Novel germ cell ablation compounds and uses thereof

Abstract

Provided herein are methods of sterilizing fish by contacting an embryonic or juvenile fish with a compound of formula (I). In some embodiments, the compound is primordazine or a derivative thereof.

What is claimed is: 
     
         1 . A compound of Formula (I): 
       
         
           
           
               
               
           
         
         wherein 
         each R 1 , R 2 , and R 3  is independently hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; —C(═O)R B ; —CO 2 R B ; —; —CN; —SCN; —SR B ; —SOR B ; —SO 2 R B ; —NO 2 ; —N(R B ) 2 ; —NHC(O)R B ; or —C(R B ) 3 ; wherein each occurrence of R B  is independently hydrogen; halogen; a protecting group; aliphatic; heteroaliphatic; acyl; aryl moiety; heteroaryl; hydroxyl; aloxy; aryloxy; alkylthioxy; arylthioxy; amino; alkylamino; dialkylamino; heteroaryloxy; heteroarylthioxy; or alkylhalo; 
         each R is independently halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; —C(═O)R B ; —CO 2 R B ; —; —CN; —SCN; —SR B ; —SOR B ; —SO 2 R B ; —NO 2;  —N(R B ) 2 ; —NHC(O)R B ; or —C(R B ) 3 ; wherein each occurrence of R B  is independently hydrogen; halogen; a protecting group; aliphatic; heteroaliphatic; acyl; aryl moiety; heteroaryl; hydroxyl; aloxy; aryloxy; alkylthioxy; arylthioxy; amino; alkylamino; dialkylamino; heteroaryloxy; heteroarylthioxy; or alkylhalo.; and 
         n is an integer 0 to 4 inclusive, 
         with the provisos that: 
         (i) when n is 0, R 1  is ethyl and R 2  is ethyl, then R 3  is not 5-methylisoxazol-3-yl; 
         (ii) when n is 0, R 1  is ethyl and R 2  is ethyl, then R 3  is not 1-phenylethyl; 
         (iii) when n is 0, R 1  is ethyl and R 2  is ethyl, then R 3  is not 4-(N-hydroxynitrosyl)phenyl; 
         (iv) when n is 0, R 1  is ethyl and R 2  is H, then R 3  is not 4-(N,N-dimethylcarbamoyl)phenyl; 
         (v) when n is 0, R 1  is ethyl and R 2  is H, then R 3  is not 4-carbamoylphenyl; and 
         (vi) when n is 0, R 1  is propyl and R 2  is H, then R 3  is not 1-phenylethyl. 
       
     
     
         2 . The compound of  claim 1 , wherein
 n is 0;   R 1  is hydrogen or a substituted or unsubstituted, branched or unbranched C 1 -C 8  alkyl, or R 1  is a linker to a solid support;   R 2  is hydrogen or a substituted or unsubstituted, branched or unbranched C 1 -C 8  alkyl; and   R 3  is hydrogen, a substituted or unsubstituted aryl, or a substituted or unsubstituted alkylheteroaryl.   
     
     
         3 . The compound of  claim 1 , wherein R1 is C1-C4 alkyl. 
     
     
         4 . The compound of  claim 3 , wherein R1 is methyl, ethyl, propyl or n-butyl. 
     
     
         5 . The compound of  claim 1 , wherein R 2  is hydrogen or C 1 -C 4  alkyl. 
     
     
         6 . The compound of  claim 5 , wherein R 2  is hydrogen or ethyl. 
     
     
         7 . The compound of  claim 1 , wherein R3 is an unsubstituted phenyl or a substituted phenyl. 
     
     
         8 . The compound of  claim 7 , wherein R3 is a phenyl substituted with acetyl or a halogen. 
     
     
         9 . The compound of  claim 1 , wherein R3 is furanylmethyl. 
     
     
         10 . The compound of  claim 1 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         11 . A fish embryo, wherein translation of an mRNA comprising a primordazine response element (PRE) is reduced after treatment with a compound of formula (I), as compared to untreated fish, wherein compound of Formula (I) is: 
       
         
           
           
               
               
           
         
         wherein 
         each R 1 , R 2 , and R 3  is independently hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; —C(═O)R B ; —CO 2 R B ; —; —CN; —SCN; —SR B ; —SOR B ; -SO 2 R B ; —NO 2 ; —N(R B ) 2 ; —NHC(O)R B ; or —C(R B ) 3 ; wherein each occurrence of R B  is independently hydrogen; halogen; a protecting group; aliphatic; heteroaliphatic; acyl; aryl moiety; heteroaryl; hydroxyl; aloxy; aryloxy; alkylthioxy; arylthioxy; amino; alkylamino; dialkylamino; heteroaryloxy; heteroarylthioxy; or alkylhalo; 
         each R is independently halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; —C(═O)R B ; —CO 2 R B ; —; —CN; —SCN; —SR B ; —SOR B ; —SO 2 R B ; —NO 2 ; —N(R B ) 2 ; —NHC(O)R B ; or —C(R B ) 3 ; wherein each occurrence of R B  is independently hydrogen; halogen; a protecting group; aliphatic; heteroaliphatic; acyl; aryl moiety; heteroaryl; hydroxyl; aloxy; aryloxy; alkylthioxy; arylthioxy; amino; alkylamino; dialkylamino; heteroaryloxy; heteroarylthioxy; or alkylhalo; and 
         n is an integer 0 to 4 inclusive, 
         with the provisos that: 
         (i) when n is 0, R 1  is ethyl and R 2  is ethyl, then R 3  is not 5-methylisoxazol-3-yl; 
         (ii) when n is 0, R 1  is ethyl and R 2  is ethyl, then R 3  is not 1-phenylethyl; 
         (iii) when n is 0, R 1  is ethyl and R 2  is ethyl, then R 3  is not 4-(N-hydroxynitrosyl)phenyl; 
         (iv) when n is 0, R 1  is ethyl and R 2  is H, then R 3  is not 4-(N,N-dimethylcarbamoyl)phenyl; 
         (v) when n is 0, R 1  is ethyl and R 2  is H, then R 3  is not 4-carbamoylphenyl; and 
         (vi) when n is 0, R 1  is propyl and R 2  is H, then R 3  is not 1-phenylethyl. 
       
     
     
         12 . The fish embryo of  claim 11 , wherein the mRNA is nanos1 or deadend. 
     
     
         13 . A fish germ cell, wherein nanos1 mRNA is localized to discrete puncta.