Synthesis And Biological Activity Evaluation Of Dehydroepiandrosterone C3 Ester Derivatives And Imidazole Acetophenone Oxime Derivatives

Dehydroepiandrosterone（DHEA）is an important steroid hormone in the steroid series.It is used in weight loss,menopausal problems,depression and prevention of heart disease,breast cancer,anti-neuroinflammation,neuroprotective effects,and metabolic syndrome.All aspects play an important role.Imidazole oxime derivatives have biological activities such as anti-bacterial fungi,selective inhibition of heme oxygenase,anti-epileptic,anti-tuberculosis and anti-tumor.At present,the synthesis of imidazole oxime derivatives and the exploration of their biological activities have always been research hotspots.In the first part of this research,two series of DHEA C3 ester derivatives were synthesized using DHEA as raw materials,and their anti-neuroinflammation and anti-tumor activities were evaluated;In the second part of the work,we designed and synthesized a series of novel acetophenone imidazole oximes with the imidazole acetophenone oxime compounds with the activity of improving the neuroinflammation induced by LPS in vitro,which were selected by the high-throughput screening of the previous compound library of our research group as the lead compounds.And further explored the anti-neuroinflammation activity of such derivatives.The content mainly includes:（1）A series of DHEA derivatives with cinnamate introduced at C3 and a series of C3ester derivatives with C16 benzylidene substitution were synthesized using DHEA as a substrate.The preliminary screening results of anti-tumor activity showed that some compounds showed better anti-tumor activity than the parent compound at a concentration of 50μM.Among them,2d had the highest inhibitory rate on breast cancer cell MCF-7,which was 63%,with an IC₅₀value of 48μM;5c Huh-7 liver cancer cell has the highest inhibition rate,46%,with an IC₅₀value of 55μM.Then,compound 2d was used as the research object to further explore its anti-tumor mechanism and its influence on the cell cycle of MCF-7.When compound 2d treated MCF-7 cells,the number of cells in G0/G1phase decreased with the increase of the concentration of 2d,while the number of cells in S phase increased correspondingly.It is preliminarily indicated that the inhibitory activity of C3 ester derivatives of DHEA on MCF-7 cells is related to cell arrest in S phase.（2）Using catechol as the initial raw material designed and synthesized a series of novel（Z）-1-（2,2-dimethylbenzo[d][1,3]dioxol-5-yl）-2-（1H-imidazol-1-yl）-1-ethanone imidazole oxime derivatives,anti-neuroinflammation activity results show that most of the compounds exhibit excellent nitric oxide（NO）inhibitory activity,with IC₅₀values ranging from 0.54 to 9.30μM,of which 7a,7q,and 7r perform the most significantly,the IC₅₀values were 0.54μM,0.87μM,and 0.70μM,respectively.In order to avoid affecting the test results of NO due to the killing effect of the test compound on BV-2 cells,we also carried out a cytotoxicity test experiment on the test compound（final concentration of 20μM）,and found that all compounds had no obvious cells toxic effect.In summary,the first part of the work has screened out potential anti-tumor compounds through the synthesis of dehydroepiandrosterone C3 ester derivatives and evaluation of anti-tumor activity,which provides a further step valid reference for the development of new anti-tumor steroid drugs;In the second part of the work,through the synthesis of imidazole acetophenone oxime derivatives and the evaluation of anti-neuroinflammation activity,it was discovered for the first time that these compounds have good anti-neuroinflammation activity,which will provide a new ideas and basis for the design and development of new anti-neuroinflammation drugs,even provide more possibilities for the treatment of Alzheimer’s disease.