Synthesis of 20-O-linked 20(S)-camptothecin glycoconjugates: Impact of theside chain of the ester-linked amino acid on epimerization during the acylation reaction and on hydrolytic stability of the final glycoconjugates

To improve solubility and tumor selectivity of 20(S)-camptothecin the synth esis 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 steric ally hindered and deactivated tertiary 20-hydroxy group of 20(S)-camptothec in 1. Depending on the solvent and on the side chain of the amino acid diff erent extents of epimerization of the amino acids during the coupling react ion are observed: however. the epimers can easily be separated after remova l of the tert-butoxycarbonyl protecting group and camptothecin amino acid c onjugates 4B-E with L- and D- configured amino acids, respectively, are obt ained. Particularly, bulky and beta -branched amino acids can be attached t o camptothecin in high yields and with low epimerization. Starting from the camptothecin amino acid conjugates 4B-E the synthesis of the glycoconjugat es 11A-G is straightforward following standard procedures. The glycoconjuga te 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 a mino acid residue linked to camptothecin. Particularly, glycoconjugates 11B -E with a bulky and beta -branched amino acid at the ester linkage show hig h hydrolytic stability in aqueous solutions with less than 2.5% of 20(S)-ca mptothecin cleaved within 24 h. These results provide a basis for the selec tion of appropriate spacer groups for delivery systems of 20(S)-camptotheci n for therapeutic use.