Saframycins, analogues and uses thereof

Abstract

In recognition of the need to develop novel therapeutic agents and efficient methods for the synthesis thereof, the present invention provides novel compounds of general formula (I), and methods for the synthesis thereof. In another aspect, the present invention provides pharmaceutical compositions comprising a compound of formula (I) and a pharmaceutically acceptable carrier. In yet another aspect, the present invention provides methods for treating cancer comprising administering a therapeutically effective amount of a compound of formula (I) to a subject in need thereof.

1 - 75 . (canceled)  
   
   
       76 . A method for the synthesis of a compound having the formula (I):  
     
       
         
         
             
             
         
       
       wherein R 1  is NR A R B , —OR A , —SR A , —C(═O)R A , —C(═S)R A , —S(O) 2 R A , or an aliphatic, heteroaliphatic, aryl, heteroaryl, (aliphatic)aryl, (aliphatic)heteroaryl, (heteroaliphatic)aryl, or (heteroaliphatic)heteroaryl moiety, wherein each occurrence of R A  and R B  is independently hydrogen, —(C═O)R C , —NHR C , —(SO 2 )R C , —OR C , or an aliphatic, heteroaliphatic, aryl, or heteroaryl moiety, or R A  and R B , when taken together form an aryl, heteroaryl, cycloaliphatic, or cycloheteroaliphatic moiety, wherein each occurrence of R C  is independently hydrogen, —OR D , —SR D , —NHR D , —(C═O)R D , or an aliphatic, heteroaliphatic, aryl, or heteroaryl moiety, wherein each occurrence of R D  is independently hydrogen, a protecting group, or an aliphatic, heteroaliphatic, aryl, heteroaryl, acyl, alkoxy, aryloxy, alkylthio, arylthio, heteroaryloxy, or heteroarylthio moiety;  
       wherein R 2  is hydrogen, —OR E , ═O, —C(═O)R E , —CO 2 R E , —CN, —SCN, halogen, —SR E , —SOR E , —SO 2 R E , —NO 2 , —N(R E ) 2 , —NHC(O)R E , or an aliphatic, heteroaliphatic, aryl, or heteroaryl moiety, wherein each occurrence of R E  is independently hydrogen, a protecting group, or an aliphatic, heteroaliphatic, aryl, heteroaryl, acyl, alkoxy, aryloxy, alkylthio, arylthio, heteroaryloxy, or heteroarylthio moiety;  
       wherein R 3  is hydrogen, a nitrogen protecting group, —COOR F , —COR F , —CN, or an aliphatic, heteroaliphatic, aryl, or heteroaryl moiety, wherein each occurrence of R F  is independently hydrogen, a protecting group, or an aliphatic, heteroaliphatic, aryl, heteroaryl, alkoxy, aryloxy, alkylthio, arylthio, heteroaryloxy, or heteroarylthio moiety;  
       wherein R 4  and R 6  are each independently hydrogen, or an aliphatic, heteroaliphatic, aryl, heteroaryl, acyl, alkoxy, aryloxy, alkylthio, arylthio, heteroaryloxy, or heteroarylthio moiety;  
       wherein R 5  and R 7  are each independently hydrogen, —OR G , —C(═O)R G , —CO 2 R G , —CN, —SCN, halogen, —SR G , —SOR G , —SO 2 R G , —NO 2 , —N(R G ) 2 , —NHC(O)R G , or an aliphatic, heteroaliphatic, aryl or heteroaryl moiety, wherein each occurrence of R G  is independently hydrogen, a protecting group, or an aliphatic, heteroaliphatic, aryl, heteroaryl, acyl, alkoxy, aryloxy, alkylthio, arylthio, heteroaryloxy, or heteroarylthio moiety;  
       wherein R 8  is hydrogen, alkyl, —OH, protected hydroxyl, ═O, —CN, —SCN, halogen, —SH, protected thio, alkoxy, thioalkyl, amino, protected amino, or alkylamino;  
       wherein m is 0-5;  
       wherein X 1 , X 2 , X 3  and X 4  are each independently hydrogen, —OR H , ═O, —C(═O)R H , —CO 2 R H , —CN, —SCN, halogen, —SR H , —SOR H , —SO 2 R H , —NO 2 , —N(R H ) 2 , —NHC(O)R H , or an aliphatic, heteroaliphatic, aryl, or heteroaryl moiety, wherein each occurrence of R H  is independently hydrogen, a protecting group, or an aliphatic, heteroaliphatic, aryl, heteroaryl, acyl, alkoxy, aryloxy, alkylthio, arylthio, heteroaryloxy, or heteroarylthio moiety;  
       or wherein X 1  and R 7  taken together comprise a heterocyclic moiety;  
       whereby if at least either X 1  and X 2  or X 3  and X 4  are doubly bonded to the 6-membered ring, then the dotted bonds in either or both of the 6-membered rings represent two single bonds and one double bond, and a quinone moiety is generated, or if at least either X 1  and X 2  or X 3  and X 4  are singly bonded to the 6-membered ring, then the dotted bonds in either or both of the 6-membered rings represent two double bonds and one single bond, and a hydroquinone moiety is generated;  
       whereby each of the foregoing aliphatic, heteroaliphatic and alkyl moieties may independently be substituted or unsubstituted, branched or unbranched, or cyclic or acyclic, and each of the foregoing aryl or heteroaryl moieties may independently be substituted or unsubstituted; wherein said method comprises:  
       (a) providing a compound of formula (XV)  
       
