Gold(III) complexes of pyridyl- and isoquinolylamido ligands: structural, spectroscopic, and biological studies of a new class of dual topoisomerase I and II inhibitors (original) (raw)
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Archives of Biochemistry and Biophysics, 2011
A gold(III) compound [Au(C^N^C)(IMe)]CF 3 SO 3 (Gold III) has been reported to have anticancer properties as it is able to reduce topoisomerase IB activity in vitro and suppress tumor growth in nude mice model. Here we have investigated the mechanism of inhibition of human topoisomerase IB activity by this compound, analyzing the various steps of the catalytic cycle. DNA supercoiled relaxation and the cleavage reaction are inhibited, but Gold III does not perturb the religation reaction, in contrast to what has been observed for camptothecin. Pre-incubation of enzyme with the inhibitor before adding DNA substrate increases the inhibitory effect. In addition, when Gold III is preincubated with the enzyme it prevents the stabilization of the cleavable complex by camptothecin. The analysis of the DNA-topoisomerase binding reaction indicates that the compound acts as a topoisomerase I inhibitor by preventing the enzyme-DNA interaction.
ACS Medicinal Chemistry Letters, 2016
Scaffold-hopping of bioactive natural product aurones has been studied for the first time. 2-Arylideneimidazo[1,2-a]pyridinones as potential topoisomerase IIα (hTopoIIα)-targeting anticancer compounds were considered. A multifunctional activator, polyphosphoric acid, enabled to realize a cascade reaction of 2aminopyridine with 2,3-epoxyesters toward synthesis of 2arylideneimidazo[1,2-a]pyridinones. Most of the compounds exhibited hTopoIIα-selective poison activity with efficiency more than etoposide and DNA-binding property, while not interacting with hTopo I. The compounds showed pronounced antiproliferative activities in nanomolar range with relatively poor toxicity to normal cells, inhibition of invasiveness, and apoptotic effect. The activities for inhibition of tubulin assembly, CDK1 and pCDK1, were also observed. Interestingly, the hTopoIIα inhibitory (in vitro and ex vivo studies) and antiproliferative activities of representative potent compounds were found to be manifold higher compared to corresponding parent aurones bearing alike substitutions, indicating the importance of such scaffold-hopping strategy in medicinal chemistry research.
Journal of Photochemistry and Photobiology B: Biology, 2012
The new heterobimetallic Cu II-Sn IV 2 =Ni II-Sn IV 2 complexes 1 and 2 bearing bioactive pharmacophore ligand scaffold; 1,10-phenanthroline and ethylenediamine were synthesized and characterized by spectroscopic (IR, UV-vis, NMR, ESI-MS) and analytical methods. The in vitro DNA binding studies of 1 and 2 with CT-DNA were carried out by employing various biophysical methods which reveal strong electrostatic binding via phosphate backbone of DNA helix, in addition to partial intercalation in the minor groove and stabilized by intramolecular hydrogen bonding. To gain further insight into the molecular recognition at the target site, UV-vis titrations of 1 with 5 0-GMP was carried out and validated by 1 H and 31 P NMR. Complex 1 cleaved pBR322 DNA via oxidative pathway and exhibited high inhibition activity against Topo-I at 20 lM. Furthermore, the cytotoxicity of 1 was examined on a panel of human tumor cell lines of different histological origins showing promising antitumor activity.
Journal of Photochemistry and Photobiology B: Biology, 2010
New potential cancer chemotherapeutic complexes Cu-Sn 2 /Zn-Sn 2 3 and 4 were designed and prepared as topoisomerases inhibitors; their in vitro DNA binding studies were carried out which reveal strong electrostatic binding via phosphate backbone of DNA helix, in addition to other binding modes viz. coordinate covalent and partial intercalation. To throw insight to molecular binding event at the target site, UV-vis titrations of 3 and 4 with mononucleotides of interest, viz, 5 0-GMP and 5 0-TMP were carried out, (in case of 4) by 1 H and 31 P NMR. Cleavage studies employing gel electrophoresis demonstrate both the complexes 3 and 4 are efficient cleavage agents and are specific groove binders (complex 3 binds to both major and minor groove while complex 4 is specifically minor groove binder only). In addition, the complexes show high inhibition activity against topoisomerase I and II. However, complex 4 exhibits significant inhibitory effects on the Topo I activity at a very low concentration $2.5 lM.
Bioorganic & Medicinal Chemistry Letters, 2009
Topoisomerase II is a validated target in oncology. Among the different ways of blocking the function of this enzyme, inhibiting its ATPase activity has been relatively less investigated. In an effort to identify topoisomerase II inhibitors of a novel type, exerting their action by this mechanism, we have designed a purine inhibitor scaffold targeting the ATP-binding site of the enzyme. Searching the Novartis compound collection for molecules containing this purine motif has allowed the identification of two micromolar hits providing access to a new class of catalytic topoisomerase II inhibitors.
