Free radical generation is an inevitable consequence of aerobic existence and is implicated in a wide variety of pathological conditions including cancer, cardiovascular disease, ageing and neurodegenerative disorder. Free radicals can, however, be used to our advantage since their production is catalysed by synthetic inorganic molecules—termed artificial metallonucleases—that cut DNA strands by oxidative cleavage reactions. Here, we report the rational design and DNA binding interactions of a novel di-Cu2+ artificial metallonuclease [Cu2(tetra-(2-pyridyl)-NMe-naphthalene)Cl4] (Cu2TPNap). Cu2TPNap is a high-affinity binder of duplex DNA with an apparent binding constant (Kapp) of 107 M(bp)−1. The agent binds non-intercalatively in the major groove causing condensation and G-C specific destabilization. Artificial metallonuclease activity occurs in the absence of exogenous reductant, is dependent on superoxide and hydrogen peroxide, and gives rise to single strand DNA breaks. Pre-associative molecular docking studies with the 8-mer d(GGGGCCCC)2, a model for poly[d(G-C)2], identified selective major groove incorporation of the complex with ancillary Cu2+-phosphate backbone binding. Molecular mechanics methods then showed the d(GGGGCCCC)2 adduct to relax about the complex and this interaction is supported by UV melting experiments where poly[d(G-C)2] is selectively destabilized.
The use of Pt(IV) complexes as pro-drugs that are activated by intracellular reduction is a widely investigated approach to overcome the limitations of Pt(II) anticancer agents. A series of ten mono- and bis-carboxylated Pt(IV) complexes with axial indole-3-acetic acid (IAA) and indole-3-propionic acid (IPA) ligands were synthesized and characterized by elemental analysis, ESI-MS, FT-IR, 1H and 195Pt NMR spectroscopy. Cellular uptake, DNA platination and cytotoxicity against a panel of human tumor cell lines were evaluated. All the complexes are able to overcome cisplatin-resistance and the most potent complex, cis,cis,trans-[Pt(NH3)2Cl2(IPA)(OH)] was on average three times more active than cisplatin. Mechanistic studies revealed that the trend in cytotoxicity of the Pt(IV) complexes is primarily consistent with their ability to accumulate into cancer cells and to increase intracellular basal reactive oxygen species levels, which in turn results in the loss of mitochondrial membrane potential and apoptosis induction. The role of the indole acid ligand as a redox modulator is discussed.
The dinuclear copper(II) complex [Cu 2 {bcmp(-H)}(μ-OH)](NO 3 ) 2 ·H 2 O (1, bcmp = 2,6-bis(1,4,7-triazacyclonon-1-ylmethyl)-4-methylphenol) has been synthesized and characterized by electrospray ionization mass spectrometry, potentiometric titration and cyclovoltammetry. The X-ray structure of the analogous perchlorate salt [Cu 2 {bcmp(-H)}(μ-OH)](ClO 4 ) 2 ·2.5H 2 O (2) was determined. Cytotoxicity studies showed very promising activity of 1 against various pancreatic tumor cell lines with IC 50 values comparable or even lower than those of cisplatin. The Cu complex displayed low toxicity against a human non-tumor cell line (HEK 293) demonstrating selectivity for cancer cells. 1 converts supercoiled pUC19 plasmid DNA into the nicked form at micromolar concentrations in the absence of added reductants. A detailed kinetic study on the hydrolysis of the DNA model bis(2,4-dinitrophenyl) phosphate (BDNPP) has been performed. 1 hydrolyses BDNPP with a second order rate constant of 0.047 M s −1 at pH 8 and 40°C. Finally, single cell electrophoresis (comet assay) and fluorescence microscopy analysis showed that 1 interacts with cellular DNA and induces apoptotic cell death of Capan-1 pancreatic cancer cells. Western blotting analysis indicated that the Cu complex activates the p53 dependent pathway of apoptosis.
The dithioester (CH 2 ) 4 NCS 2 CH 3 (PyDTM, 1-pyrrolidinecarbodithioate methyl ester) has been prepared by reaction of the parent ammonium salt NH 4 PyDT ðPyDT ¼ ðCH 2 Þ 4 NCS
Keywords: Drug design / Antitumor agents / Cytotoxicity / Zinc / DNA / DNA cleavageThe dinuclear zinc complex [Zn 2 {bcmp(-H)}(μ-Cl)](ClO 4 ) 2 · H 2 O {bcmp = 2,6-bis(1,4,7-triazacyclonon-1-ylmethyl)-4-methylphenol} has been synthesized and structurally characterized. The DNA binding affinity was assessed by ethidium bromide fluorescence quenching experiments. The complex relaxes supercoiled pUC19 DNA into the nicked form at low micromolar concentration. Mechanistic studies were carried out using the DNA and RNA models bis(2,4-dinitrophenyl) phosphate (BDNPP) and 2-hydroxypropyl p-nitrophenyl
Watching closely: A fluorescent probe was engineered to detect the clinically relevant platinum drug cisplatin within a complex cellular environment, thus providing a direct means for visualizing its cell entry and the activation of platinum(IV) prodrugs in cancer cells.
