Modifications of geldanamycin via CuAAC altering affinity to chaperone protein Hsp90 and cytotoxicity.

Autor: Skrzypczak N; Faculty of Chemistry, Adam Mickiewicz University, Uniwersytetu Poznańskiego 8, 61-614, Poznań, Poland., Buczkowski A; Unit of Biophysical Chemistry, Department of Physical Chemistry, Faculty of Chemistry, University of Lodz, Pomorska 165, Lodz, 90-236, Poland., Bohusz W; Faculty of Chemistry, Adam Mickiewicz University, Uniwersytetu Poznańskiego 8, 61-614, Poznań, Poland., Nowak E; Faculty of Chemistry, Adam Mickiewicz University, Uniwersytetu Poznańskiego 8, 61-614, Poznań, Poland., Tokarska K; Faculty of Chemistry, Adam Mickiewicz University, Uniwersytetu Poznańskiego 8, 61-614, Poznań, Poland., Leśniewska A; Faculty of Chemistry, Adam Mickiewicz University, Uniwersytetu Poznańskiego 8, 61-614, Poznań, Poland., Alzebari AM; Faculty of Chemistry, Adam Mickiewicz University, Uniwersytetu Poznańskiego 8, 61-614, Poznań, Poland., Ruszkowski P; Department of Pharmacology, Poznan University of Medical Sciences, Rokietnicka 5a, 60-806, Poznań, Poland., Gdaniec M; Faculty of Chemistry, Adam Mickiewicz University, Uniwersytetu Poznańskiego 8, 61-614, Poznań, Poland., Bartl F; Lebenswissenschaftliche Fakultӓt, Institut fȕr Biologie, Biophysikalische Chemie Humboldt-Universitӓt zu Berlin, Invalidenstraße 42, Berlin, Germany., Przybylski P; Faculty of Chemistry, Adam Mickiewicz University, Uniwersytetu Poznańskiego 8, 61-614, Poznań, Poland. Electronic address: piotrp@amu.edu.pl.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2023 Aug 05; Vol. 256, pp. 115450. Date of Electronic Publication: 2023 May 12.
DOI: 10.1016/j.ejmech.2023.115450
Abstrakt: Functionalization of alkyne (1) and azide (2) derivatives of geldanamycin (GDM) via dipolar cycloaddition CuAAC yielded 35 new congeners (3-37) with C(17)-triazole arms bearing caps of different nature (basic vs. acidic, hydrophilic vs. hydrophobic). Confrontation of biological data (anticancer activity vs. toxicity in normal cells) with lipophilicity (clogP), dissociation constants (K d ) of complexes with Hsp90 and binding modes to Hsp90 revealed SAR in specific subgroups of GDM derivatives. The most potent GDM congeners 14-16, bearing C(17)-triazole-benzyl-halogen arms exhibited the most optimal clogP values of 2.7-3.1 at favourable binding to Hsp90 (K d Hsp90  at μM level). The anticancer activity of 14-16 (IC 50  = 0.23-0.41 μM) is higher than those of GDM (IC 50  = 0.58-0.64 μM) and actinomycin D (ActD, IC 50  = 0.62-0.71 μM) in SKBR-3, SKOV-3 and PC-3 cell lines, with a comparable cytotoxicity in healthy cells. The relationship between structure and attractive anticancer potency (IC 50  = 0.53-0.74 μM) is also observed for congeners with C(17)-triazole-saccharide or C(17)-triazole-unsaturated arms. In the former, the absolute configuration at C(4) (ᴅ-glucose vs. ᴅ-galactose) whereas in the latter the length of the unsaturated arm influences the cytotoxic effects due to different binding strength (K d , ΔE) and modes with Hsp90. Among all triazole congeners of GDM that are biologically attractive and exhibit lower toxicity in normal cells than GDM and ActD, the derivative 22, bearing the C(17)-triazole-cinnamyl arm, shows the lowest K d (Hsp90), optimal clogP = 2.82, the best pro-apoptotic properties in SKBR-3 and SKOV-3 and the best selectivity indices (SI). For the most potent GDM derivatives with C(17)-triazole arm, the docking studies have suggested the importance of the intermolecular stabilization between the arm and the D57 or Y61 of Hsp90.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
Databáze: MEDLINE
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