Synthesis and Anticancer Activity of Gold(I)-Chloroquine Complexes
Journal of the Mexican Chemical Society, 2017
Two new gold(I) -chloroquine complexes, Au(CQ)(Cl) (1) and Au(CQ)(tgta) (2), were prepared and their most probable structure were established through a combination of different spectroscopic and analytical techniques. Their interaction with two important targets of action, DNA and thioredoxin reductase (TrxR), were nvestigated. These studies showed that complexes 1 and 2 displayed two types of interaction with DNA, covalent binding through the metal center, and additionally a non-covalent interaction that is electrostatic in the case of complex 1, but intercalative for complex 2, which is similar to that displayed by free CQ. The experimental data indicated that these gold-CQ complexes also possess the ability to inhibit TrxR. These results led us to test their cytotoxicity against 6 tumor cell lines. The complexes displayed cytotoxic activity against the PC-3, SKBR-3, HT-29, LoVo and B16/BL6 lines. These finding suggest that gold(I)-CQ compounds, particularly [Au(CQ)(PPh3)]PF6, are...
Journal of Inorganic Biochemistry, 2019
Herein, a robust docking protocol was developed by using a low-cost workflow to highlight the modulation at ATPase domain from Human Topoisomerase IIα (TOP2A) towards four novels Pd(II)-complexes bearing N, S-donor ligands. In vitro TOP2A inhibition assay confirmed the ability of them to prevent the enzyme functions into concentration ranging at 6.25-25 μM. These results exhibited more effectivity than anticancer agent etoposide (35 μM) and merbarone (40-50 μM). The compounds were screened via Resazurin assay and revealed higher cytotoxicity as well as selectivity index (SI) against MCF-7 tumour cell lines than HEK-293 normal cells (IC50 = 1.81-4.46 μM and SI = 1.39-5.01). Further, RBCs hemolytic test suggested in vitro non-toxic character for compound 4, previously evaluated as the most effective TOP2A inhibitor.
JACS Au, 2021
In this work, a pair of gold(III) complexes derived from the analogous tetrapyridyl ligands H 2 biqbpy1 and H 2 biqbpy2 was prepared: the rollover, bis-cyclometalated [Au(biqbpy1)Cl ([1]Cl) and its isomer [Au-(biqbpy2)Cl ([2]Cl). In [1] + , two pyridyl rings coordinate to the metal via a Au−C bond (C ∧ N ∧ N ∧ C coordination) and the two noncoordinated amine bridges of the ligand remain protonated, while in [2] + all four pyridyl rings of the ligand coordinate to the metal via a Au−N bond (N ∧ N ∧ N ∧ N coordination), but both amine bridges are deprotonated. As a result, both complexes are monocationic, which allowed comparison of the sole effect of cyclometalation on the chemistry, protein interaction, and anticancer properties of the gold(III) compounds. Due to their identical monocationic charge and similar molecular shape, both complexes [1]Cl and [2]Cl displaced reference radioligand [ 3 H]dofetilide equally well from cell membranes expressing the K v 11.1 (hERG) potassium channel, and more so than the tetrapyridyl ligands H 2 biqbpy1 and H 2 biqbpy2. By contrast, cyclometalation rendered [1]Cl coordinatively stable in the presence of biological thiols, while [2]Cl was reduced by a millimolar concentration of glutathione into metastable Au(I) species releasing the free ligand H 2 biqbpy2 and TrxR-inhibiting Au + ions. The redox stability of [1]Cl dramatically decreased its thioredoxin reductase (TrxR) inhibition properties, compared to [2]Cl. On the other hand, unlike [2]Cl, [1]Cl aggregated into nanoparticles in FCS-containing medium, which resulted in much more efficient gold cellular uptake. [1]Cl had much more selective anticancer properties than [2]Cl and cisplatin, as it was almost 10 times more cytotoxic to human cancer cells (A549, A431, A375, and MCF7) than to noncancerous cells (MRC5). Mechanistic studies highlight the strikingly different mode of action of the two compounds: while for [1]Cl high gold cellular uptake, nuclear DNA damage, and interaction with hERG may contribute to cell killing, for [2]Cl extracellular reduction released TrxR-inhibiting Au + ions that were taken up in minute amounts in the cytosol, and a toxic tetrapyridyl ligand also capable of binding to hERG. These results demonstrate that bis-cyclometalation is an appealing method to improve the redox stability of Au(III) compounds and to develop gold-based cytotoxic compounds that do not rely on TrxR inhibition to kill cancer cells.