The hydroxo complex cis-[L 2 Pt(µ-OH)] 2 (NO 3 ) 2 , (L ) PMePh 2 , 1a), in CH 3 CN solution, deprotonates the NH 2 group of 9-methyladenine (9-MeAd) to give the cyclic trinuclear species cis-[L 2 Pt{9-MeAd(−H)}] 3 (NO 3 ) 3 , (L ) PMePh 2 , 2a), in which the nucleobase binds the metal centers through the N(1), N(6) atoms. In solution at room temperature, 2a slowly reacts with the solvent to form quantitatively the mononuclear azametallacycle cis-[L 2 PtNHdC(Me){9-MeAd(−2H)}]NO 3 (L ) PMePh 2 , 3a), containing as anionic ligand the deprotonated form of molecule N-(9-methyl-1,9-dihydro-purin-6-ylidene)-acetamidine. In the same experimental conditions, the hydroxo complex with PPh 3 (1b) forms immediately the insertion product 3b. Single-crystal X-ray analyses of 3a and 3b show the coordination of the platinum cation at the N(1) site of the purine moiety and to the N atom of the inserted acetonitrile, whereas the exocyclic amino nitrogen binds the carbon atom of the same CN group. The resulting six-membered ring is slightly distorted from planarity, with carbon−nitrogen bond distances for the inserted nitrile typical of a double bond [C(3)− N(2) ) 1.292(7) Å in 3a and 1.279(11) Å in 3b], while the remaining CN bonds of the metallocycle are in the range of 1.335(8)−1.397(10) Å. A detailed multinuclear 1 H, 31 P, 13 C, and 15 N NMR study shows that the nitrogen atom of the inserted acetonitrile molecule binds a proton suggesting for 3a,b an imino structure in solution. In DMSO and chlorinated solvents, 3a slowly releases the nitrile reforming the trinuclear species 2a, whereas 3b forms the mononuclear derivative cis-[L 2 Pt{9-MeAd(−H)}]NO 3 (L ) PPh 3 , 4b), in which the adeninate ion chelates the metal center through the N(6) and N(7) atoms. Complex 4b is quantitatively obtained when 1b reacts with 9-MeAd in DMSO and can be easily isolated if the reaction is carried out in CH 2 Cl 2 . In CH 3 CN solution, at room temperature, 4b slowly converts into 3b indicating that the insertion of acetonitrile is a reversible process. A similar metalmediated coupling reaction occurs when 1a,b react with 1-methylcytosine (1-MeCy) in CH 3 CN. The resulting complexes, cis-[L 2 PtNHdC(Me){1-MeCy(−2H)}]NO 3 , (L ) PMePh 2 , 5a and PPh 3 , 5b), contain the deprotonated form of the ligand N-(1-methyl-2-oxo-2,3-dihydro-1H-pyrimidin-4-ylidene)-acetamidine. The X-ray analysis of 5a shows the coordination of the metal at the N(3) site of the pyrimidine cycle and to the nitrogen atom of the acetonitrile, with features of the six-membered metallocycle only slightly different from those found in 3a and 3b. In CD 3 CN/ CH 3 13 CN solution complexes 5a,b undergo exchange of the inserted nitrile, while in DMSO or chlorinated solvents they irreversibly release CH 3 CN to form species not yet fully characterized. No insertion of CH 3 CN occurs when the hydroxo complexes are stabilized by PMe 3 and PMe 2 Ph.
Five new platinum(IV) derivatives of carboplatin each incorporating the histone deacetylase inhibitor 4-phenylbutyrate in axial position were synthesized and characterized by H andPt NMR spectroscopy, electrospray ionization mass spectrometry and elemental analysis, namely cis,trans-[Pt(CBDCA)(NH)(PBA)(OH)] (1), cis,trans-[Pt(CBDCA)(NH)(PBA)] (2), cis,trans-[Pt(CBDCA)(NH)(PBA)(bz)] (3), cis,trans-[Pt(CBDCA)(NH)(PBA)(suc)] (4) and cis,trans-[Pt(CBDCA)(NH))(PBA)(ac)] (5) (PBA=4-phenylbutyrate, CBDCA=1,1-cyclobutane dicarboxylate, bz=benzoate, suc=succinate and ac=acetate). The reduction behavior in the presence of ascorbic acid was studied by high performance liquid chromatography. The cytotoxicity against a panel of human tumor cell lines, histone deacetylase (HDAC) inhibitory activity, cellular accumulation and the ability to induce apoptosis were evaluated. The most effective complex, compound 3, was found to be up to ten times more effective than carboplatin and to decrease cellular basal HDAC activity by approximately 18% in A431 human cervical cancer cells.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
334 Leonard St
Brooklyn, NY 11211
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.