         
           
           
               
               
           
         
       
       (b) reacting said compound of formula (XV) under suitable conditions to generate a compound of formula (I):  
       
         
           
           
               
               
           
         
       
       wherein X 1 -X 4 , R 1 -R 8 , and m are as described above, and  
       wherein the step of providing a compound of formula (XV) further comprises: 
 (1) reacting a first N-protected and a second C-protected α-amino aldehyde precursor having the structures:  
                     
 under suitable conditions to generate a tetrahydroisoquinoline core having the structure (IX):  
                     
 (2) optionally reacting said tetrahydroisoquinoline core under suitable conditions to diversify R 3 ;  
 (3) reacting a third aldehyde precursor having the structure: R 9 (CH 2 ) m CHO, with said tetrahydroisoquinoline core structure (XIV) under suitable conditions to generate a trimer of aldehydes having the structure:  
                     
 (4) reacting said trimer of aldehydes under suitable conditions to generate a compound of structure (XV),  
 
       wherein P 1  is hydrogen or a nitrogen protecting group;  
       X 5  and X 6  taken together represent a carbon protecting group, optionally substituted with a solid support unit; and  
       R 9  is NR L R M , —OR L , —SR L , —C(═O)R L , —C(═S)R L , —S(O) 2 R L , or an aliphatic, heteroaliphatic, aryl, heteroaryl, (aliphatic)aryl, (aliphatic)heteroaryl, (heteroaliphatic)aryl, or (heteroaliphatic)heteroaryl moiety, wherein each occurrence of R L  and R M  is independently hydrogen, —(C═O)R N , —NHR N , —(SO 2 )R N , —OR N , or an aliphatic, heteroaliphatic, aryl, or heteroaryl moiety, or R L  and R M , when taken together form an aryl, heteroaryl, cycloaliphatic, or cycloheteroaliphatic moiety, wherein each occurrence of R N  is independently hydrogen, —OR P , —SR P , —NHR P , —(C═O)R P , or an aliphatic, heteroaliphatic, aryl, or heteroaryl moiety, wherein each occurrence of R P  is independently hydrogen, a protecting group, or an aliphatic, heteroaliphatic, aryl, heteroaryl, acyl, alkoxy, aryloxy, alkylthio, arylthio, heteroaryloxy, or heteroarylthio moiety.  
     
   
   
       77 . The method of  claim 76 , wherein for the intermediates (XIV) and (XV) R 9  is —NHP 2 , P 2  is a nitrogen protecting group, and the intermediates have the structures (XIVa) and (XVa):  
     
       
         
         
             
             
         
       
     
   
   
       78 . The method of  claim 76 , wherein R 9 (CH 2 ) m CHO is (aliphatic)(C═O)(CH 2 ) m CHO, (heteroaliphatic)(C═O) (CH 2 ) m CHO, (aliphatic)(CH 2 ) m CHO, (heteroaliphatic)(CH 2 ) m CHO, aryl(aliphatic)(CH 2 ) m CHO, aryl(heteroaliphatic)(CH 2 ) m CHO, -heteroaryl(aliphatic)(CH 2 ) m CHO, or heteroaryl(heteroaliphatic)(CH 2 ) m CHO, wherein each of the aliphatic, and heteroaliphatic moieties is independently cyclic or acyclic, linear or branched, or substituted or unsubstituted and wherein the aryl and heteroaryl moieties are independently substituted or unsubstituted.  
   
