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Cephalosporins, after penicillins, are the most widely used antibacterial agents in infectious diseases and the cause of adverse immune reactions in the world. Whether a patient with a suspected allergy to a β-lactam can safely take a cephalosporin is often a matter of debate. However, there are no tests with enough sensitivity to detect allergy to cephalosporins. Understanding the way in which the drug metabolizes after protein conjugation is important if we are to make advances in the diagnosis of clinical allergy. Structural studies of cephalosporin−protein adducts have never been addressed successfully and are difficult to investigate. Our approach to determine the requirements involved in antigenic determinant structures consisted of designing and synthesizing a proposed skeleton that remains linked to the carrier protein after chemical degradation in cephalosporin conjugated to carrier proteins. In this study, a series of proposed epitopes were efficiently synthesized following a versatile methodology, involving the condensation of the R1acyl side chains of native cephalosporins, with the nuclear fragment structures (derived from amino acids or other aminofunctionalized molecules). The final well-defined structures 1−4 (a−f), representing a fragment from the proposed cephalosporin−Lys(protein) adduct intermediate, consist of closely related low-molecular-weight molecules, differing only in the functional group at C-3 and the R1side chains. They were assessed with sera from patients allergic to cephalosporins to study structure−IgE molecular recognition relationships. These IgE showed an enhanced recognition to proposed new skeleton epitopes with adequate functionality at C-3, with the specifities mainly related to the R1acyl side chain. Thus, this study led us to refine the model haptenic structures of cephalosporins and gain insight into the chemical mechanism of epitope formation. [ABSTRACT FROM AUTHOR]