1,721,203 research outputs found
Study of Topoisomerase IIa inhibitors as potential anti-cancer drugs
No full textTopoisomerase II is an essential enzyme that is required for every process that involves the opening of DNA double helix: it helps to regulate under- and overwinding and removes knots and tangle. In order to carry out its function, topoisomerase II generates transient double stranded breaks in DNA. Vertebrate species encode two types of topoisomerase II: IIα and IIβ. Topoisomerase IIα is essential for cellular proliferation and is typical of the G2/M phase. Each subunits of this homodimeric enzyme is composed of two functionally distinct domains, the ATP-binding domain and the DNA cleavage-religation domain, that require respectivley one ATP molecule and two metal ions (Mg2+).
TopoII has been widely exploited as target for anti-tumor drugs. To this aim, we analyzed two classes of compounds, isatin and quinoline thiosemicarbazone derivatives, by means of the molecular docking technique, trying to understand their mechanism of action. Using the Autodock4 software package we investigated the affinity and the binding mode of these compounds in the functional sites of both domains and we compared the results with experimental data obtained in cells and on the pure enzyme in vitro. Copper complexes of both classes of compounds were also studied, which experimentally were found to have a higher inhibitory effect on tumor cells.
Despite of the similarity of their chemical structure with that of ATP, the quinoline derivatives and the corresponding copper complexes did not show, in the ATP-binding site, a binding energy comparable with that of the endogenous ligand, nor a preferred position. This led us to exclude this site as competitive binding site for our compounds. For this reasons, we tried to test all the quinoline compounds in the cleavage site, taking into account the presence of a cleaved DNA fragment. The results showed that only copper complexes had good binding energy and clustered conformations, with the metal atom bound to the phosphate group of broken DNA. This suggested us a possible interference on the successive DNA ligation. In addition, we identified the two copper complexes with the greatest affinity, in close agreement with experimental results.
The results obtained for isatin derivatives seem to indicate a less favoured binding energy in the cleavage site, even if they still interact with the DNA phosphate group. Docking simulations are still in progress into the ATP-binding site to compare the results
Discovery of antibacterial manganese(i) tricarbonyl complexes through combinatorial chemistry
Full text link: The continuous rise of antimicrobial resistance is a serious threat to human health and already causing hundreds of thousands of deaths each year. While natural products and synthetic organic small molecules have provided the majority of our current antibiotic arsenal, they are falling short in providing new drugs with novel modes of action able to treat multidrug resistant bacteria. Metal complexes have recently shown promising results as antimicrobial agents, but the number of studied compounds is still vanishingly small, making it difficult to identify promising compound classes or elucidate structure-activity relationships. To accelerate the pace of discovery we have applied a combinatorial chemistry approach to the synthesis of metalloantibiotics. Utilizing robust Schiff-base chemistry and combining 7 picolinaldehydes with 10 aniline derivatives, and 6 axial ligands, either imidazole/pyridine-based or solvent, we have prepared a library of 420 novel manganese tricarbonyl complexes. All compounds were evaluated for their antibacterial properties and 10 lead compounds were identified, re-synthesised and fully characterised. All 10 compounds showed high and broad activity against Gram-positive bacteria. The best manganese complex displayed low toxicity against human cells with a therapeutic index of >100. In initial mode of action studies, we show that it targets the bacterial membrane without inducing pore formation or depolarisation. Instead, it releases its carbon monoxide ligands around the membrane and inhibits the bacterial respiratory chain. This work demonstrates that large numbers of metal complexes can be accessed through combinatorial synthesis and evaluated for their antibacterial potential, allowing for the rapid identification of promising metalloantibiotic lead compounds
Unprecedented one-pot synthesis of an unsymmetrical cisplatin-based Pt(iv)-acetamidato complex
No full textWe describe herein a novel Pt(iv)-acetamidato complex as a result of the one-pot reaction between cisplatin and the highly reactive peroxyacetimidic acid generated in situ. This is the first example of a Pt(iv) complex containing a N-donor ligand coordinated during the Pt(ii) → Pt(iv) oxidation step. Remarkably, the Pt(iv)-amidato compound is highly soluble and stable in water; it represents an interesting building block for the further development of Pt(iv) antitumor prodrugs
μ-1,2,4,5-Tetrazine-N1:N4-bis(pentaammineruthenium) Tetracation: Synthesis and X-ray Structure
No full textThe 2:1 reaction of [Ru(H2O)2(NH3)5]2+ with 1,2,4,5-tetrazine (tz) gives rise to the formation of the dinuclear complex ion [{Ru(NH3)5}2(μ-tz-N1:N4)]4+. Its tetraphenylborate and hexafluoro-phosphate salts have been fully characterized; the X-ray structure of the former has also been determined
NATURAL ALDEHYDE THIOSEMICARBAZONES AND THEIR NICKEL COMPLEXES: SYNTHESIS, CHARACTERIZATION AND STUDIES ON THEIR BIOLOGICAL PROPERTIES
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Synthesis and structural characterization of bismuth complexes with sulphur-containing ligands: The crystal and molecular structures of two derivatives of BiBr3 and Bi2(SO4)3 with imidazolidine-2-thione
No full textThe paper reports the structural and spectroscopic properties of two complexes between BiBr3, Bi2(SO4)3 and imidazolidine-2-thione (etu) having formulae BiBr3·3etu (I) and [Bi(etu)4]2(SO4)3·2H2O (II). Complex I is monoclinic, space group P21/n, Z=4, with a=8.142(2), b=15.611(3), c=16.316(3) Å, β=97.38(3)°, R=0.041. II is orthorhombic, space group Pbcn, a=10.930(1), b=16.795(1), c=27.890(1) Å, Z=4 and R=0.052. In both structures bismuth is octahedrally coordinated, in I three bromines and three sulphurs from etu molecules are present and the coordinated polyhedron is only moderately deformed, while in II four sulphurs of etu ligands and two oxygen sulphate with very different Bi-O distances [2.413(12) and 2.715(13) Å] are present. © 1992 Plenum Publishing Corporation
Synthesis, characterization, crystal structure and antiproliferative in vitro activity of long-chain aliphatic thiosemicarbazones and their Ni(II) complexes
No full textIn the course of a research on metal-based compounds active on white blood cell cancers (leukemia, lymphoma and myeloma) nine aliphatic thiosemicarbazones and their nickel complexes have been synthesized with the aim to test their effect on histiocytic lymphoma U937 cell proliferation. All compounds were characterized by elemental, IR and NMR spectra analyses and for five of the complexes also by X-ray crystallography diffraction analysis. Heptanal thiosemicarbazone and the corresponding nickel complex were chosen after a solubility/stability test to carry out preliminary experiments in vitro on human leukemia cell line U937. The complex possesses a remarkable biological activity in inhibiting cell growth and in inducing apoptosis
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