DNA-cleaving Properties Research Articles

ChemInform Abstract: The Hexadehydro‐Diels—Alder Reaction: A New Chapter in Aryne Chemistry

AbstractReview: 22 refs.

Interaction of methotrexate, an anticancer agent, with copper(II) ions: coordination pattern, DNA-cleaving properties and cytotoxic studies.

The acid–base properties and the Cu(II) binding processes of methotrexate (MTX) were characterized by selected spectroscopic techniques and potentiometric measurements. The pH titration data showed that MTX behaves as a triprotic ligand. The deprotonation constants were determined for α-COOH and γ-COOH groups and (N1)H+ from the pteridine ring. Taking all the obtained results into consideration, a coordination pattern was proposed. The DNA-cleaving activity and reactive oxygen species (ROS) generation were investigated for both MTX and the Cu(II)–MTX system. The complex displayed a promising nuclease activity toward plasmid DNA in the presence of hydrogen peroxide. Interestingly, the induction of ROS, such as hydroxyl radicals, superoxide anions or singlet oxygen, was excluded and a different mechanism of DNA degradation was proposed. As MTX is now commonly used in anticancer therapy i.e. against lung cancer, basic cell-based studies were carried out to establish if its Cu(II) complex exhibits higher cytotoxic properties than the ligand alone. Activities of both compounds were also tested against colon carcinoma. Moreover, the determined values of IC50 were confronted with the cytotoxic activity of cisplatin.Electronic supplementary materialThe online version of this article (doi:10.1007/s00044-014-1074-1) contains supplementary material, which is available to authorized users.

A Tri‐copper(II) Complex Displaying DNA‐Cleaving Properties and Antiproliferative Activity against Cancer Cells

A new disubstituted terpyridine ligand and the corresponding tri-copper(II) complex have been prepared and characterised. The binding affinity and binding mode of this tri-copper complex (as well as the previously reported mono- and di-copper analogues) towards duplex DNA were determined by using UV/Vis spectroscopic titrations and fluorescent indicator displacement (FID) assays. These studies showed the three complexes to bind moderately (in the order of 10(4) M(-1)) to duplex DNA (ct-DNA and a 26-mer sequence). Furthermore, the number of copper centres and the nature of the substituents were found to play a significant role in defining the binding mode (intercalative or groove binding). The nuclease potential of the three complexes was investigated by using circular plasmid DNA as a substrate and analysing the products by agarose-gel electrophoresis. The cleaving activity was found to be dependent on the number of copper centres present (cleaving potency was in the order: tri-copper>di-copper>mono-copper). Interestingly, the tri-copper complex was able to cleave DNA without the need of external co-reductants. As this complex displayed the most promising nuclease properties, cell-based studies were carried out to establish if there was a direct link between DNA cleavage and cellular toxicity. The tri-copper complex displayed high cytotoxicity against four cancer cell lines. Of particular interest was that it displayed high cytotoxicity against the cisplatin-resistant MOLT-4 leukaemia cell line. Cellular uptake studies showed that the tri-copper complex was able to enter the cell and more importantly localise in the nucleus. Immunoblotting analysis (used to monitor changes in protein levels related to the DNA damage response pathway) and DNA-flow cytometric studies suggested that this tri-copper(II) complex is able to induce cellular DNA damage.

Initiation of DNA strand cleavage by 1,2,4-benzotriazine 1,4-dioxide antitumor agents: mechanistic insight from studies of 3-methyl-1,2,4-benzotriazine 1,4-dioxide.

