Haloacetamido Analogues of 2-Amino-2-deoxy-D-glucose and 2-Amino-2-deoxy-D-galactose. Syntheses and Effects on the Friend Murine Erythroleukemia

Thomas P. Fondy, Susan B. Roberts, Asterios S. Tsiftsoglou, Alan C. Sartorelli

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

2-Deoxy-2-(haloacetamido)-D-glucose and 2-deoxy-2-(haloacetamido)-D-galactose (fluoro, chloro and bromo) were prepared by de-O-acetylation of the appropriate l,3,4,6-tetra-O-acetyl-2-deoxy-2-(haloacetamido)-β-D-hexose with triethylamine. The l,3,4,6-tetra-O-acetyl-2-deoxy-2-(chloroacetamido)- and l,3,4,6-tetra-O-acetyl-2-deoxy-2-(bromoacetamido)-β-D-hexoses were produced by condensation of a haloacetyl anhydride with 1,3,4,6-tetra-O-acetyl-2-amino-2-deoxy-β-D-hexose hydrochloride in pyridine. The hydrochlorides were converted to free bases for condensation with fluoroacetic acid in the presence of dicyclohexylcarbodiimide to produce 1,3,4,6-tetra-O-acetyl-2-deoxy-2-(fluoroacetamido)-β-D-hexoses. The chloroacetamido and bromoacetamido derivatives were from 3-to 12-fold more toxic on a molar basis to BDF1 mice when administered as lipophilic tetra-O-acetates than as the free sugars; no significant difference existed between the glucose and galactose forms. The fluoroacetamido analogue of the glucose series was fivefold more toxic than the comparable fluoroacetamido derivative of the galactose series; no difference existed in the toxicities of the free sugars and the tetra-O-acetates with either of the fluo-roacetamide-containing hexoses. Cytotoxicity against log-phase cultured Friend erythroleukemia cells was greatest with the tetra-O-acetylated bromoacetamido derivatives in both the gluco and galacto series, these agents being three- to fourfold more cytotoxic than tetra-O-acetylated chloroacetamido derivatives and 20-fold more cytotoxic than tetra-O-acetylated fluoroacetamido sugars. The N-chloroacetamido derivative in the glucose series was 50-fold more cytotoxic as the tetra-O-acetate than as the free nonacetylated sugar. These results support the concept that tetra-O-acetylated derivatives of the chloroacetamido and bromoacetamido carbohydrate analogues function as lipophilic alkylating agents and lose biological activity when converted to hydrophilic free hydroxyl forms, whereas the fluoroacetamido derivatives exert their effects as the de-O-acetvlated form.

Original languageEnglish (US)
Pages (from-to)1222-1225
Number of pages4
JournalJournal of Medicinal Chemistry
Volume21
Issue number12
DOIs
StatePublished - Jan 1 1978

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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