Synthesis and β-lactamase-mediated activation of a cephalosporin-taxol prodrug Original Research Article

Synthesis and β-lactamase-mediated activation of a cephalosporin-taxol prodrug Original Research Article Pages 223-227 Maria L. Rodrigues, Paul Carter, Cindy Wirth, Sheldon Mullins, Arthur Lee, Brent K. Blackburn Close preview | PDF (548 K) | Related articles | Related reference work articles AbstractAbstract | ReferencesReferences Abstract Background: Enzyme-activatable prodrugs in conjunction with antibody-enzyme fusion proteins may enhance the anti-tumor efficacy of antibodies and reduce the toxic side effects of conventional chemotherapeutics. Cephalosporins have proven to be highly versatile triggers for the enzymatic activation of such prodrugs. Results: A cephern prodrug of taxol (PROTAX) was synthesized by substituting the C-3′ position of cephalothin with 2′-(γ-arninobutyryl) taxol. Hydrolysis of PROTAX by β-lactamase rapidly released 2′-(γ-anainobutyryl) taxol (kcatKM = (1.4 ± 0.1) × 105 s−1 M−1), which yielded taxol following intramolecular displacement. PROTAX is inactive in a microtubule assembly assay in vitro but has similar activity to taxol following prolonged activation with β-lactamase. PROTAX is ≈10-fold less toxic than taxol against SK-BR-3 breast tumor cells in vitro but has activity approaching that of taxol following prolonged activation with a fusion protein comprising β-lactamase fused to a tumor-targeting antibody fragment. Conclusions: Tubulin polymerization activity is abolished and cytotoxicity is reduced in the PROTAX prodrug compared to taxol. Activation of PROTAX by β-lactamase followed by self-immolation restores the activity of PROTAX to that of free taxol.