Elucidation of Structure-Activity Relationships in Indolobenzazepine-Derived Ligands and Their Copper(II) Complexes : The Role of Key Structural Components and Insight into the Mechanism of Action

Research output: Journal Publications and Reviews (RGC: 21, 22, 62)21_Publication in refereed journalpeer-review

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Author(s)

  • Irina Kuznetcova
  • Felix Bacher
  • Samah Mutasim Alfadul
  • Max Jing Rui Tham
  • Wee Han Ang
  • Peter Rapta
  • Vladimir B. Arion

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Detail(s)

Original languageEnglish
Pages (from-to)10167-10181
Journal / PublicationInorganic Chemistry
Volume61
Issue number26
Online published17 Jun 2022
Publication statusPublished - 4 Jul 2022

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Abstract

Indolo[3,2-d][1]benzazepines (paullones), indolo[3,2-d][2]benzazepines, and indolo[2,3-d][2]benzazepines (latonduines) are isomeric scaffolds of current medicinal interest. Herein, we prepared a small library of novel indolo[3,2-d][2]benzazepine-derived ligands HL1-HLand copper(II) complexes 1-4. All compounds were characterized by spectroscopic methods (1H and 13C NMR, UV-vis, IR) and electrospray ionization (ESI) mass spectrometry, while complexes 2 and 3, in addition, by X-ray crystallography. Their purity was confirmed by HPLC coupled with high-resolution ESI mass spectrometry and/or elemental analysis. The stability of compounds in aqueous solutions in the presence of DMSO was confirmed by 1H NMR and UV-vis spectroscopy measurements. The compounds revealed high antiproliferative activity in vitro in the breast cancer cell line MDA-MB-231 and hepatocellular carcinoma cell line LM3 in the low micromolar to nanomolar concentration range. Important structure-activity relationships were deduced from the comparison of anticancer activities of HL1-HL4 and 1-4 with those of structurally similar paullone-derived (HL5-HLand 5-7) and latonduine-derived scaffolds (HL8-HL11 and 8-11). The high anticancer activity of the lead drug candidate 4 was linked to reactive oxygen species and endoplasmic reticulum stress induction, which were confirmed by fluorescent microscopy and Western blot analysis.

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Citation Format(s)

Elucidation of Structure-Activity Relationships in Indolobenzazepine-Derived Ligands and Their Copper(II) Complexes : The Role of Key Structural Components and Insight into the Mechanism of Action. / Kuznetcova, Irina; Bacher, Felix; Alfadul, Samah Mutasim; Tham, Max Jing Rui; Ang, Wee Han; Babak, Maria V.; Rapta, Peter; Arion, Vladimir B.

In: Inorganic Chemistry, Vol. 61, No. 26, 04.07.2022, p. 10167-10181.

Research output: Journal Publications and Reviews (RGC: 21, 22, 62)21_Publication in refereed journalpeer-review

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