Click strategy using disodium salts of amino acids improves the water solubility of plinabulin and KPU-300

Publication date: Available online 4 May 2017
Source:Bioorganic & Medicinal Chemistry
Author(s): Fumika Yakushiji, Kyohei Muguruma, Yoshiki Hayashi, Takuya Shirasaka, Ryosuke Kawamata, Hironari Tanaka, Yushi Yoshiwaka, Akihiro Taguchi, Kentaro Takayama, Yoshio Hayashi
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

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