β-lactam-containing prodrug-cephalosporin-doxorubicin (C-Dox)

β-lactam-containing prodrug-cephalosporin-doxorubicin (C-Dox) is a chemical conjugate designed for site-specific drug delivery, primarily utilized within the framework of Antibody-Directed Enzyme Prodrug Therapy (ADEPT) (Vrudhula et al., 1995, J. Med. Chem.). It is not a biological target but a prodrug consisting of the cytotoxic anthracycline doxorubicin covalently linked to a cephalosporin carrier. The molecule remains inactive until it encounters the enzyme β-lactamase, which is typically localized to tumor sites via an antibody-enzyme conjugate (Jung, 2001, Curr. Med. Chem.). Upon enzymatic cleavage of the β-lactam ring, a spontaneous 1,6-elimination reaction occurs, releasing active doxorubicin into the local tumor environment. The released doxorubicin then exerts its therapeutic effect by intercalating into DNA and inhibiting Topoisomerase II, leading to double-strand breaks and programmed cell death (PubChem, CID 31703). This prodrug strategy is intended to enhance the therapeutic index of doxorubicin by reducing systemic exposure and associated toxicities, such as cardiomyopathy.

Other names

Cephalosporin-doxorubicinC-Doxβ-lactamase-activated doxorubicin prodrugCephalosporin-Adriamycin conjugate

The prodrug is activated by the enzyme β-lactamase, which cleaves the β-lactam ring of the cephalosporin moiety. This cleavage triggers a spontaneous chemical rearrangement (1,6-elimination) that releases the active cytotoxic agent, doxorubicin. The free doxorubicin then enters the cell nucleus, intercalates into DNA, and inhibits the enzyme Topoisomerase II, preventing DNA ligation and inducing apoptosis.