Click strategy using disodium salts of amino acids improves the water solubility of plinabulin and KPU-300.
Bioorg Med Chem
; 25(14): 3623-3630, 2017 07 15.
Article
em En
| MEDLINE
| ID: mdl-28528081
ABSTRACT
Plinabulin and KPU-300 are promising anti-microtubule agents; however, the low water solubility of these compounds (<0.1µg/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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Base de dados:
MEDLINE
Assunto principal:
Sais
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Benzofenonas
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Água
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Dicetopiperazinas
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Aminoácidos
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article