Lectin-Mediated Drug Targeting: Discrimination of Carbohydrate-Mediated Cellular Uptake between Tumor and Liver Cells with Neoglycoconjugates Carrying Fucose Epitopes Regioselectively Modified in the 3-Position

Abstract

The circumvention of efficient "carbohydrate traps" in the liver is required for targeting glycoconjugates on tumor cells. As shown in the model system of bovine serum albumin (BSA) conjugates, the nature of R(1)-R(3) of the fucose epitope plays an important role in the discrimination of cellular uptake between tumor and liver cells as well as in the cytotoxic activity.

Synthesis of 20-O-linked 20(S)-Camptothecin Glycoconjugates: Impact of the Side Chain of the Ester-linked Amino Acid on Epimerization During the Acylation Reaction and on Hydrolytic Stability of the Final Glycoconjugates

“…In previous studies we have optimized modified fucoside residues for preferential receptor-mediated uptake into tumor cells using neoglycoconjugates of bovine serum albumine [12]. Here, we describe the attachment of these optimized fucoside derivatives to the 20-hydroxy group of the camptothecin molecule via ester linked dipeptide spacers.…”

“…The assignment of the D-and L-configuration to the polar and non polar epimers in the leucine series is based on an X-ray structure of the acetylated product derived from the polar 4E(D) fraction indicating the D-configuration of leucine [14]. Unexpectedly, when Boc-D-Leu-NCA is employed in the coupling reaction, also no configurative stability is observed (table 1, entry 11,12).…”

“…Subsequent removal of the tert-butoxycarbonyl-protecting groups give the peptide conjugates 7A -G ready for linkage to the carbohydrate moiety (table 2). The synthesis of p-aminophenyl 3-O-methyl-β-L-fucopyranoside has been described previously [12]. After transformation into the isothiocyanate 8 with thiophosgene the carbohydrate building block is linked to the appropriately protected peptide conjugates of camptothecin 7A -G. Subsequent removal of the fluorenyl-9-methoxycarbonyl protecting group with piperidine, work up and treatment of the compounds 10A -G with 1 equivalent of an aqueous hydrochloride solution gives the glycoconjugates 11A -G. The hydrochlorides 11A -G show good water solubility (> 5mg/ml) and hydrolytic stability of the ester bond which depends on the side chain of the amino acid residue linked to camptothecin (table 2) …”

“…The yields for each particular conjugate are listed in table 2. (8) 0.069 mol of p-aminophenyl 3-O-methyl-β-L-fucopyranoside [12] are dissolved in 1.8 ltr. dioxane/water 1:1 (v/v).…”

Phase I and pharmacokinetic study of Bay 38-3441, a camptothecin glycoconjugate, administered as a 30-minute infusion daily for five days every 3 weeks in patients with advanced solid malignancies

“…The peptide-carbohydrate portion of the molecule stabilizes the lactone ring and allows selective uptake of this compound into lysosomal compartments of tumor cells by an active transport mechanism [17,18]. Camptothecin is then split from the peptide-carbohydrate intracellularly, permitting camptothecin binding to the DNA-topoisomerase I complex.…”