Jasmonate derivatives and compositions thereof

Abstract

The disclosure describes jasmonate conjugates and nanocarried and/or microcarried jasmonate conjugates and pharmaceutical compositions thereof, as well as use thereof for treating or preventing angiogenesis-related or NF-κB-related disorders. Also disclosed are methods of making the conjugates.

1 . A conjugate 
       
         
           
           
               
               
           
         
       
       in which M 1  is a jasmonate compound or a derivative thereof, M 2  is a compound different from M 1  and is covalently attached to M 1  and 
       
         
           
           
               
               
           
         
       
       between M 1  and M 2  denotes or indirect attachment of M 2  to M 1 . 
     
     
         2 . The conjugate of  claim 1 , wherein the jasmonate compound is selected from the group consisting of jasmonic acid, 7-iso -j asmonic acid, 9,10-dihydrojasmonic acid, 9,10-dihydro-isojasmonic acid, 2,3-didehydrojasmonic acid, 3,4-didehydrojasmonic acid, 3,7-didehydrojasmonic acid, 4,5-didehydrojasmonic acid, 4,5-didehydro-7-isojasmonic acid, cucurbic acid, 6-epi-cucurbic acid, 6-epi-cucurbic acid-lactone, 12-hydroxy-jasmonic acid, 12-hydroxy-jasmonic acid-lactone, 11-hydroxy-jasmonic acid, 8-hydroxy-jasmonic acid, homo-jasmonic acid, dihomo-jasmonic acid, 11-hydroxy-dihomo-jasmonic acid, 8-hydroxy-dihomo-jasmonic acid, tuberonic acid, tuberonic acid-O-β-glucopyranoside, cucurbic acid-O-β-glucopyranoside, 5,6-didehydro-jasmonic acid, 6,7-didehydro-jasmonic acid, 7,8-didehydro-jasmonic acid, cis-jasmone, dihydrojasmone, and a lower alkyl ester thereof. 
     
     
         3 . The conjugate of  claim 1 , wherein M 2  is selected from resveratrol, a gambogic acid, perillyl alcohol, curcumin, a flavonoid, 10-hydroxydecenoic acid, acetogenin, phosphatidylethanolamine, a chemical component of propolis, a chemical component of Emu oil, a chemical component of Emu oil, a chemical component or an extract of bitter gourd ( Momordica charantia ), Coenzyme Q10, a chemical component of Argan oil, a chemical component or an extract of  Euphorbia tirucalli , and derivatives thereof. 
     
     
         4 . The conjugate of  claim 1 , wherein the conjugate is of Formula (I): 
       
         
           
           
               
               
           
         
       
       wherein
 n is 1, 2, 3, or 4; 
 X is O or S; 
 Y is O, NH, or OC(O); 
 each occurrence of Z independently is CH or N; 
 R 1  is H, alkyl, alkenyl, or alkynyl; 
 each occurrence of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12  independently is H, NH 2 , NHCOR 13 , —N═CHR 14 , —N═CH-R 13 , —NHCH 2 R 15 , —NHCH 2 R 13 , —NHSO 2 R 15 , —NHCONHR 15 , —N═CHR 16 , —COOR 16 , —CONR 16 R 16 , —CONR 16 R 15 , —CN, —COCH 2 Cl, —CONHNH 2 , R 17 , R 16 , —OR 16 , —SR 16 , —NO 2 , —COR 16 , —NO, —N 3 , —OCN, —NCS, —COOR 16 , —COCN, —NR 16 R 16 , —SOR 16 , —SO 2 R 16 , —SO 3 R 16 , —CH 2 OR 16 , 
 
       
         
           
           
               
               
           
         
       
       alternatively, when valence permits, any two neighboring R 11  or neighboring R 11  and R 12 , together with the two carbon atoms to which they attach, form a carbon-carbon double bond or a cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl, or heteroaryl group;
 R 13  is R 14 , R 16 , —CH 2 OR 15 , —CH═CHR 15 , —CH 2 CHR 15 COR 16 , —C 2 H 4 OR 15 , —C 3 H 6 OR 15 , —C 2 H 4 SCOR 16 , —CH 2 SCOR 16 , —COOR 16 , —CH 2 S—R 18 , —CH 2 —R 18 , —CH═CH—R 18 , in which R 18  is cycloalkyl, 5- or 6-membered heteroaryl, or 5- to 12-memebered heterocycloalkyl and R 18  is optionally substituted with one or more of —COOR 16 , R 16  and R 17 ; 
 R 14  is phenyl optionally substituted with one or more R 16 ; 
 R 15  is phenyl optionally substituted with one or more substituents selected from R 13  and R 16 ; 
 R 16  is H, alkyl optionally substituted with halo or hydroxyl, alkenyl, phenyl, or —CH 2 R 14 ; and 
 R 17  is halo. 
 
     
     
         5 . The conjugate of  claim 4 , wherein the conjugate is of Formula (Ia) or (Ib): 
       
         
           
           
               
               
           
         
       
     
     
         6 . A composition comprising a carrier and the conjugate of  claim 1 . 
     
     
         7 . The composition of  claim 6 , being a pharmaceutical composition and the carrier is a pharmaceutically acceptable carrier. 
     
     
         8 . The composition of  claim 6 , being a cosmetic composition and the carrier is a cosmetically acceptable carrier. 
     
     
         9 . A method of treating an angiogenesis-related disorder, comprising administering an effective amount of a conjugate of  claim 1  in a subject in need thereof. 
     
     
         10 . The method of  claim 9 , wherein the angiogenesis-related disorder is cancer. 
     
     
         11 . The method of  claim 10 , wherein the cancer is leukemia, colon cancer, breast cancer, prostate cancer, pancreas cancer, liver cancer, skin cancer, ovary cancer, melanoma, or a sarcoma. 
     
     
         12 . The method of  claim 9 , wherein the angiogenesis-related disorder is an inflammatory disease. 
     
     
         13 . The method of  claim 12 , wherein the inflammatory disease is inflammatory bowel disease. 
     
     
         14 . A method of treating an NF-κB-related disorder, comprising administering an effective amount of a conjugate of  claim 1  in a subject in need thereof. 
     
     
         15 . The method of  claim 14 , wherein the NF-κB-related disorder is a viral, bacterial, or fungal infection.