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.

• Authors: Jaekwang Lee, Suyeal Bae, Seo-Hee Lee, Hojin Choi, Young Hoon Kim, Soo Jin Kim, Gyu Tae Park, Seung Kee Moon, Dal-Hyun Kim, Sungsook Lee, Soon Kil Ahn, Nam Song Choi, Kyung Joo Lee
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 20 Issue 21 Pg. 6327-30 (Nov 01 2010) ISSN: 1464-3405 [Electronic] England
• PMID: 20850313 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2010. Published by Elsevier Ltd.

Chemical References

• Antineoplastic Agents
• Benzophenones
• Prodrugs
• Tubulin
• Tubulin Modulators
• Water

Topics

• Animals
• Antineoplastic Agents (chemical synthesis, pharmacology)
• Benzophenones (chemical synthesis, pharmacokinetics, pharmacology)
• Cell Proliferation (drug effects)
• HL-60 Cells
• Humans
• Injections, Intravenous
• Male
• Mice
• Mice, Inbred BALB C
• Prodrugs (chemical synthesis, chemistry)
• Rats
• Rats, Sprague-Dawley
• Solubility
• Tubulin (biosynthesis)
• Tubulin Modulators (chemical synthesis, pharmacokinetics, pharmacology)
• Water
• Xenograft Model Antitumor Assays