Polyamines useful as anti-parasitic and anti-cancer therapeutics and as lysine-specific demethylase inhibitors

Abstract

Polyamine, polyamine/guanidino, and polyamine/biguanide compounds are disclosed. The compounds are useful as anti-cancer and anti-parasitic treatments. The compounds are also useful as inhibitors of the enzyme lysine-specific demethylase-1.

1 . A compound having a formula selected from the group consisting of:  
     
       
         
         
             
             
         
       
     
     wherein: 
 n is an integer from 1 to 12;  
 m and p are independently an integer from 1 to 5;  
 q is 0 or 1;  
 each R 1  is independently selected from the group consisting of C 1 -C 8  substituted or unsubstituted alkyl, C 6 -C 20  substituted or unsubstituted aryl or heteroaryl and C 7 -C 24  substituted or unsubstituted aralkyl or heteroaralkyl;  
 each R 2  is independently selected from hydrogen or a C 1 -C 8  substituted or unsubstituted alkyl;  
 R 3  and R 4  are independently selected from the group consisting of hydrogen, C 1 -C 8  substituted or unsubstituted alkyl, C 6 -C 20  substituted or unsubstituted aryl and C 7 -C 24  substituted or unsubstituted aralkyl;  
 R 5 , R 9 , R 6 , R 7  and R 8  are independently selected from the group consisting of hydrogen and C 1 -C 8  substituted or unsubstituted alkyl;  
 A, R 10  and R 11  are independently (CH 2 ) 1-5  or ethene-1,1-diyl;  
 R 12  and R 13  are independently selected from the group consisting of hydrogen, C 2 -C 8  substituted or unsubstituted alkenyl and C 1 -C 8  substituted or unsubstituted alkyl;  
 R 15  and R 14  are independently selected from the group consisting of hydrogen, C 1 -C 8  substituted or unsubstituted n-alkyl or (C 3 -C 8 ) branched alkyl, C 6 -C 20  substituted or unsubstituted aryl or heteroaryl and C 7 -C 24  substituted or unsubstituted aralkyl or heteroaralkyl;  
 R 16  and R 17  are independently hydrogen or a C 1 -C 8  substituted or unsubstituted alkyl;  
 R 18  and R 19  are independently selected from the group consisting of: hydrogen, C 1 -C 8  unsubstituted alkyl, C 1 -C 8  n-alkyl substituted with a cycloalkyl group comprising at least two rings, C 7 -C 24  substituted or unsubstituted aralkyl or heteroaralkyl comprising at least two rings;  
 R 20  and R 21  are independently selected from the group consisting of hydrogen, C 1 -C 8  substituted or unsubstituted alkyl, and C 7 -C 24  substituted or unsubstituted aralkyl;  
 X of formula (VIII) is —(CH 2 ) 1-5 — or cyclohex-1,3-diyl;  
 R 22  and R 23  are independently selected from the group consisting of hydrogen, n-butyl, ethyl, cyclohexylmethyl, cyclopentylmethyl, cyclopropylmethyl, cycloheptylmethyl, cyclohexyleth-2-yl and benzyl;  
 R 24  is an amino-substituted cycloalkyl or a C 2 -C 8  substituted or unsubstituted alkanoyl; R 25    
 is a C 1 -C 8  substituted or unsubstituted alkyl or a C 7 -C 24  substituted or unsubstituted aralkyl.  
 
   
   
       2 . The compound of  claim 1 , wherein the compound is of the formula (I):  
     
       
         
         
             
             
         
       
     
     or a salt, solvate, or hydrate thereof, wherein: 
 n is an integer from 1 to 12;  
 m and p are independently an integer from 1 to 5;  
 q is 0 or 1;  
 each R 1  is independently selected from the group consisting of;  
 C 1 -C 8  substituted or unsubstituted alkyl, C 4 -C 15  substituted or unsubstituted cycloalkyl, C 3 -C 15  substituted or unsubstituted branched alkyl, C 6 -C 20  substituted or unsubstituted aryl, C 6 -C 20  substituted or unsubstituted heteroaryl, C 7 -C 24  substituted or unsubstituted aralkyl, and C 7 -C 24  substituted or unsubstituted heteroaralkyl and,  
 each R 2  is independently selected from hydrogen or a C 1 -C 8  substituted or unsubstituted alkyl.  
 
