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

Abstract

To improve solubility and tumor selectivity of 20(S)-camptothecin the synthesis of 20-O-linked glycoconjugates 11A—G is described. Particular focus of the paper is the utilization of N-tert-butoxycarbonyl protected amino acid N-carboxy anhydrides (UNCAs) 2a—f for an efficient acylation of the sterically hindered and deactivated tertiary 20-hydroxy group of 20(S)-camptothecin 1. Depending on the solvent and on the side chain of the amino acid different extents of epimerization of the amino acids during the coupling reaction are observed; however, the epimers can easily be separated after removal of the tert-butoxycarbonyl protecting group and camptothecin amino acid conjugates 4B—E with L- and D- configured amino acids, respectively, are obtained. Particularly, bulky and β-branched amino acids can be attached to camptothecin in high yields and with low epimerization. Starting from the camptothecin amino acid conjugates 4B—E the synthesis of the glycoconjugates 11A—G is straightforward following standard procedures. The glycoconjugate hydrochlorides 11A—G show good water solubility (> 5mg- ml) and hydrolytic stability of the ester bond which again depends on the side chain of the amino acid residue linked to camptothecin. Particularly, glycoconjugates 11B—E with a bulky and β-branched amino acid at the ester linkage show high hydrolytic stability in aqueous solutions with less than 2.5% of 20(S)-camptothecin cleaved within 24 h. These results provide a basis for the selection of appropriate spacer groups for delivery systems of 20(S)-camptothecin for therapeutic use.