Carbohydrate Derivatives of the Antitumour Alkaloid 9-Hydroxyellipticine

Abstract

The synthesis of L-arabinosyl derivatives of 2-naphthol and the quaternised ellipticines Celiptium (2) and Ellipravin (3) is reported. Naphth-2-yl 2′,3′,4′-tri-O-acetyl-α-L-arabinopyranoside was prepared under Konigs−Knorr and Mitsunobu conditions in nonpolar aprotic solvents and using 2,3,4-tri-O-acetyl-L-arabinopyranosyl fluoride as the glycosyl donor. These conditions were not applicable to the corresponding glycosidation reactions with the quaternised 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 pro-drugs 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. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)