   
       79 . The method of  claim 76 , wherein R 9 (CH 2 ) m CHO is CH 3 (CH 2 ) 1-6 CHO; (protecting group)O(CH 2 ) 1-6 CHO; (protecting group)NH(CH 2 ) 1-6 CHO; (protecting group)S(CH 2 ) 1-6 CHO; (alkyl)O(C═O)CHO; (aryl)(alkenyl)CHO; (heteroaryl)(alkenyl)CHO; (aryl)CHO; or (heteroaryl)CHO, wherein each of the aliphatic, and heteroaliphatic moieties is independently cyclic or acyclic, linear or branched, or substituted or unsubstituted and wherein the aryl and heteroaryl moieties are independently substituted or unsubstituted.  
   
   
       80 . The method of  claim 76 , wherein X 5  is CN and X 6  is a heterocyclic moiety optionally substituted with a solid support unit.  
   
   
       81 . The method of  claim 76 , wherein the alkaloid structure (I) generated is that of saframycin A.  
   
   
       82 . The method of  claim 76 , wherein the method is stereoselective and the alkaloid structure (I) generated is that of −(−) saframycin A.  
   
   
       83 . The method of  claim 76 , wherein the compound of formula (I) has the structure of formula (Ia):  
     
       
         
         
             
             
         
       
     
   
   
       84 . The method of  claim 76 , wherein the compound of formula (I) has the structure of formula (II):  
     
       
         
         
             
             
         
       
     
   
   
       85 . The method of  claim 76 , wherein the compound of formula (I) has the structure of formula (III):  
     
       
         
         
             
             
         
       
     
   
   
       86 . The method of  claim 76 , wherein the compound of formula (I) has the structure of formula (IV):  
     
       
         
         
             
             
         
       
     
   
   
       87 . The method of  claim 76 , wherein the compound of formula (I) has the structure of formula (V):  
     
       
         
         
             
             
         
       
     
   
   
       88 . The method of  claim 76 , wherein the compound of formula (I) has the structure of formula (VI):  
     
       
         
         
             
             
         
       
     
   
   
       89 . The method of  claim 76 , wherein the compound of formula (I) has the structure of formula (VII):  
     
       
         
         
             
             
         
       
     
   
   
       90 . The method of  claim 76 , wherein the compound of formula (I) has the structure of formula (VIII):  
     
       
         
         
             
             
         
       
     
   
   
       91 . The method of  claim 76 , wherein the compound of formula (I) has the structure of formula (IX):  
     
       
         
         
             
             
         
       
       wherein R 1  is a substituted or unsubstituted, cyclic or acyclic, branched or unbranched aliphatic or heteroaliphatic moiety, or is a substituted or unsubstituted aryl or heteroaryl moiety.  
     
   
   
       92 . The method of  claim 76 , wherein the compound of formula (I) has the structure of formula (X):  
     
       
         
         
             
             
         
       
       wherein R 1  is a substituted or unsubstituted, cyclic or acyclic, branched or unbranched aliphatic or heteroaliphatic moiety, or is a substituted or unsubstituted aryl or heteroaryl moiety.  
     
   
   
       93 . The method of  claim 76 , wherein the compound of formula (I) has one or more of the following limitations: 
 when m is 1, R 1  excludes any one or more of the following groups: —NH(protecting group), —NH 2 , —NHCOCOMe, —NHCOC(Me)(OMe)(OMe), —NHCOCH(NH 2 )CH 3 , —NHCOCH(NH(acyl))CH 3 —NHCOCH(NH 2 )Ac, or NHCOCH(NHCOOBn)(Me); —O(C═O)C(CH 3 )═C(CH 3 )H; —OH, —O(protecting group), —O(COCH 3 ), —O(C═O)CH 2 CH 3 ; or    when m is 1; when X 1 , X 2 , X 3  and X 4  are each ═O; when R 2  is —CN or —OH; when R 4  and R 6  are each —CH 3 ; when R 5  and R 7  are each —OCH 3 ; when R 8  is H; and R 1  is —NH(C═O)R C , then R C  is not —CH(NR W R Y )(CH 2 R Z ) where R W  and R Y  are each independently hydrogen or C 1-7  alkyl, aryl(C 1-4 )alkyl, (C 1-4 )alkylaryl, a substituted sulfonyl (—S(O) 2 —) group, or a substituted acyl group, and where R Z  is hydrogen or C 1-4  alkyl; or    when m is 1; when X 1 , X 2 , X 3  and X 4  are each ═O; when R 2  is —CN; when R 4  and R 6  are each —CH 3 ; when R 5  and R 7  are each —OCH 3 ; when R 8  is H; and R 1  is —NH(C═O)R C , then R C  is not —C(OH)(Me)CH 2 (C═O)Me; or    when m is 1 and when R 2  is H; and R 1  is —NH(C═O)R C , then R C  is not —CH(Me)NH(C═O)O(CH 2 )Ph; or    when m is 0; R 2  is H; X 3  is H; and R 1  is —C(═O)R A , then R A  is not —O(alkyl); or    when R 2  is H; m is 1; and R 1  is —OR A , then R A  is not —C(═O)R C , or S(O) 2 R C , wherein R C  is an alkyl moiety.    
   
