title: 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.affiliation: Chong Kun Dang Research Institute, CKD Pharmaceuticals Inc., PO Box 74, Chonan, Republic of Korea.
authors.forename: Jaekwang
authors.initials: J
authors.lastname: Lee
authors.forename: Suyeal
authors.initials: S
authors.lastname: Bae
authors.forename: Seo-Hee
authors.initials: SH
authors.lastname: Lee
authors.forename: Hojin
authors.initials: H
authors.lastname: Choi
authors.forename: Young Hoon
authors.initials: YH
authors.lastname: Kim
authors.forename: Soo Jin
authors.initials: SJ
authors.lastname: Kim
authors.forename: Gyu Tae
authors.initials: GT
authors.lastname: Park
authors.forename: Seung Kee
authors.initials: SK
authors.lastname: Moon
authors.forename: Dal-Hyun
authors.initials: DH
authors.lastname: Kim
authors.forename: Sungsook
authors.initials: S
authors.lastname: Lee
authors.forename: Soon Kil
authors.initials: SK
authors.lastname: Ahn
authors.forename: Nam Song
authors.initials: NS
authors.lastname: Choi
authors.forename: Kyung Joo
authors.initials: KJ
authors.lastname: Lee
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D001577:Benzophenones / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D014404:Tubulin / Q000096:biosynthesis*; D050257:Tubulin Modulators / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D014867:Water; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001577:Benzophenones; D011355:Prodrugs; D014404:Tubulin; D050257:Tubulin Modulators; D014867:Water