   
   
       3 . The compound of  claim 1 , wherein the compound is of the formula (II):  
     
       
         
         
             
             
         
       
     
     or a salt, solvate, or hydrate thereof, wherein: 
 n is an integer from 1 to 12;  
 m and p are independently an integer from 1 to 5;  
 q is 0 or 1;  
 each R 1  is independently selected from the group consisting of C 1 -C 8  substituted or unsubstituted alkyl, C 6 -C 20  substituted or unsubstituted aryl and C 7 -C 24  substituted or unsubstituted aralkyl; and  
 each R 2  is independently hydrogen or a C 1 -C 8  substituted or unsubstituted alkyl.  
 
   
   
       4 . The compound of  claim 1 , wherein the compound is of the formula (III):  
     
       
         
         
             
             
         
       
     
     or a salt, solvate, or hydrate thereof, wherein: 
 n is an integer from 1 to 12;  
 m and p are independently an integer from 1 to 5;  
 R 3  and R 4  are independently selected from the group consisting of hydrogen, C 1 -C 8  substituted or unsubstituted alkyl, C 6 -C 20  substituted or unsubstituted aryl and C 7 -C 24  substituted or unsubstituted aralkyl;  
 R 5 , R 9 , R 6 , R 7  and R 8  are independently selected from the group consisting of hydrogen and C 1 -C 8  substituted or unsubstituted alkyl; and wherein  
 either:  
 m and p are not the same integer, or  
 at least one of R 5 , R 9 , R 6 , R 7  and R 8  is a C 1 -C 8  substituted or unsubstituted alkyl.  
 
   
   
       5 . The compound of  claim 1 , wherein the compound is of the formula (IV):  
     
       
         
         
             
             
         
       
     
     or a salt, solvate, or hydrate thereof, wherein: 
 A, R 10  and R 11  are independently (CH 2 ) n  or ethene-1,1-diyl;  
 n is an integer from 1 to 5;  
 R 12  and R 13  are independently selected from the group consisting of hydrogen, C 2 -C 8  substituted or unsubstituted alkenyl and C 1 -C 8  substituted or unsubstituted alkyl; and  
 at least one of A, R 10 , R 11 , R 12  and R 13  comprises an alkenyl moiety.  
 
   
   
       6 . The compound of  claim 1 , wherein the compound is of the formula (V):  
     
       
         
         
             
             
         
       
     
     or a salt, solvate, or hydrate thereof, wherein: 
 n is an integer from 1 to 8;  
 m is an integer from 1 to 8;  
 R 15  and R 14  are independently selected from the group consisting of hydrogen, C 1 -C 8  substituted or unsubstituted n-alkyl, C 3 -C 8  substituted or unsubstituted branched alkyl, C 6 -C 20  substituted or unsubstituted aryl or heteroaryl and C 7 -C 24  substituted or unsubstituted aralkyl or heteroaralkyl;  
 R 16  and R 17  are independently hydrogen or a C 1 -C 8  substituted or unsubstituted alkyl; and  
 wherein:  
 the compound contains no more than three secondary amino groups except when R 17  is a C 1 -C 8  substituted or unsubstituted alkyl; and  
 the compound is free from a methylphosphonate or hydroxy moiety.  
 
   
   
       7 . The compound of  claim 1 , wherein the compound is of the formula (VI):  
     
       
         
         
             
             
         
       
     
     or a salt, solvate, or hydrate thereof, wherein: 
 n is an integer from 1 to 12;  
 m and p are independently an integer from 1 to 5;  
 R 18  and R 19  are independently selected from the group consisting of:  
 hydrogen,  
 C 1 -C 8  unsubstituted alkyl,  
 C 1 -C 8  n-alkyl substituted with a cycloalkyl group comprising at least two rings,  
 C 7 -C 24  substituted or unsubstituted aralkyl or heteroaralkyl comprising at least two rings; and  
 wherein:  
 n is 1 when R 18  and R 19  are identical C 1 -C 8  n-alkyl moities substituted with a cycloalkyl group comprising at least two rings, or are identical aryl moieties comprising at least two rings; and  
 at least one of R 18  and R 19  is either a C 1 -C 8  n-alkyl substituted with a cycloalkyl group comprising at least two rings or a C 7 -C 24  substituted or unsubstituted aralkyl comprising at least two rings.  
 
