Aurkb small-molecule inhibitors and uses thereof

Abstract

Disclosed are a small-molecule AURKB inhibitor and applications thereof. The invention is directed to a diindolylmethane compound of formula (I) or a stereoisomer, a tautomer, a solvate, a prodrug, a N-oxide or a pharmaceutically acceptable salt thereof. The invention also provides an application of the small-molecule inhibitor and a modified derivative thereof (such as a stereoisomer, a tautomer, a solvate, a prodrug, an N-oxide or a pharmaceutically acceptable salt) in the preparation of an antitumor drug. The small-molecule AURKB inhibitor identified herein is slightly toxic to those normal cells and can significantly inhibit the expression of a downstream gene E2F2 mediated in the phosphorylation of an AURKB substrate histone H3S10. Therefore, the small-molecule inhibitor, as an anti-tumor drug, can effectively inhibit the proliferation of various tumor cells and induce the apoptosis of tumor cells.

What is claimed is; 
     
         1 . A diindolylmethane compound of formula (I), or a stereoisomer, a tautomer, a solvate, prodrug, an N-oxide or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is CH or a heteroatom selected from N, O, S or N→O; 
         R 2  and R 3  each are independently hydrogen, unsubstituted saturated or unsaturated C 1 ˜C 6  linear alkyl, branched alkyl, alicyclic hydrocarbon, aromatic ring or heteroaromatic ring; saturated or unsaturated C 1 ˜C 6  linear alkykl, branched alkyl, alicyclic hydrocarbon, aromatic ring or heteroaromatic ring substituted by alcohol, amino, nitrogen, sulfur, oxygen, halogen or carbonyl; or halogen, hydroxyl, nitro group, cyano group, amino, trifluoromethyl, trichloromethyl, tribromomethyl or triiodomethyl; 
         each R 4  is independently hydrogen, unsubstitued saturated or unsaturated C 1 ˜C 6  linear alkyl, branched alkyl, alicyclic hydrocarbon, aromatic ring or heteroaromatic ring; or saturated or unsaturated C 1 ˜C 6  linear alkyl, branched alkyl, alicyclic hydrocarbon, aromatic ring or heteroaromatic ring substituted by alcohol, amino, nitrogen, sulfur, oxygen, halogen or carbonyl; or halogen, hydroxyl, nitro group, cyano group, amino, carboxyl, aldehyde group, ester group, triffuoromethyl, trichloromethyl, tibromomethyl, triiodomethyl trimethylsilyl; 
         each R 5  and R 7  are independently hydrogen, unsubstituted saturated or unsaturated C 1 ˜C 6  linear alkyl, branched alkyl, alicyclic hydrocarbon, aromatic ring or heteroaromatic ring; or saturated or unsaturated C 1 ˜C 6  linear alkyl, branched alkyl, alicyclic hydrocarbon, aromatic ring or heteroaromatic ring substituted by alcohol, amino, nitrogen, sulfur, oxygen, halogen or carbonyl; or halogen, hydroxyl, nitro group, cyano group, amino, carboxyl, aldehyde group, ester group, trifluoromethyl, trichloromethyl, tribromomethyl, triiodomethyl, trimethylsilyl, phosphate or sulfate; and 
         R 6  is hydrogen, unsubstituted saturated and unsaturated C 1 ˜C 6  linear alkyl, branched alkyl, alicyclic hydrocarbon, aromatic ring or heteroaromatic ring; saturated and unsaturated C 1 ˜C 6  linear alkyl, branched alkyl, alicyclic hydrocarbon, aromatic ring or heteroaromatic ring substituted by alcohol, amino, nitrogen, sulfur, oxygen, halogen or carbonyl; or halogen, hydroxyl, nitro group, cyano group, amino, carboxyl, aldehyde group, ester group, trifluoromethyl, trichloromethyl, tribromomethyl, triiodomethyl, trimethylsilyl, phosphate or sulfate. 
       
     
     
         2 . A method of preparing the diindolylmethane compound of  claim 1 , or a stereoisomer, a tautomer, a solvate, a prodrug, an N-oxide or a pharmaceutically acceptable salt thereof, comprising:
 reacting compound 1 with compound 2 in the presence of scandium triflate catalyst under nitrogen atmosphere to produce the diindolylmethane compound of formula (I);   wherein the reaction is represented by the following reaction scheme:   
       
         
           
           
               
               
           
         
       
     
     
         3 . A method of treating a disease or symptom caused by AURKB-related abnormal cell growth, function or behavior in a patient, comprising: administering to the patient an effective amount of the diindolylmethane compound of  claim 1 , or a stereoisomer, a tautomer, a solvate, a prodrug, an N-oxide or a pharmaceutically acceptable salt thereof, or a composition comprising the same. 
     
     
         4 . The method of  claim 3 , wherein the disease or symptom comprises: abnormal proliferative disease comprising cancer, immune disease, cardiovascular disease, viral infection, inflammation, metabolic/endocrine disorder comprising diabetes and obesity, and neurologic disease. 
     
     
         5 . The method of  claim 4 , wherein the cancer is any one cancer selected from non-small cell lung cancer, acute and chronic leukemia, liver cancer, gastric cancer, colorectal cancer, ovarian cancer and melanoma. 
     
     
         6 . A pharmaceutical composition for treating a disease or symptom caused by AURKB-related abnormal cell growth, function or behavior, comprising a therapeutically effective amount of the diindolylmethane compound of  claim 1 , or a stereoisomer, a tautomer, a solvate, a prodrug, N-oxide or a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable carrier, auxiliary or excipient. 
     
     
         7 . A method of treating non-small cell lung cancer in a patient, comprising: administering to the patient an effective amount of a diindolylmethane compound of formula (I-a), or a stereoisomer, a tautomer, a solvate, a prodrug, an N-oxide or a pharmaceutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
         Disclosed are a small-molecule AURKB inhibitor and applications thereof. The invention is directed to a diindolylmethane compound of formula (I) or a stereoisomer, a tautomer, a solvate, a prodrug a N-oxide or a pharmaceutically acceptable salt thereof. The invention also provides an application of the small-molecule inhibitor and a modified derivative thereof (such as a stereoisomer, a tautomer, a solvate, a prodrug, an N-oxide or a pharmaceutically acceptable salt) in the preparation of an antitumor drug. The small-molecule AURKB inhibitor identified herein is slightly toxic to those normal cells and can significantly inhibit the expression of a downstream gene E2F2 mediated in the phosphorylation of an AURKB substrate histone H3S10. Therefore, the small-molecule inhibitor, as an anti-tumor drug, can effectively inhibit the proliferation of various tumor cells and induce the apoptosis tumor cells.