The antitumor agent 3-amino-1,2,4-benzotriazine 1,4-dioxide (tirapazamine, TPZ, 1) gains medicinal activity through its ability to selectively damage DNA in the hypoxic cells found inside solid tumors. This occurs via one-electron enzymatic reduction of TPZ to yield an oxygen-sensitive drug radical (2) that leads to oxidatively generated DNA damage under hypoxic conditions. Two possible mechanisms have been considered to account for oxidatively generated DNA damage by TPZ. First, homolysis of the N-OH bond in 2 may yield the well-known DNA-damaging agent, hydroxyl radical. Alternatively, it has been suggested that elimination of water from 2 generates a benzotriazinyl radical (4) as the ultimate DNA-damaging species. In the studies described here, the TPZ analogue 3-methyl-1,2,4-benzotriazine 1,4-dioxide (5) was employed as a tool to probe the mechanism of DNA damage within this new class of antitumor drugs. Initially, it was demonstrated that 5 causes redox-activated, hypoxia-selective oxidation of DNA and small organic substrates in a manner that is completely analogous to TPZ. This suggests that 5 and TPZ damage DNA by the same chemical mechanism. Importantly, the methyl substituent in 5 provides a means for assessing whether the putative benzotriazinyl intermediate 7 is generated following one-electron reduction. Two complementary isotopic labeling experiments provide evidence against the formation of the benzotriazinyl radical intermediate. Rather, a mechanism involving the release of hydroxyl radical from the activated drug radical intermediates can explain the DNA-cleaving properties of this class of antitumor drug candidates.

Base-Catalyzed Reactivity of Sulfur- and Selenium-Bridged Cyclic Alkynes: Tandem Isomerization and Cycloaromatization versus Isomerization and Nucleophilic Addition

The synthesis and base-catalyzed reactivity of some novel sulfur- and selenium-bridged cyclic di- and tetralkynes, derived from 1,2- and 1,4-dihydroxybenzene and 1,2-bis(bromomethyl)benzene, are described. The cyclic propargylic sulfides and selenides undergo base-induced isomerization to the corresponding allenes, followed by cycloaromatization of the latter by diradical or anionic mechanisms, depending on the nature of the base. Because of the lack of stability of the expected diradical intermediate, the corresponding allenic sulfones undergo nucleophilic addition, which is responsible for their DNA-cleaving properties. (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)

Efficient relay syntheses and assessment of the DNA-cleaving properties of the pyrrole alkaloid derivatives permethyl storniamide A, lycogalic acid A dimethyl ester, and the halitulin core

Palladium catalyzed Suzuki- and Negishi cross coupling reactions are used to convert the now readily available 3,4-dibromopyrrole derivatives 13 and 26 into the core structures of different pyrrole alkaloids. Several compounds of this series exhibit respectable cytotoxicity and resensitize multidrug resistant (MDR) cancer cell lines at non-toxic concentrations. Cytotoxicity and MDR reversal can be efficiently uncoupled by per- O-methylation of the peripheral hydroxyl groups. For the storniamide core structure 9 it is demonstrated that this chemical modification goes hand in hand with a complete loss of the DNA-cleaving capacity of the alkaloid.

Total synthesis of the turrianes and evaluation of the DNA-cleaving properties.

The first total synthesis of three naturally occurring cyclophane derivatives belonging to the turriane family of natural products is described. Their sterically hindered biaryl entity is formed by reaction of the Grignard reagent derived from aryl bromide 10 with the oxazoline derivative 18, and the macrocyclic tether of the targets is efficiently forged by ring closing metathesis. While conventional RCM catalyzed by the ruthenium-carbene complexes 33 or 34 invariably leads to the formation of mixtures of both stereoisomers with the undesirable (E)-alkene prevailing, ring closing alkyne metathesis (RCAM) followed by Lindlar reduction of the resulting cycloalkynes 37 and 38 opens a convenient and stereoselective entry into this class of compounds. RCAM can either be accomplished by using the tungsten alkylidyne complex [(tBuO)3 [triple bond] WCCMe3] or by means of a catalyst formed in situ from [Mo(CO)6] and para-trifluoromethylphenol. The latter method is significantly accelerated when carried out under microwave heating. Furthermore, the judicious choice of the protecting groups for the phenolic -OH functions turned out to be crucial. PMB-ethers were found to be compatible with the diverse reaction conditions en route to 3-5; their cleavage, however, had to be carried out under carefully optimized conditions to minimize competing O-C PMB migration. Turrianes 3-5 are shown to be potent DNA cleaving agents under oxidative conditions when administered in the presence of copper ions.