   
   
       8 . The compound of  claim 1 , wherein the compound is of the formula (VII):  
     
       
         
         
             
             
         
       
     
     or a salt, solvate, or hydrate thereof, wherein: 
 n is an integer from 1 to 12;  
 m and p are independently an integer from 1 to 5;  
 q is 0 or 1;  
 R 20  and R 21  are independently selected from the group consisting of hydrogen, C 1 -C 8  substituted or unsubstituted alkyl, —C(═O)—C 1 -C 8  substituted or unsubstituted alkyl, —C(═O)—C 1 -C 8  substituted or unsubstituted alkenyl, —C(═O)—C 1 -C 8  substituted or unsubstituted alkynyl, and C 7 -C 24  substituted or unsubstituted aralkyl; and  
 wherein the compound comprises at least one moiety selected from the group consisting of t-butyl, isopropyl, 2-ethylbutyl, 1-methylpropyl, 1-methylbutyl, 3-butenyl, isopent-2-enyl, 2-methylpropan-3-olyl, ethylthiyl, phenylthiyl, propynoyl, 1-methyl-1H-pyrrole-2-yl, trifluoromethyl, cyclopropanecarbaldehyde (cyclopropylcarbonyl), halo-substituted phenyl, nitro-substituted phenyl, alkyl-substituted phenyl, 2,4,6-trimethylbenzyl, halo-S-substituted phenyl, para-(F 3 S)-phenyl, azido and 2-methylbutyl.  
 
   
   
       9 . The compound of  claim 1 , wherein the compound is of the formula (VIII):  
     
       
         
         
             
             
         
       
     
     or a salt, solvate, or hydrate thereof, wherein: 
 m and p are independently an integer from 1 to 5;  
 X is —(CH 2 )n- or cyclohex-1,3-diyl;  
 n is an integer from 1 to 5;  
 R 22  and R 23  are independently selected from the group consisting of hydrogen, n-butyl, ethyl, cyclohexylmethyl, cyclopentylmethyl, cyclopropylmethyl, cycloheptylmethyl, cyclohexyleth-2-yl, benzyl; and  
 wherein:  
 when n is 5, at least one of R 22  and R 23  is hydrogen;  
 when R 22  is ethyl, R 23  is selected from the group consisting of hydrogen, n-butyl, ethyl, cyclopentylmethyl, cyclohexyleth-2-yl and benzyl;  
 when R 23  is ethyl, R 22  is selected from the group consisting of hydrogen, n-butyl, ethyl, cyclopentylmethyl, cyclohexyleth-2-yl and benzyl; and  
 when X is cyclohex-1,3-diyl, R 22  and R 23  are not identical benzyl or cyclopropylmethyl moieties.  
 
   
   
       10 . The compound of  claim 1 , wherein the compound is of the formula (IX):  
     
       
         
         
             
             
         
       
     
     or a salt, solvate, or hydrate thereof, wherein: 
 p is an integer from 1 to 5;  
 R 24  is an amino-substituted C 3 -C 15  cycloalkyl or a C 2 -C 8  substituted or unsubstituted alkanoyl; and  
 R 25  is a C 1 -C 8  substituted or unsubstituted alkyl or a C 7 -C 24  substituted or unsubstituted aralkyl.  
 
   
   
       11 . The compound of  claim 1 , wherein the compound is a compound listed in Table A.  
   
   
       12 . A pharmaceutical composition comprising the compound of  claim 1  and a pharmaceutically acceptable carrier.  
   
   
       13 . A kit comprising the compound and instructions for use as an anticancer or antiparasitic agent.  
   
   
       14 . A method of inhibiting a histone demethylase, comprising administering an amount of a polyamine, polyaminoguanidine, or polyaminobiguanide compound sufficient to inhibit the histone demethylase by at least about 50%.  
   
   
       15 . The method of  claim 14 , comprising administering an amount of a polyaminoguanidine or polyaminobiguanide compound sufficient to inhibit the histone demethylase by at least about 50%.  
   
   
       16 . A method of treating cancer, comprising administering a compound of  claim 1  in a therapeutically effective amount.  
   
   
       17 . A method of treating unregulated cell growth, comprising administering a compound of  claim 1  in a therapeutically effective amount.  
   
   
       18 . A method of treating a parasitic infection, comprising administering a compound of  claim 1  in a therapeutically effective amount.  
   
   
       19 . A method of inhibiting a histone demethylase enzyme, by contacting the enzyme with one or more of the compounds of  claim 1  in an amount sufficient to inhibit the enzyme.  
   
   
       20 . The method of  claim 19 , wherein the compound contains at least one guanidine moiety or at least one biguanide moiety.  
   
   
       21 . The method of  claim 19 , wherein the enzyme is lysine-specific demethylase-1.