Linkable Lewis X Analogs
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 .