| Due to its easy absorption,high efficiency,high safety,and less impact on the environment,organic selenium compounds have attracted widespread attention,especially their application in the field of anticancer,which has made significant progress,providing important support for the prevention and control of cancer.Non-steroidal anti-inflammatory drugs(NSAIDs)can significantly inhibit tumor cells,thereby playing a good anti cancer and preventive role,but they also bring certain toxic reactions.It is a promising research to modify existing non-steroidal anti-inflammatory drugs,improve their tumor inhibitory ability,and reduce toxic side effects.The purpose of this study is to investigate the combination of organic selenium compounds with non-steroidal anti-inflammatory drugs and exert their advantages in tumor inhibition.At present this study designed and systhesized four types of organic selenium derivatives with anti-tumor activity and low toxicity.Through these studies,we hope to find more effective anti-tumor drugs.1.The first type of organic selenium derivatives: A class of organic selenium derivatives with a total of 16 novel molecules introduced with selenocyanidin and diselenide structures was synthesized,using six non-steroidal anti-inflammatory drugs,nicotinic acid,and isonicotinic acid as the basic skeleton,and amide group as the linking group.MTT method was used to study their proliferation inhibitory activities on human colon adenocarcinoma cell line(Caco2),human gastric cancer cell line(BGC-823),human breast cancer cell line(MCF-7)and human prostate cancer cell line(PC-3).After screening,we found two of the most active compounds,I-1f and I-1g,which can significantly reduce the quantity of the anti-apoptotic protein Bcl-2 in PC-3 cells,while significantly increasing the expression levels of proinflammatory cytokine IL-2 and a proapoptotic caspase protein caspase-3,a proapoptotic caspase protein.In addition,most derivatives exhibit moderate to good glutathione peroxidase-like activity compared to ebselen.The proapoptotic and antioxidant activities of these two compounds indicate that compounds I-1f and I-1g can induce tumor cell apoptosis via antioxidant way,thereby exerting their inhibitory activity on tumor cells.This also provides a certain reference basis for the design and optimization of the molecular structure of organic selenium derivatives of non-steroidal anti-inflammatory drugs.2.The second type of organic selenium derivatives: A class of organic selenium derivatives with a total of 16 novel molecules introduced with the structures of isoselenocyanates and selenium-urea were synthesized,using eight nonsteroidal anti-inflammatory drugs as the basic skeleton,and amide groups as linking groups.MTT method was used to study their proliferation inhibitory activities on human colon cancer cells line(SW480),human cervical cancer cells line(He La),human lung cancer cells line(A549),and human breast cancer cells line(MCF-7).Finally,two compounds with the strongest activity,II-6b and II-6f,were selected,which can significantly reduce the expression level of anti-apoptotic protein Bcl-2 in MCF-7 cells,while significantly increasing the expression level of proinflammatory cytokine IL-2 and a proapoptotic caspase protein caspase-3,a proapoptotic caspase protein.Then,the antioxidant activity was evaluated.The experimental results showed that compounds II-6b and II-6f can induce tumor cell apoptosis by scavenging reactive oxygen species,antioxidant,and promoting DNA damage repair,thereby exerting their inhibitory activity on tumor cells.Finally,the drug sensitivity of compounds II-6b and II-6f to the selenium containing enzyme thioredoxin reductase 1(Trx R1)was studied,and molecular flexible docking experiments were conducted.The binding affinity and the possibility of covalent reactions were analyzed and evaluated.The results indicate that compound II-6b is the most likely to become a Trx R1 inhibitor,with the highest average binding energy and greater potential for selenium cysteine interaction.3.The third type of organic selenium derivatives: A class of organic selenium derivatives with a total of 20 novel molecules introduced with selenocyanidin and trifluoromethyl selenium structures were synthesized,using 10 nonsteroidal anti-inflammatory drugs as basic skeletons,and amide groups as linking groups.MTT method was used to study their proliferation inhibitory activities on human colon cancer cells line(SW480),human cervical cancer cells line(He La),human lung cancer cells line(A549),and human breast cancer cells line(MCF-7).Finally,two compounds with the strongest activity,III-2h and III-2i,were selected,which can significantly reduce the expression level of anti-apoptotic protein Bcl-2 in MCF-7 cells,while significantly increasing the expression level of proinflammatory cytokine IL-2 and caspase-3,a proapoptotic caspase protein.Then,the antioxidant activity was evaluated.The experimental results showed that compounds III-2h and III-2i can induce tumor cell apoptosis by scavenging reactive oxygen species,antioxidant,and promoting DNA damage repair,thereby exerting their inhibitory activity on tumor cells.Finally,the drug sensitivity of compounds III-2h and III-2i to the selenium containing enzyme thioredoxin reductase 1(Trx R1)was studied,and molecular flexible docking experiments were conducted.The binding affinity and the possibility of covalent reactions were analyzed and evaluated.The results indicate that compound III-2h is the most likely to become a Trx R1 inhibitor,with the highest average binding energy and greater potential for selenium cysteine interaction.4.The fourth type of organic selenium derivatives: A class of organic selenium derivatives with a total of 20 novel molecules introduced with selenocyanidin and trifluoromethyl selenium structures were synthesized,using 10 nonsteroidal anti-inflammatory drugs as the basic skeleton,and ester groups as linking groups.MTT method was used to study their proliferation inhibitory activities on human colon adenocarcinoma cell line(Caco2),human gastric cancer cell line(BGC-823),human breast cancer cell line(MCF-7)and human prostate cancer cell line(PC-3).Finally,three compounds with the strongest activity,IV-2a,IV-2g,and IV-2i,were selected,which can significantly reduce the expression level of anti-apoptotic protein Bcl-2 in BGC-823 cells,while significantly increasing the expression level of proinflammatory cytokine IL-2 and caspase-3.Then,antioxidant activity was evaluated.The experimental results showed that compounds IV-2a,IV-2g,and IV-2i can induce tumor cell apoptosis by scavenging reactive oxygen species,antioxidant,and promoting DNA damage repair,thereby exerting their inhibitory activity on tumor cells.Finally,the drug sensitivity of compounds IV-2a,IV-2g,and IV-2i to the selenium containing enzyme thioredoxin reductase 1(Trx R1)was studied,and molecular flexible docking experiments were conducted.The binding affinity and the possibility of covalent reactions were analyzed and evaluated.The results indicate that compound IV-2a is the most likely to become a Trx R1 inhibitor,with the highest average binding energy and greater potential for selenium cysteine interaction.In summary,this study designed and synthesized four new types of organic selenium derivatives.Through experimental models,effective compounds with tumor cell inhibitory activity were screened out,and their drug sensitivity was studied.The results were relatively ideal,and the above synthesized and screened new compounds may become potential novel anticancer drugs. |
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