Design,synthesis And Study Of Anti-tumor Activity Of Novel Androgen Receptor Antagonist

Androgen receptor(AR)is closely related to the initiation and progression of prostate cancer(PCa),and is believed to be a crucial target for anti-PCa drug research.AR antagonists can inhibit tumor growth by affecting androgen-AR signaling pathways.However,the abnormal AR aberrations can lead to secondary resistance to first and second generation AR antagonists.The third generation AR antagonist darolutamide(ODM-201)has strong antagonistic activities against different AR mutants,but has a short half-life,leading to high-dose clinical administration.Therefore,ODM-201 is used as our lead compound with the expectation to obtain new AR antagonists with stronger activity and higher metabolic stability.Using isosteres,increasing isopropylamine side chain substituent steric hindrance,and replacing hydrophobic ring,we designed and synthesized 3 series of 16 compounds(2-1a-2-1f,2-2a-2-2f,2-3a-2-3d),and 15 compounds were tested in vitro for anti-tumor activity.The AR antagonistic activity test showed that 2-1b,2-1c,2-1f and 2-3c(IC50=0.13 μM;0.08 μM;0.12 μM;0.16 μM)had equal or better activities compared to control(IC50=0.1 1 μM).The potential structure-activity relationship can be summarized as:(1)Introducing cyclopropyl into the chiral center of isopropylamine,the antagonistic activity can be maintained.In the molecular docking model,a large unoccupied space around the side chain is also observed,indicating that this site can accommodate substituents of appropriate sizes;(2)The pyrazole ring on the left has a greater influence on the conformation of the series of compounds,and is an essential part for activity;(3)Different amide bond isosteres can maintain or increase the activity of the compounds,but the hydrogen bond donor-NH needs to be retained.And the activity of the compound with reversed amide bond is the strongest;(4)The five-membered lactone benzene ring doesn’t have an advantage in this series of derivatives,which can lead to the loss of important interaction between the compound and the binding pocket;and the activity of the aromatic ring fragment with a liner side chain is better than that of the five-membered lactone benzene ring fragments,among which acetylpyrazole ring fragments have the best activityIn the cell antiproliferation test,all 3 compounds showed that they were equivalent to or better than the control,among them,the activity of 2-1f is 2 times higher than the control(2-1f:IC50=2.51 μM;ODM-201:IC50=5.72 μM),which can be used as a lead compound for next-generation AR antagonists for further research.Furthermore,CYP17 is an important catalytic enzyme in androgen biosynthesis,and has been studied as a non-negligible target for the development of anti-PCa drugs as well,With enzalutamide as the lead compound,a series of nitrogen-containing heterocycles were designed on the right benzene ring substituent expected to coordinate with the heme iron atom in the enzyme activity pocket to exert inhibitory activity.Developing a new type of AR antagonist with both AR antagonistic activity and CYP17 enzyme inhibitory activity is the main purpose of the research.A total of 9 thiohydantoin compunds(3-1-3-9)were designed and synthesized.The exploration of in vitro activity will be carried out.