Synthesis and Oral Uptake Studies of Lipidic and Glyco-Lipidic Conjugates of β-Lactam Antibiotics

Abstract

Lipidic and glyco‐lipidic cephalosporin conjugates 1c and 1i were synthesised as diastereomeric mixtures to improve their oral absorption. 2‐(tert‐Butoxycarbonylamino)tetradecanoic acid was condensed with thiazole 1d and by following basecatalysed hydrolysis of the fully protected rac‐1e, the free acid rac‐1f was produced. This was then used to acylate the carboxy‐protected cephalosporin analog 1g by using a modified Vilsmeier reaction. Removal of the protecting groups of 1b resulted in conjugate 1c. Cephalosporin conjugate li, which contains a sugar moiety in addition to a lipidic amino acid residue, was synthesised to produce a drug conjugate with both lipophilic and hydrophilic properties [radiolabelled (C) analogs 1a, 1c and 1i were also synthesised]. The radio‐labelled parent 1a and conjugates 1c and 1i were administered orally to rats and uptake of the radiolabel in the blood, various organs, urine and faeces was determined. The results showed that an increase in lipophilicity caused an increase in the oral uptake, suggesting that conjugation to lipidic amino acids and peptides is a useful approach to the improvement of the absorption of poorly absorbed drugs. (Formula Presented.)