharmacophores.1,2,3-triazole is rich in electrons,which make it able to be combined with various targets to produce a variety of biological activities,such as anti-tumor,anti-bacterial,anti-inflammatory,making it be widely used in the field of medicine.Therefore,we hope to improve fat soluble and antitumor activity of matrine by introducing 1,2,3-triazole active fragment to obtain potential matrine derivatives.Based on a large amount of literature research and summarizing the progress of the structural modification of matrine and its derivatives in recent years,the research group used the combination principle of drug design to combine 1,2,3-triazole into the structure of matrine.This research group uses matrine as the starting material,and the triazolyl groups were introduced into the tricyclic structure of matrine through a series of reactions such as ring-opening hydrolysis reaction,alkylation reaction,azide reaction and click reaction,during which 10 benzyltriazole matrine derivatives 5a-5j and 12 phenyltriazolomatrine derivatives8a-8l were synthesized,respectively.The different substituted benzyl and phenyl fragments were introduced at the 1-position of triazole,the effect of different types of substituents on activity was investigated.All the synthesized target compounds were characterized and confirmed via ~1H-NMR,¹³C-NMR and HRMS.Finally,the anti-proliferative activity and anti-pulmonary fibrosis activity of the target compounds were tested.The results showed that most of the compounds had higher antiproliferative activity than the parent compound matrine;Among them,5e（Inhibition rate:89.4%～93.3%）showed obvious antiproliferative activity on the four tumor cells tested,and the activity was better than the positive control drug etoposide（Inhibition rate:55.3%～76.6%）.Preliminary structure-activity relationship studies have shown that increased liposolubility is beneficial to improve the anticancer activity of matrine derivatives.In addition,the tested compounds showed different anti-proliferative effects on different tumor cell lines,and the anti-proliferative effect on MCF-7 tumor cells was significantly better than other tumor cell lines and showed certain sensitivity.Among them,the antitumor activity against MCF-7 was up to 98.2%in 8h.The anti-pulmonary fibrosis activity test results showed that the tested compounds（5e,8b,8c,8g,8h,and 8l）had no obvious anti-proliferative effect on NIH3T3 cells,and the anti-pulmonary fibrosis activity was weak.