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-α-d-glucopyranoside)}-1-ferrocene carboxamide (3), {1-O-(2,3,4,6-tetra-O-benzyl-d-glucopyranose)}-1-ferrocene carboxylate (4), and {6-O-(1,2,3,4-tetra-O-acetyl-β-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-α-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-β-d-glucopyranose)}-1,1‘-ferrocene carboxylate (10). {6-N-(Methyl-6-amino-6-deoxy-α-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, 1H 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.