Click strategy using disodium salts of amino acids improves the water solubility of plinabulin and KPU-300. Issue 14 (15th July 2017)

• Record Type: Journal Article
• Authors: Yakushiji, Fumika; Muguruma, Kyohei; Hayashi, Yoshiki; Shirasaka, Takuya; Kawamata, Ryosuke; Tanaka, Hironari; Yoshiwaka, Yushi; Taguchi, Akihiro; Takayama, Kentaro; Hayashi, Yoshio
• Is Part Of: Bioorganic & medicinal chemistry. Volume 25:Issue 14(2017)
• Page Start: 3623
• Page End: 3630
• Publication Date: 2017-07-15
• Subjects: Water solubility -- Plinabulin -- KPU-300 -- Click -- Disodium salt; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2017.04.024
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: Plinabulin and KPU-300 are promising anti-microtubule agents; however, the low water solubility of these compounds (<0.1 µg/mL) has limited their pharmaceutical advantages. Here, we developed five water-soluble derivatives of plinabulin and KPU-300 with a click strategy using disodium salts of amino acids. The mother skeleton, diketopiperazine (DKP), was transformed into a monolactim-type alkyne and a copper-catalyzed alkyne azide cycloaddition (CuAAC) combined azides that was derived from amino acids as a water-solubilizing moiety. The conversion of carboxyl groups into disodium salts greatly improved the water solubility by 0.8 million times compared to the solubility of the parent molecules. In addition, the α-amino acid side chains of the water-solubilizing moieties affected both the water solubility and the half-lives of the compounds during enzymatic hydrolysis. Our effort to develop a variety of water-soluble derivatives using the click strategy has revealed that the replaceable water-solubilizing moieties can alter molecular solubility and stability under enzymatic hydrolysis. With this flexibility, we are approaching to the in vivo study using water-soluble derivative.