Moenomycin analogs, methods of synthesis, and uses thereof

Abstract

The present invention provides novel moenomycin analogs as well as pharmaceutical compositions thereof, methods of synthesis, and methods of use in treating an infection by administering an inventive compound to a subject in need thereof. The moenomycin analogs may be prepared synthetically, biosynthetically, or semi-synthetically. The analogs are particularly useful in treating or preventing infections caused by Gram-positive organisms. Certain inventive compounds may have a broader spectrum of coverage, which includes Gram-negative organisms.

1 - 113 . (canceled) 
     
     
         114 . A method of synthesizing moenomycin or a derivative thereof, the method comprising hydrolyzing the phosphate linkage connecting the carbohydrate group of moenomycin or a derivative thereof to the lipid sidechain. 
     
     
         115 . The method of  claim 114  further comprising replacing the original carbohydrate group of moenomycin or a derivative thereof with a new carbohydrate group. 
     
     
         116 . The method of  claim 114  further comprising replacing the original lipid sidechain of moenomycin or a derivative thereof with a new sidechain. 
     
     
         117 . The method of  claim 115 , wherein the new carbohydrate group is a dissacharide, a trisaccharide, a tetrasaccharide, or a pentasaccharide. 
     
     
         118 . The method of  claim 114  further comprising O-alkylating the linker group. 
     
     
         119 . The method of  claim 114  further comprising protecting any free hydroxyl groups with a hydroxyl protecting group. 
     
     
         120 . The method of  claim 114  further comprising removing any hydroxyl protecting groups. 
     
     
         121 . A method of synthesizing moenomycin or a derivative thereof, the method comprising isolating a first intermediate from a cell culture, and synthetically modifying the first intermediate to provide a second intermediate. 
     
     
         122 . The method of  claim 121  further comprising purifying the first intermediate. 
     
     
         123 . The method of  claim 122  further comprising contacting the second intermediate with a second cell culture to obtain a third intermediate. 
     
     
         124 . The method of  claim 122  further comprising contacting the second intermediate with one or more enzymes selected from the group consisting of moeA4, moeB4, moeC4, moeB5, moeA5, moeD5, moeJ5, moeE5, moeF5, moeH5, moeK5, moeM5, moeN5, moeO5, moeX5, moeP5, moeR5, moeS5, moeGT1, moeGT2, moeGT3, moeGT4, and moeGT5. 
     
     
         125 . The method of  claim 121 , wherein the step of synthetically modifying the first intermediate comprises removing a carbohydrate moiety. 
     
     
         126 . The method of  claim 121 , wherein the step of synthetically modifying the first intermediate comprises replacing a carbohydrate moiety with a different carbohydrate moiety. 
     
     
         127 . The method of  claim 121 , wherein the step of synthetically modifying the first intermediate comprises removing the lipid side chain. 
     
     
         128 . The method of  claim 121 , wherein the step of synthetically modifying the first intermediate comprises replacing the lipid side chain with a new sidechain. 
     
     
         129 . The method of  claim 128 , wherein the new side chain is an optionally substituted C 1-30  aliphatic moiety, wherein 0 to 10 methylene units are optionally replaced with —O—, —NR x —, —S—, —C(═O)—, —C(═NR x )—, —S(═O)—, —S(═O) 2 —, —N═N—, —C═N—, —C(R y )═C(R y )—, —N—O—, an optionally substituted arylene, or an optionally substituted heteroarylene moiety, wherein each instance of R x  is, independently, H, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, or an amino protecting group; and each instance of R y  is, independently, H, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, or optionally substituted heteroaryl. 
     
     
         130 . The method of  claim 121 , wherein the cell culture is a bacterial cell culture. 
     
     
         131 . The method of  claim 130 , wherein the bacterial cell culture is a  Streptomyces  species. 
     
     
         132 . The method according to  claim 131 , wherein the  Streptomyces  species is  Streptomyces ghanaensis  or  Streptomyces lividans.    
     
     
         133 . A method of synthesizing moenomycin or a derivative thereof comprising exchanging the lipid side chain of Moenomycin A, Moenomycin A 1.2 , Moenomycin C 1 , Moenomycin C 3 , Moenomycin C 4 , AC326-alpha, or Pholipomycin with a different side chain R 9 , wherein R 9  is optionally substituted C 1-30  aliphatic moiety, wherein 0 to 10 methylene units are optionally replaced with —O—, —NR x —, —S—, —C(═O)—, —C(═NR x )—, —S(═O)—, —S(═O) 2 —, —N═N—, —C═N—, —C(R y )═C(R y )—, —N—O—, an optionally substituted arylene, or an optionally substituted heteroarylene moiety, wherein each instance of R x  is, independently, H, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, or an amino protecting group; and each instance of R y  is, independently, H, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, or optionally substituted heteroaryl.