Skip to main content

Research Repository

Advanced Search

Indolo[2,3- e ]benzazocines and indolo[2,3- f ]benzazonines and their copper( ii ) complexes as microtubule destabilizing agents †

Wittmann, Christopher; Dömötör, Orsolya; Kuznetcova, Irina; Spengler, Gabriella; Reynisson, Jóhannes; Holder, Lauren; Miller, Gavin J.; Enyedy, Eva A.; Bai, Ruoli; Hamel, Ernest; Arion, Vladimir B.

Indolo[2,3- e ]benzazocines and indolo[2,3- f ]benzazonines and their copper( ii ) complexes as microtubule destabilizing agents † Thumbnail


Authors

Christopher Wittmann

Orsolya Dömötör

Irina Kuznetcova

Gabriella Spengler

Lauren Holder

Eva A. Enyedy

Ruoli Bai

Ernest Hamel

Vladimir B. Arion



Abstract

A series of four indolo[2,3-e]benzazocines HL1–HL4 and two indolo[2,3-f]benzazonines HL5 and HL6, as well as their respective copper(ii) complexes 1–6, were synthesized and characterized by 1H and 13C NMR spectroscopy, ESI mass spectrometry, single crystal X-ray diffraction (SC-XRD) and combustion analysis (C, H, N). SC-XRD studies of precursors Vd, VIa·0.5MeOH, of ligands HL4 and HL6·DCM, and complexes 2·2DMF, 5·2DMF, 5′·iPrOH·MeOH provided insights into the energetically favored conformations of eight- and nine-membered heterocycles in the four-ring systems. In addition, proton dissociation constants (pKa) of HL1, HL2 and HL5, complexes 1, 2 and 5, overall stability constants (log β) of 1, 2 and 5 in 30% (v/v) DMSO/H2O at 298 K, as well as thermodynamic solubility of HL1–HL6 and 1–6 in aqueous solution at pH 7.4 were determined by UV–vis spectroscopy. All compounds were tested for antiproliferative activity against Colo320, Colo205 and MCF-7 cell lines and showed IC50 values in the low micromolar to sub-micromolar concentration range, while some of them (HL1, HL5 and HL6, 1, 2 and 6) showed remarkable selectivity towards malignant cell lines. Ethidium bromide displacement studies provided evidence that DNA is not the primary target for these drugs. Rather, inhibition of tubulin assembly is likely the underlying mechanism responsible for their antiproliferative activity. Tubulin disassembly experiments showed that HL1 and 1 are effective microtubule destabilizing agents binding to the colchicine site. This was also confirmed by molecular modelling investigations. To the best of our knowledge, complex 1 is the first reported transition metal complex to effectively bind to the tubulin-colchicine pocket.

Journal Article Type Article
Acceptance Date Jul 3, 2023
Online Publication Date Jul 4, 2023
Publication Date Jul 4, 2023
Deposit Date Jul 20, 2023
Publicly Available Date Jul 20, 2023
Journal Dalton Transactions
Print ISSN 1477-9226
Electronic ISSN 1477-9234
Publisher Royal Society of Chemistry
Peer Reviewed Peer Reviewed
Volume 52
Issue 29
Pages 9964-9982
DOI https://doi.org/10.1039/d3dt01632c
Publisher URL https://pubs.rsc.org/en/content/articlelanding/2023/DT/D3DT01632C

Files





You might also like



Downloadable Citations