Carbohy drate Research, 144 (1985) 305-315 Elsevler Science Publishers B.V.. Amsterdam - Printed in The Netherlands SYNTHESIS AND ANTITUMOR ACTIVITY OF 2’-BROMO- AND 2’- CHLORO-3’-ACETOXY-3’-DEAMINODAUNORUBICIN ANALOGS* zyxwvutsrqponmlkj DEREK HORTON, WALDEMAR PRIEBE. AND OSCAR VARELA Department of Chemistry, The Ohio State University, Columbus, Ohro 43210 (U.S.A.) (Received February 1st. 1985; accepted for publication, April 12th. 1985) ABSTRACT Bromination of 3,4-di-0-acetyl-L-rhamnal (7) and subsequent glycosidic coupling under Koenig+Knorr conditions with daunomycinone gave a mixture of three compounds having the p-L-gluco (lo), cr-L-gluco (ll), and u-L-manno (12) configurations. Analogous bromination of 3,4-di-0-acetyl-L-fucal (13) followed by coupling with daunomycinone gave a mixture of three glycosides having the P-L- galacto (16), a-L-galacto (17), and cy-L-talo (18) configurations. Chlorination of 7 and coupling with daunomycinone in the presence of silver triflate gave products having the cr-L-gluco (21) and cx-L-manno (22) configurations, whereas 13, under similar conditions, gave only one stereoisomeric product, that having the cu-L- galacto (24) configuration. Compounds 12 and 22 showed high in vivo activity in the P-388 lymphocytic leukemia assay. INTRODUCTION The recognized high activity of doxorubicin (1) and daunorubicin (2) against various types of human cancer, tempered by various undesirable side-effects’, has motivated a search for analogs of greater efficacy and decreased cardiotoxicity. In this laboratory, systematic modification of these anthracycline glycosides in the carbohydrate portion has been conducted, together with some variations in the aglycon. Previous publications2,3 described the synthesis of the 3’-deamino-2’-iodo- analog (5) of daunorubicin (2) and of its 4’-epimer 6. The biological properties of 5 and 6 established that a substituent at position 2’ does not inevitably lead to loss of antitumor activity. These analogs were synthesized because of the demonstrated activity of 3’-acetoxyj (3) and 3’-hydroxy5 (4) doxorubicin analogs; the syntheses employed as precursors the glycal diacetates 7 and 13. Biological tests showed that the introduction of an axial iodine atom at C-2’ truns to the glycosidic bond leads316 to enhanced activity, especially in the L-rhamnal-derived compound 6. *Supported, m part, by Grant No. GM-11976 from the National Institute of General Medical Sciences, National Institutes of Health. 000%6215/85/% 03.30 @ 1985 Elsevier Science Publishers B.V.