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Biological Evaluation of Double Point Modified Analogues of 1,25-Dihydroxyvitamin D2 as Potential Anti-Leukemic Agents.
Corcoran, Aoife; Nadkarni, Sharmin; Yasuda, Kaori; Sakaki, Toshiyuki; Brown, Geoffrey; Kutner, Andrzej; Marcinkowska, Ewa.
Afiliación
  • Corcoran A; Faculty of Biotechnology, University of Wroclaw, 14a Joliot-Curie, Wroclaw 50-383, Poland. aoifecorkie@hotmail.com.
  • Nadkarni S; Pharmaceutical Research Institute, 8 Rydygiera, Warsaw 01-793, Poland. s.nadkarni@ifarm.eu.
  • Yasuda K; Department of Biotechnology, Faculty of Engineering, Toyama Prefectural University, 5180 Kurokawa, Imizu, Toyama 939-0398, Japan. z02232@mail.pu-toyama.ac.jp.
  • Sakaki T; Department of Biotechnology, Faculty of Engineering, Toyama Prefectural University, 5180 Kurokawa, Imizu, Toyama 939-0398, Japan. tsakaki@pu-toyama.ac.jp.
  • Brown G; School of Immunity and Infection, University of Birmingham, Vincent Drive, Edgbaston, Birmingham, West Midlands B15 2TT, UK. G.BROWN@bham.ac.uk.
  • Kutner A; Pharmaceutical Research Institute, 8 Rydygiera, Warsaw 01-793, Poland. a.kutner@ifarm.eu.
  • Marcinkowska E; Faculty of Biotechnology, University of Wroclaw, 14a Joliot-Curie, Wroclaw 50-383, Poland. ema@cs.uni.wroc.pl.
Int J Mol Sci ; 17(2)2016 Feb 01.
Article en En | MEDLINE | ID: mdl-26840307
Structurally similar double-point modified analogues of 1,25-dihydroxyvitamin D2 (1,25D2) were screened in vitro for their pro-differentiating activity against the promyeloid cell line HL60. Their affinities towards human full length vitamin D receptor (VDR) and metabolic stability against human vitamin D 24-hydroxylase (CYP24A1) were also tested. The analogues (PRI-1730, PRI-1731, PRI-1732, PRI-1733 and PRI-1734) contained 5,6-trans modification of the A-ring and of the triene system, additional hydroxyl or unsaturation at C-22 in the side chain and reversed absolute configuration (24-epi) at C-24 of 1,25D2. As presented in this paper, introduction of selected structural modifications simultaneously in two distinct parts of the vitamin D molecule resulted in a divergent group of analogues. Analogues showed lower VDR affinity in comparison to that of the parent hormones, 1,25D2 and 1,25D3, and they caused effective HL60 cell differentiation only at high concentrations of 100 nM and above. Unexpectedly, introducing of a 5,6-trans modification combined with C-22 hydroxyl and 24-epi configuration switched off entirely the cell differentiation activity of the analogue (PRI-1734). However, this analogue remained a moderate substrate for CYP24A1, as it was metabolized at 22%, compared to 35% for 1,25D2. Other analogues from this series were either less (12% for PRI-1731 and PRI-1733) or more (52% for PRI-1732) resistant to the enzymatic deactivation. Although the inactive analogue PRI-1734 failed to show VDR antagonism, when tested in HL60 cells, its structure might be a good starting point for our design of a vitamin D antagonist.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Ensayos de Selección de Medicamentos Antitumorales / Leucemia / Ergocalciferoles / Antineoplásicos Límite: Humans Idioma: En Revista: Int J Mol Sci Año: 2016 Tipo del documento: Article País de afiliación: Polonia Pais de publicación: Suiza
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Ensayos de Selección de Medicamentos Antitumorales / Leucemia / Ergocalciferoles / Antineoplásicos Límite: Humans Idioma: En Revista: Int J Mol Sci Año: 2016 Tipo del documento: Article País de afiliación: Polonia Pais de publicación: Suiza