Synthesis of multivalent beta-lactosyl clusters as potential tumor metastasis inhibitors.
A beta-lactosyl residue was linked to the amino groups of L-lysyl-L-lysine through spacer arms of three different lengths (C2, C4, and C9) to give trivalent beta-lactosyl clusters in order to increase the inhibitory activity of the beta-lactosyl group against tumor cell colonization. Thus, O-(2,3,4,6-tetra-O-acetyl-beta-D-galactopyranosyl)-(1-->4)-2,3, 6-tri-O-acetyl-glucopyranosyl trichloroacetimidate was treated with methyl or benzyl hydroxyethanoate, methyl or benzyl 4-hydroxybutanoate, and methyl 9-hydroxynonanoate, respectively, in the presence of trimethylsilyl trifluoromethanesulfonate to give the corresponding beta-lactosides. These were coupled to L-lysyl-L-lysine, after conversion to the N-hydroxysuccinimide esters, to yield the corresponding trivalent beta-lactosyl-L-lysyl-L-lysine conjugates in good yields. The beta-lactosyl group with a C4 spacer arm was also coupled similarly to poly(L-lysine) (M(r) 3800) to form a polyvalent beta-lactosyl cluster. Coinjection of the trivalent (with C2 and C4 spacer arms) and polyvalent beta-lactosyl clusters with the highly metastatic B16 murine melanoma cells inhibited the formation of lung colonies in C57/BL mice, whereas the trivalent cluster with a C9 spacer arm displayed no activity.
Dean
B
B
Biomembrane Institute and University of Washington, Seattle 98119.
Oguchi
H
H
Cai
S
S
Otsuji
E
E
Tashiro
K
K
Hakomori
S
S
Toyokuni
T
T
D000818:Animals; D016588:Anticarcinogenic Agents / Q000138:chemical synthesis* / Q000627:therapeutic use; D002236:Carbohydrate Conformation; D002240:Carbohydrate Sequence; D004151:Dipeptides; D015195:Drug Design; D005260:Female; D006027:Glycosides / Q000138:chemical synthesis* / Q000627:therapeutic use; D007202:Indicators and Reagents; D008175:Lung Neoplasms / Q000517:prevention & control* / Q000556:secondary*; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009362:Neoplasm Metastasis
D016588:Anticarcinogenic Agents; D004151:Dipeptides; D006027:Glycosides; D007202:Indicators and Reagents; C008245:lactosides; C024575:lysyllysine