Synthesis, structure, and biological activity of ferrocenyl carbohydrate conjugates

Seven ferrocenyl carbohydrate conjugates were synthesized. Coupling reactions of monosaccharide derivatives with ferrocene carbonyl chloride produced {6-N-(methyl 2,3,4-tri-O-acetyl-6-amino-6-deoxy-R-D-glucopyranoside)}1- ferrocene carboxamide (3), {1-O-(2,3,4,6-tetra-O-benzyl-D-glucopyranose)}-1-ferrocene carboxylate (4), and {6O- (1,2,3,4-tetra-O-acetyl-beta-D-glucopyranose)}-1-ferrocene carboxylate (5). Similarly, 1,1’-bis(carbonyl chloride)ferrocene was coupled with the appropriate sugars to produce the disubstituted analogues bis {6-N-(methyl 2,3,4-tri- O-acetyl-6-amino-6-deoxy-R-D-glucopyranoside)}- 1,1’-ferrocene carboxamide (8), bis {1-O-(2,3,4,6-tetra-O-benzyl-D- glucopyranose)}- 1,1’-ferrocene carboxylate (9), and bis {6-O-(1,2,3,4-tetra-O-acetyl-beta-D-glucopyranose)}- 1,1’-ferrocene carboxylate (10). {6-N-(Methyl-6-amino-6-deoxy-R-D-glucopyranoside)}-1-ferrocene carboxamide monohydrate (12) was synthesized via amide coupling of an activated ferrocenyl ester with the corresponding carbohydrate. All compounds were characterized by elemental analysis, H-1 NMR spectroscopy, and mass spectrometry. X-ray crystallography confirmed the solid-state structure of three ferrocenyl carbohydrate conjugates: 2-N-(1,3,4,6-tetra-O- acetyl-2-amino-2-deoxy-D-glucopyranose)-1-ferrocene carboxamide (1), 1-S-(2,3,4,6-tetra-O-acetyl-1-deoxy-1-thio-D- glucopyranose)-1-ferrocene carboxylate (2), and 12. The above compounds, along with bis {2-N- ( 1,3,4,6-tetra-O- acetyl-2-amino-2-deoxy-D-glucopyranose)}-1,1’-ferrocene carboxamide (6), bis {1- S- (2,3,4,6-tetra-O- acetyl-1-deoxy-1- thio-D-glucopyranose)}- 1,1’-ferrocene carboxylate (7), and 2-N-(2-amino-2-deoxy-D-glucopyranose)-1-ferrocene carboxamide (11) were examined for cytotoxicity in cell lines (L1210 and HTB-129) and for antimalarial activity in Plasmodium falciparum strains (D10, 3D7, and K1, a chloroquine- resistant strain). In general, the compounds were nontoxic in the human cell line tested (HTB-129), and compounds 4, 7, and 9 showed moderate antimalarial activity in one or more of the P. falciparum strains.