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A novel hybrid drug between two potent anti-tubulin agents as a potential prolonged anticancer approach.
Marchetti, Paolo; Pavan, Barbara; Simoni, Daniele; Baruchello, Riccardo; Rondanin, Riccardo; Mischiati, Carlo; Feriotto, Giordana; Ferraro, Luca; Hsu, Lih-Ching; Lee, Ray M; Dalpiaz, Alessandro.
Afiliação
  • Marchetti P; Department of Chemical and Pharmaceutical Sciences, University of Ferrara, 44121 Ferrara, Italy. Electronic address: paolo.marchetti@unife.it.
  • Pavan B; Department of Life Sciences and Biotechnology, University of Ferrara, 44121 Ferrara, Italy. Electronic address: pvnbbr@unife.it.
  • Simoni D; Department of Chemical and Pharmaceutical Sciences, University of Ferrara, 44121 Ferrara, Italy. Electronic address: daniele.simoni@unife.it.
  • Baruchello R; Department of Chemical and Pharmaceutical Sciences, University of Ferrara, 44121 Ferrara, Italy. Electronic address: riccardo.barucchello@unife.it.
  • Rondanin R; Department of Chemical and Pharmaceutical Sciences, University of Ferrara, 44121 Ferrara, Italy. Electronic address: riccardo.rondanin@unife.it.
  • Mischiati C; Department of Biomedical and Speciality Surgical Sciences, Surgery and Experimental Medicine, University of Ferrara, 44121 Ferrara, Italy. Electronic address: carlo.mischiati@unife.it.
  • Feriotto G; Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, 44121 Ferrara, Italy. Electronic address: giordana.feriotto@unife.it.
  • Ferraro L; Department of Life Sciences and Biotechnology, University of Ferrara, 44121 Ferrara, Italy. Electronic address: frl@unife.it.
  • Hsu LC; School of Pharmacy, College of Medicine, National Taiwan University, Taipei 10050, Taiwan. Electronic address: lihchinghsu@gmail.com.
  • Lee RM; Lestoni Corp., Richmond, VA 23219-155, USA. Electronic address: richvain@gmail.com.
  • Dalpiaz A; Department of Chemical and Pharmaceutical Sciences, University of Ferrara, 44121 Ferrara, Italy. Electronic address: dla@unife.it.
Eur J Pharm Sci ; 91: 50-63, 2016 Aug 25.
Article em En | MEDLINE | ID: mdl-27262542
We report the design, synthesis and biological characterisation of a novel hybrid drug by conjugation of two tubulin inhibitors, a hemiasterlin derivative A (H-Mpa-Tle-Aha-OH), obtained by condensation of three non-natural amino acids, and cis-3,4',5-trimethoxy-3'aminostilbene (B). As we have previously demonstrated synergy between A and B, we used a monocarbonyl derivative of triethylene glycol as linker (L) to synthesise compounds A-L and A-L-B; via HPLC we analysed the release of its potential hydrolysis products A, A-L, B and B-L in physiological fluids: the hybrid A-L-B undergo hydrolysis in rat whole blood of the ester bond between A and L (half-life=118.2±9.5min) but not the carbamate bond between B and L; the hydrolysis product B-L was further hydrolyzed, but with a slower rate (half-life=288±12min). The compound A-L was the faster hydrolyzed conjugate (half-life=25.4±1.1min). The inhibitory activity of the compounds against SKOV3 ovarian cancer cell growth was analysed. The IC50 values were 7.48±1.27nM for A, 40.3±6.28nM for B, 738±38.5nM for A-L and 37.9±2.11nM for A-L-B. The anticancer effect of A-L-B was evidenced to be obtained via microtubule dynamics suppression. Finally, we stated the expression of the active efflux transporters P-gp (ABCB1) and MRP1 (ABCC1) in the human normal colon epithelial NCM460 cell line by reverse-transcription PCR. Via permeation studies across NCM460 monolayers we demonstrate the poor aptitude of A to interact with active efflux transporters (AET): indeed, the ratio between its permeability coefficients for the basolateral (B)→apical (A) and B→A transport was 1.5±0.1, near to the ratio of taltobulin (1.12±0.06), an hemiasterlin derivative able to elude AETs, and significantly different form the ratio of celiprolol (3.4±0.2), an AET substrate.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Oligopeptídeos / Estilbenos / Moduladores de Tubulina / Antineoplásicos Limite: Animals / Humans / Male Idioma: En Ano de publicação: 2016 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Oligopeptídeos / Estilbenos / Moduladores de Tubulina / Antineoplásicos Limite: Animals / Humans / Male Idioma: En Ano de publicação: 2016 Tipo de documento: Article