Design,Synthesis And Antitumor Activity Evaluation Of Novel Steroidal Heterocycles

As the most popular fields of drug discovery,steroids have been paid more and more attention by many chemists due to their unique structure and multiple access points,and expanding the variety of steroid structure and biological activity has become the most priority among priorities.Steroid structural transformation is not limited to the intrinsic activity of hormonal,and the antibacterial,antitumor effect and more potential have been found.Steroidal heterocyclic compounds is hotspot of steroidal chemical modification,and introducing heterocyclic structure into the steroid skeleton structure can make steroidal compound abundant,increase its structure of novelty,complexity and diversity,endow with fresh biological activity,and lay the foundation for the research and development of steroid drugs.In this paper,we designed,synthesized three series of steroid based heterocyclic derivative,and evaluated the antitumor activity and antibacterial activity,which mainly included the following aspects:(1)By one pot four component method,steroidal spiroindole cyclohexadiene derivativesⅡ-8a-m have been synthesized efficiently.Compound Ⅱ-8a and Ⅱ-8b have good antibacterial activity against Staphylococcus aureus G+ and MRSA,and the best is MIC50 = 2 μM;Compounds also have inhibitory effect on PC-3,good Hela and EC-109 cells,especially Ⅱ-8a and Ⅱ-8b showed strong effect on the activity,which is 4 times of 5-FU toward PC-3 and is up to 8 times toward Hela,and all the compounds synthesized showed excellent selectivity between cancer and normal cells(GES-1).Moreover,compound Ⅱ-8a can promote the mitochondrial membrane potential of PC-3 cells and induce the apoptosis of PC-3 cells in a concentration dependent manner,especially in the early apoptotic cells.(2)An efficient and practical acid-promoted cascade reaction has been developed to access steroidal pyrimidine derivatives Ⅱ-14a-r from aromatic aldehydes,urea and compound Ⅱ-11 achieved through transesterification of DHEA and ethyl acetoacetate.Inhibitory effect ofcompounds Ⅱ-14a-r on lung cancer A549 is the best,the degree of Ⅱ-14 k can reach 3 times more than 5-FU(IC50 = 4.0 μM,5-FU IC50 = 12.0 μM),and Ⅱ-14 l is also 2 times,other methyl,isopropyl isobutyl phenyl,alkyl substituted pyrimidine derivatives also showed excellent inhibitory activity.(3)α,β–unsaturated ketone structure was synthesized from Claisen-Schmidt condensation of aromatic aldehydes with DHEA.Assembly of steroidal spirothiophene derivatives Ⅱ-19a-f with the formation of a C-C key,a C-S key and an all carbon quaternary carbon chiral center in one step was described.All the compounds have strong inhibitory activity on EC-109,PC-3,Hela and F10B16,especially PC-3 and Hela,in which compound Ⅱ-19 a is better than inhibition effect of 5-FU(IC50 = 1.8 μM,5-FU IC50 = 15.4 μM);Compound Ⅱ-19 a can significantly induce apoptosis of PC-3 cells in a concentration dependent manner,especially in the late stage of apoptosis.Further mitochondrial studies showed that compound Ⅱ-19 a could also decrease the mitochondrial membrane potential of PC-3 cells with increasing concentration.