The First Metal-Based Paullone Derivative with High Antiproliferative Activity in Vitro

Abstract

9-Bromo-7,12-dihydroindolo[3,2-d][1]benzazepin-6(5H)-one, kenpaullone, which displays similarities in the activity profile to flavopiridol, was modified by chemical transformations at the lactam unit to provide a peripheral binding site able to accommodate metal ions. The first metal-based paullone has been prepared and characterized by single-crystal X-ray diffraction methods, solid-state cross-polarization magic angle spinning 13C NMR spectroscopy, electrospray ionization mass spectra, and electronic spectra. The gallium complex [GaL2]Cl.2.5H2O, the metal-free ligand (HL), and the starting compound used for the preparation of HL were assessed in vitro for their cytotoxicity in a panel of human tumor cell lines. The gallium complex was found to be 1.5-18-fold more cytotoxic than HL, with an average IC50 value of 2.0 microM.

Preclinical characterization of anticancer gallium(III) complexes: Solubility, stability, lipophilicity and binding to serum proteins

“…1. The compounds were synthesized and characterized at the Institute of Inorganic Chemistry, University of Vienna as described elsewhere [6,8,12,13]. Human serum albumin (min.…”

“…This finding provides evidence in favor of a modern metallodrug-developing concept [7] that implies combining a metal ion and a ligand which are both pharmaceutically active and aimed at attacking the same molecular target (most likely, ribonucleotide reductase in the case of gallium thiosemicarbazonates). Another complex with high gallium-induced anticancer activity in vitro, KP1438, is formed by the reaction of Ga(III) with a paulone derivative [8]. Still, gallium complexes are thought to be immature with regard to the number of compounds examined, especially if one takes into account the well-known activity of this metal against malignant tumors and a diversity of anticancer complexes of other metals such as platinum(II) or ruthenium(III).…”

Synthesis and structural peculiarities of gallium Complexes with novel paullone derivatives

“…Since lactams could be converted into amidines and hydrazones providing a binding site for metals, the synthesis of ruthenium complexes with 9-bromo-6-(α-picolylamino)-7,12-dihydroindolo [3,2-d][1]benzazepine (1, Fig. 1) [5,6] and a gallium complex with two N-(9-bromo-7,12-dihydroindolo [3,2-d][1]benzazepin-6(5H)-ylidene-N'-(2-hydroxybenzylidene)azine ligands (3, see Scheme 1) has been performed [7].…”

“…9-Bromo-7,12-dihydroindolo [3,2-d][1]benzazepin-6-ylhydrazine 2 was prepared as described previously [7]. Gallium chloride, hydrazine hydrate, hexamethyldisiloxane, 2-acetylpyridine and sodium acetylacetonate monohydrate were purchased from Sigma-Aldrich and used as received.…”

Metallomics related to gallium compounds: biochemical and xenobiochemical aspects

“…The gallium adduct of a paullone derivative, 9-bromo-7,12-dihydroindolo[3,2-d][1]benzazepin-6(5H)-one (denoted kenpaullone), displayed a 1.5-18-fold increase in cytotoxicity compared to the free ligand on a range of human tumour cell lines [51].…”