   
       94 . The method of  claim 76 , wherein m is 0 or 1.  
   
   
       95 . The method of  claim 76 , wherein wherein R 2  is CN, —SCN, ═O, OH, protected hydroxyl, H, or alkoxy.  
   
   
       96 . The method of  claim 76 , wherein R 2  is hydrogen, hydroxyl, —CN or —SCN.  
   
   
       97 . The method of  claim 76 , wherein R 8  is hydrogen.  
   
   
       98 . The method of  claim 76 , wherein X 1 , X 2 , X 3 , and X 4  are each independently alkoxy, OH, protected hydroxyl, or ═O.  
   
   
       99 . The method of  claim 76 , wherein R 2  is CN, —SCN, ═O, OH, protected hydroxyl, H, or alkoxy; R 3  is hydrogen, a nitrogen protecting group, —CN, aliphatic, or aryl; R 4  and R 6  are each alkyl; R 5  and R 7  are each alkyloxy or thioalkyl; R 8  is hydrogen, alkyl, —OH, protected hydroxyl, ═O, CN, halogen, SH, alkoxy, thioalkyl, amino, or alkylamino; and X 1 , X 2 , X 3 , and X 4  are each independently alkoxy, OH or ═O.  
   
   
       100 . The method of  claim 76 , wherein R 2  is —CN, —SCN, —OH, protected hydroxyl, H, or alkoxy; R 3  is hydrogen, a nitrogen protecting group, aliphatic, or aryl; R 4  and R 6  are each alkyl; R 5  and R 7  are each alkyloxy or thioalkyl; X 1  and X 4  are each —OH; R 8  is hydrogen, alkyl, OH, protected hydroxyl, ═O, CN, halogen, SH, alkoxy, thioalkyl, amino, or alkylamino; and X 2  and X 3  are each alkyloxy or thioalkyl.  
   
   
       101 . The method of  claim 76 , wherein X 1  is OH, X 2  is OCH 3 , X 3  is OCH 3 , X 4  is OH, R 2  is CN, H or OH, R 3  is Me, R 4  is CH 3 , R 5  is OCH 3 , R 6  is CH 3 , R 7  is OCH 3 , and R 8  is H.  
   
   
       102 . The method of  claim 76 , wherein R 1  is OR A , SR A , or NR A R B , wherein R A  and R B  are each independently hydrogen, —(C═O)R C  or an aliphatic, heteroaliphatic, aryl, or heteroaryl moiety, wherein R C  is —(C═O)R D , or an aliphatic, heteroaliphatic, aryl or heteroaryl moiety, and wherein R D  is an aliphatic, heteroaliphatic, aryl, or heteroaryl moiety, or wherein R A  and R B , taken together, form a heterocyclic moiety, whereby each of said aliphatic and heteroaliphatic moieties is independently substituted or unsubstituted, branched or unbranched, or cyclic or acyclic, and each of said aryl, heteroaryl and heterocyclic moieties is independently substituted or unsubstituted.  
   
   
       103 . The method of  claim 76 , wherein R 1  is OR A , SR A , or NR A R B , wherein R A  and R B  are each independently hydrogen, —(C═O)R C , or an aryl, (aliphatic)aryl, (heteroaliphatic)aryl, heteroaryl, (aliphatic)heteroaryl, or (heteroaliphatic)heteroaryl moiety, wherein R C  is an aryl, (aliphatic)aryl, (heteroaliphatic)aryl, heteroaryl, (aliphatic)heteroaryl, or (heteroaliphatic)heteroaryl moiety, or wherein R A  and R B  taken together form a heterocyclic moiety, whereby each of said aliphatic and heteroaliphatic moieties is independently substituted or unsubstituted, branched or unbranched, or cyclic or acyclic, and each of said aryl, heteroaryl and heterocyclic moieties is independently substituted or unsubstituted.  
   
