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

The collection includes files related to the publication: N. Skrzypczak, A. Buczkowski, W. Bohusz, E. Nowak, K. Tokarska, A. Leśniewska, A. M. Alzebari, P. Ruszkowski, M. Gdaniec, F. Bartl, P. Przybylski. Modifications of geldanamycin via CuAAC altering affinity to chaperone protein Hsp90 and cytotoxicity EuropeanJournalofMedicinalChemistry 256 (2023) 115450.The collection is the Supplementary data to this article:Supplementary data to this article contain: copies of all 1H and 13C NMR as well as FT-IR spectra for 1–37 together with selected 2D NMR correlations; x-ray data of 1 (Fig. S3), binding energy profits (ΔE; Table S1) and modes of GDM congeners 3, 4, 6, 7, 8, 10–12, 14, 16, 19, 20 and 23 with Hsp90 (Figs. S1–S3).The collection includes figures used in the publication: :Fig. 1 Geldanamycin (GDM) and its structural analogues (17-AAG and IPI-504) considered at various stages of clinical trials.   Fig. 2 The concept of designing a series of potentially active GDM derivatives. Fig. 3 Structures of C(17)-alkyne and C(17)-azide geldanamycin derivatives (1 and 2) and their transformation into triazole congeners (3–37) via dipolar CuAAC cycloaddition.Fig. 4 Structure of alkyne derivative 1 with the atom numbering, determined by x-ray crystallography (CCDC 2192495). Displacement ellipsoids are shown at the 50% probability level.Fig. 5 1H–13C HMBC correlations illustrating successful formation of the triazole moiety and the linkage between (a) the triazole and benzoquinone portions, as well as between (b) the triazole and the C(17)-arm cap, for the case of derivative 23. Fig. 6 Isothermal titration calorimetry (ITC) thermal effects of 30 μM Hsp90 solution titrated with 200 μM ligand solution of: geldanamycin GDM (grey circles ), 22 (blue squares ), 14 (red diamonds ) and 23 (green triangles ) in 10 mM phosphorous buffer solution (pH 7.4) at 25 ◦C. ITC curves of Hsp90 binding interactions with ligands were described with the one-site independent binding model (solid lines). Fig. 7 Docking of GDM triazole congeners into the N-binding domain pocket of Hsp90 (PDB 3Q5J [38]): (a) 30, ΔE (30 – Hsp90) =- 51.12 kcal/mol; (b) 29, ΔE (29 – Hsp90) =- 54.83 kcal/mol; (c) 22, ΔE (22 – Hsp90) =- 44.18 kcal/mol; (d) 5, ΔE (5 – Hsp90) =- 45.81 kcal/mol; (e) 34, ΔE (34 – Hsp90) =- 44.39 kcal/mol; (f) 35, ΔE (35 – Hsp90) =- 33.18 kcal/mol; interactions between Hsp90 and GDM congeners are marked by yellow dots; calculated by MOG-PM6 using MYOZYME algorithm (Scigress F.J. 2.6, EU 3.1.9) [39]. The collection also included a file (References) with the list of literature used in this paper:References - Literature cited in the publication