Redox-activated, hypoxia-selective DNA cleavage by quinoxaline 1,4-di- N-oxide

Quinoxaline 1,4-dioxide ( 4) is the historical prototype for modern heterocyclic N-oxide antitumor agents such as 3-amino-1,2,4-benzotriazine 1,4-dioxide (tirapazamine, 1) and 3-amino-2-quinoxalinecarbonitrile 1,4-dioxide ( 11). Early experiments in bacterial cell lines suggested that enzymatic, single-electron reduction of quinoxaline 1,4-dioxides under low-oxygen (hypoxic) conditions leads to DNA damage. Here the ability of quinoxaline 1,4-dioxide to cleave DNA has been explicitly characterized using in vitro assays. The hypoxia-selective DNA-cleaving properties of 4 reported here may provide a chemical basis for understanding the cytotoxic and mutagenic activities of various quinoxaline 1,4-dioxide antibiotics.

Base catalyzed [2,3]-sigmatropic rearrangements of propargylic sulfonium and selenonium salts

The synthesis and reactivity of bis-γ-substituted and unsubstituted propargylic sulfonium and selenonium salts under various basic conditions have been investigated. While the former compounds reacted only by [2,3]-sigmatropic rearrangement of the corresponding sulfur ylides, the latter salts exhibited a wider range of reactivity and showed potent DNA-cleaving properties.

Total Synthesis and DNA-Cleaving Properties of Thiarubrine C

Total Synthesis and DNA-Cleaving Properties of Thiarubrine C

Shortcut Syntheses of Naturally Occurring 5-Alkylresorcinols with DNA-Cleaving Properties.

Resorcinols such as 1-5 bearing long alkyl- or alkenyl substituents at the C-5 position, including bola-formed bis-resorcinol derivatives, have recently been isolated from natural sources and were shown to exhibit exceptional DNA-cleaving properties under oxidative conditions. Previous synthetic approaches to such compounds seem inappropriately lengthy with regard to their structural simplicity. Disclosed is a very flexible synthesis which assembles these targets from triflate 7 and well accessible alkenes, dienes, enynes, or dienynes, respectively, by means of a boron-mediated reaction manifold. As a typical example, hexadeca-1,15-dien-8-yne 11 is hydroborated with 9-H-9-BBN at all possible sites, the alkenyl borane entity of the resulting tris-borane 12 is selectively cleaved off to afford the desired (Z)-alkene group in a stereoselective manner, the remaining two terminal alkylboranes are treated with NaOMe, and the bis-borate complex 13 thus formed is finally used as the nucleophile for a palladium-catalyzed Suzuki cross-coupling reaction with triflate 7. This sequence is carried out in one pot and provides product 14 in 62% overall yield. Demethylation of 14 (and analogues) can be conveniently achieved by means of 9-iodo-9-BBN to afford the natural product 5. The efficiency and flexibility of this unprecedented approach which combines different features of classical and modern boron chemistry is further demonstrated by the synthesis of anacardic and ginkgolic acid derivatives.

Enantioselective Synthesis of Neocarzinostatin Chromophore Aglycon

Neocarzinostatin is the first of the “enediyne” antitumor agents to be characterized and is further distinguished as the first chromoprotein antibiotic.1 The DNA-cleaving properties of the neocarzinostatin protein-chromophore complex have been shown to reside solely within the chromophore component (1) which, in isolation, is exceedingly unstable.2,3 The strain, structural complexity, and, most importantly, high reactivity of the chromophore core define an extraordinarily challenging synthetic target. In this work, we describe an enantioselective route that provides for the first time neocarzinostatin chromophore aglycon (2), a substance which proves to be even less stable than 1 and which, almost certainly, could not be derived from the parent antibiotic.

1,2-Dithiolan-3-one 1-oxides: a class of thiol-activated DNA-cleaving agents that are structurally related to the natural product leinamycin.