   
       104 . The method of  claim 76 , wherein R 1  is —NR A C(═O)R C , wherein R A  is hydrogen or lower alkyl, and R C  is a substituted or unsubstituted, branched or unbranched, cyclic or acyclic aliphatic or heteroaliphatic moiety, or a substituted or unsubstituted aryl or heteroaryl moiety, or wherein R A  and R C  taken together form a heterocyclic or heteroaryl moiety.  
   
   
       105 . The method of  claim 76 , wherein R 1  is NR A C(═O)R C , wherein R A  is hydrogen or lower alkyl, and R C  is an aryl, (aliphatic)aryl, (aliphatic)heteroaryl, heteroaryl, (heteroaliphatic)aryl, or (heteroaliphatic)heteroaryl moiety, or wherein R A  and R C  taken together form a heterocyclic or heteroaryl moiety; whereby each of said aliphatic and heteroaliphatic moieties is independently substituted or unsubstituted, branched or unbranched, or cyclic or acyclic, and each of said aryl, heteroaryl and heterocyclic moieties is independently substituted or unsubstituted.  
   
   
       106 . The method of  claim 76 , wherein R 1  is a substituted or unsubstituted, branched or unbranched, cyclic or acyclic aliphatic or heteroaliphatic moiety, or a substituted or unsubstituted aryl or heteroaryl moiety.  
   
   
       107 . The method of  claim 76 , wherein R 1  is an aryl, (aliphatic)aryl, (aliphatic)heteroaryl, heteroaryl, (heteroaliphatic)aryl, or (heteroaliphatic)heteroaryl moiety; whereby each of said aliphatic and heteroaliphatic moieties is independently substituted or unsubstituted, branched or unbranched, or cyclic or acyclic, and each of said aryl, heteroaryl and heterocyclic moieties is independently substituted or unsubstituted;  
   
   
       108 . The method of  claim 76 , wherein any one or more of R 1 , R A , R B , R C , or R D  is independently any one of the following groups:  
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       wherein each occurrence of R J  is independently hydrogen, a protecting group, —OR K , ═O, —C(═O)R K , —CO 2 R K , —CN, —SCN, halogen, —SR K , —SOR K , —SO 2 R K , —NO 2 , —N(R K ) 2 , —NHC(O)R K , —B(OR K ) 2 , or an aliphatic, heteroaliphatic, aryl, or heteroaryl moiety, wherein each occurrence of R K  is independently hydrogen, or an aliphatic, heteroaliphatic, aryl, or heteroaryl moiety, or wherein two occurrences of R K , taken together form a cyclic aliphatic or heteroaliphatic moiety; wherein each occurrence of Y is independently O, S or NH; wherein each occurrence of x is independently 0-5; and wherein each occurrence of n is independently 0-3, or wherein R J  is a labeling reagent, whereby each of said aliphatic and heteroaliphatic moieties are independently substituted or unsubstituted, branched or unbranched or cyclic or acyclic, and each of said aryl and heteroaryl moieties is independently substituted or unsubstituted.  
     
   
   
       109 . The method of  claim 108 , wherein R 1  is NR A R B , R A  is hydrogen, R B  is —(C═O)R C , and R C  is iii, iv, vii, viii, ix, x, xv, or xvii, or R A  and R C  taken together form the structure of i or ii.  
   
   
       110 . The method of  claim 108 , wherein R 1  is NR A R B  and R A  is hydrogen, R B  is —(C═O)R C , and R C  is  
     
       
         
         
             
             
         
       
     
   
   
       111 . The method of  claim 108 ,  109 , or  110 , wherein R J  is hydrogen, halogen, —OH, lower alkyl or lower alkoxy.  
   
   
       112 . The method of  claim 108 ,  109 , or  110 , wherein R J  is a linker-biotin or a linker-fluorescein moiety.  
   
   
       113 . The method of  claim 108 ,  109 , or  110 , wherein x is 1 or 2.  
   
   
       114 . The method of  claim 76 , wherein the compound of formula (I) has the structure of any one of the formulae: