Linkable Lewis X Analogs

Abstract

Disclosed herein is a class of linkable tetrasaccharide compounds that includes the amino phenyl glycoside of sialyl Lewis X (SLe X ) and related analogs. These compounds have conjugatable nucleophilic groups, making them useful in preparing multimeric SLe X compositions. In particular, the disclosed SLe X compounds can be used to prepare selectin binding ligand conjugates by linking them to a reporter moiety, such as a contrast agent, a radiodiagnostic agent, or a cytotoxic or chemotherapeutic agent. The SLe X compounds and conjugates of the invention exhibit binding to selectin that is similar to native Sialyl Le X , and are, therefore, useful for diagnosing and treating selectin-mediated disorders and related conditions.

1 . A compound comprising a sialyl Lewis X analog of formula (I) 
       
         
           
           
               
               
           
         
         wherein 
         Z is hydrogen, C 1 -C 6  acyl, or 
       
       
         
           
           
               
               
           
         
         Y is C(O), SO 2 , HNC(O), OC(O), or SC(O); 
         G 1  and G 2  are each independently C(R 9 ) 2 , NR 10 , O, or S; 
         L is alkylidene, cycloalkylidene, arylidene, or vinylidene; 
         R 2  is hydrogen, C(O)R 8 , SO 2 R 8 , C(S)R 8 , COCH 3 , or  14 COCH 3 ; 
         R4 is hydrogen, C 1 -C 6  alkyl, aryl, arylalkyl, substituted aryl, or substituted arylalkyl; 
         R 3  and R 5  are each independently hydrogen, benzyl, methoxybenzyl, dimethoxybenzyl, or C 1 -C 6  acyl; and 
         R 1 , R 7 , R 8 , R 9 , and R 10  are each independently hydrogen, a C 1 -C 6  alkyl, an aryl, a substituted aryl, or a phenyl C 1 -C 3  alkenyl group, 
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         2 . The compound of  claim 1 , wherein Y is carbonyl, R 1  is hydrogen or methyl, and Z is an α-L-fucosyl having hydroxy groups that are free or blocked with a benzyl or C 1 -C 6  acyl protecting group. 
     
     
         3 . The compound of 1, wherein said analog has the formula 
       
         
           
           
               
               
           
         
         wherein, 
         R is hydrogen, COCH 3  or  14 COCH 3 ; 
         R′ is hydrogen or acyl; and 
         R″ is hydrogen or methyl. 
       
     
     
         4 . The compound of  claim 3 , wherein R is hydrogen, R′ is acyl, and R″ is methyl. 
     
     
         5 . The compound of  claim 3 , wherein R is COCH 3 , and R′ and R″ are hydrogen. 
     
     
         6 . The compound of  claim 3 , wherein R is  14 COCH 3 , and R′ and R″ are hydrogen. 
     
     
         7 - 38 . (canceled) 
     
     
         39 . A pharmaceutical composition comprising the compound of  claim 1 , or a pharmaceutically acceptable salt thereof, dissolved or dispersed in a pharmaceutically acceptable carrier. 
     
     
         40 - 42 . (canceled) 
     
     
         43 . A method for treating or diagnosing a selectin-mediated disorder, said method comprising administering to a patient a cellular adhesion-inhibiting amount of the compound of  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         44 . (canceled) 
     
     
         45 . A method for preparing a selectin binding ligand conjugate comprising attaching the linkable sialyl Lewis X compound of  claim 1  to a reporter moiety. 
     
     
         46 . The method of  claim 45 , wherein said reporter moiety comprises a cytotoxic or therapeutic agent. 
     
     
         47 . The method of  claim 45 , wherein said reporter moiety comprises a diagnostic imaging agent. 
     
     
         48 . (canceled) 
     
     
         49 . A method for preparing a sialyl Lewis X analog, said method comprising the steps of:
 (a) coupling together a glucosaminyl residue, a fucosyl residue, and a galactosyl residue to produce a trisaccharide; and   (b) joining a sialyl residue to said trisaccharide to form a tetrasaccharide.   
     
     
         50 . The method of  claim 49 , wherein said coupling of step (a) comprises the steps of:
 (i) coupling said glucosaminyl residue with said fucosyl residue to produce a disaccharide; and   (ii) coupling said disaccharide with said galactosyl residue to produce said trisaccharide.   
     
     
         51 . A compound prepared by the method of  claim 50 .