Carbohydrate derivatives of the antitumour alkaloid 9-hydroxyellipticine

Annaleise R. Grummitt, Margaret M. Harding, Pia I. Anderberg, Alison Rodger

Research output: Contribution to journalArticlepeer-review

17 Citations (Scopus)

Abstract

The synthesis of L-arabinosyl derivatives of 2-naphthol and the quatemised ellipticines Celiptium (2) and Ellipravin (3) is reported. Naphth-2-yl 2′,3′,4′-tri-O-acetyl-α-L-arabinopyranoside was prepared under Königs-Knorr and Mitsunobu conditions in nonpolar aprotic solvents and using 2,3,4-tri-O-acetyl-L-arabinopyranosyl fiuoride fluoride as the glycosyl donor. These conditions were not applicable to the corresponding glycosidation reactions with the quatemised ellipticines 2 and 3 which are soluble only in polar solvents. Formation of the 9-(α-L-arabinopyranosyl)ellipticine derivatives 13 and 14 was achieved by using 2,3,4-tri-O-acetyl-L-arabinopyranosyl bromide in the presence of sodium methoxide in methanol. Improved yields were obtained under the same conditions by incorporation of an ether linker between the sugar and ellipticine to give derivatives 15 and 16. The glycolate esters 17 and 18, which were prepared using 2-(2′,3′,4′-tri-O-acetyl-α-L-arabinopyranosyl) glycolic acid, undergo hydrolysis suggesting that these compounds could function as prodrugs in vivo. Linear dichroism studies of the interaction of Celiptium (2) and the stable L-arabinosyl ellipticine derivatives 3, 15 and 16 with calf thymus DNA are consistent with intercalation of the ellipticine chromophore, positioning the sugars at the 2- and 9-positions in the major and minor grooves of DNA.

Original languageEnglish
Pages (from-to)63-71
Number of pages9
JournalEuropean Journal of Organic Chemistry
Issue number1
Publication statusPublished - Jan 2003
Externally publishedYes

Keywords

  • Antitumour agents
  • DNA
  • Drug design
  • Glycosides
  • Heterocycles

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