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

Synthesis and evaluation of various amino acid prodrugs of 1 led to the discovery of 3· HCl (R = ( S)-isopropyl) which was shown to have potent antitumor efficacy in mouse xenografts. Pharmacokinetic study in rats was also described. 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.