Discovery of a potent tubulin polymerization inhibitor: Synthesis and evaluation of water-soluble prodrugs of benzophenone analog

Abstract Prodrugs have proven to be very useful in enhancing aqueous solubility of sparingly water-soluble drugs, thereby increasing in vivo efficacy without a need of special excipients. In vitro and in vivo evaluations of a number of amino acid prodrugs of 1 , a previously identified potent tubulin polymerization inhibitor and cytotoxic against various cancer cell lines led to the discovery of 3 · HCl ( l -valine attached) which is highly efficacious in mouse xenografts bearing human cancer. Pharmacokinetic analysis in rats revealed that compound 1 was released immediately upon administration of 3 · HCl intravenously, with rapid clearance of 3 · HCl indicating the effective cleavage of prodrug. Compound 3 · HCl (CKD-516) has now been progressed to phase 1 clinical trial.