Leinamycin is a recently discovered, thiol-dependent DNA-cleaving natural product. The mechanism of DNA cleavage by leinamycin is unknown. Inspired by this intriguing natural product, we have investigated the DNA-cleaving properties of three 1,2-dithiolan-3-one 1-oxides (1-3) that are structurally related to the suspected DNA-cleaving "core" of leinamycin. It was found that, similar to leinamycin, these three 1,2-dithiolan-3-one 1-oxides are thiol-dependent DNA-cleaving agents. At the concentrations of 1-3 used in these experiments (approximately 100 microM), efficient DNA cleavage is absolutely dependent on added thiol, with optimum cleavage occurring at 5-10 equiv (500 microM-1 mM) of added thiol. 2-Mercaptoethanol, glutathione, dithiothreitol, and thiophenol function with approximately equal efficiency as triggering agents for the cleavage reaction. DNA cleavage by 1-3 is not highly pH-dependent. Cleavage of DNA by these sulfur heterocycles is diminished by the removal of molecular oxygen from the reaction medium, by the radical scavengers methanol, ethanol, and mannitol, and by the enzyme catalase. Superoxide dismutase does not suppress DNA cleavage by these compounds. When diethylenetriaminepentaacetic acid is employed in these reactions as a chelator of adventitious trace metal ions, DNA cleavage is efficiently inhibited. The S-deoxy analog of 1 does not cleave DNA under conditions where 1 effects efficient thiol-mediated cleavage of DNA. These experiments indicate that, in concert with thiols, 1,2-dithiolan-3-one 1-oxides convert molecular oxygen to DNA-cleaving oxygen radicals. The marked effect of catalase further suggests that molecular oxygen is converted to hydrogen peroxide which ultimately cleaves DNA via a trace metal-dependent Fenton reaction. This work demonstrates that 1,2-dithiolan-3-one 1-oxides represent a general class of thiol-potentiated DNA-cleaving molecules.

Maduropeptin: an antitumor chromoprotein with selective protease activity and DNA cleaving properties.

Maduropeptin (MDP) is a recently isolated antitumor antibiotic, consisting of an enediyne-containing chromophore embedded in a highly acidic protein. This holoantibiotic damages duplex DNA in vitro, producing a mixture of single- and double-strand breaks at selected sites. The chromophore, isolated as the methanol adduct from the protein-containing holoantibiotic, exhibits the same selectivity and cleavage chemistry as the chromoprotein complex. Preliminary evidence suggests that the primary DNA breaks involve 4'-H abstraction from the deoxyribose sugars at the cleavage sites. Unlike most other enediyne antitumor antibiotics, DNA strand scission is not bioreductively induced by MDP or the methanol adduct of the chromophore. This was also observed for the C1027 chromophore. DNA cleavage is inhibited in the presence of certain cations (Ca2+, Mg2+) as was observed with the kedarcidin chromophore. 1H NMR spectroscopy studies on the methanol adduct of the maduropeptin chromophore in the presence of calcium chloride provide clues regarding its activation and give insight as to the regions of the chromophore important for DNA binding. Our results suggest that the solvent artifact of the chromophore may in essence be a prodrug and it regenerates the parent chromophore as in the holoantibiotic prior to cleaving DNA. As with kedarcidin and neocarzinostatin, maduropeptin exhibits a high affinity for histones, in vitro, cleaving them to low molecular mass peptides. Histone H1, the most opposite in net charge, is cleaved most readily. This latter activity may serve to disrupt the chromatin superstructure in vivo, prior to exposing the DNA to the chromophore.

(1R)-4,5-Benzocyclodeca-4-ene-2,6-diyn-1-yl 2,3,4,6-Tetra-O-acetyl-β-D-glucopyranoside and 4,5-Benzocyclodeca-4-ene-2,6-diyn-1-one

The title compounds, C 28 H 30 O 10 and C 14 H 10 O, have been synthesized during the course of a program designed to prepare molecules with DNA-cleaving properties. The geometry of the strained benzodiyne system has been determined, the S configuration at the propargylic center established and the orientation of the sugar unit in relation to the aglycon defined. The results are compared with those for other derivatives. The molecular packing is governed by normal van der Waals interactions

Calicheamicin θ: A Rationally Designed Molecule with Extremely Potent and Selective DNA Cleaving Properties and Apoptosis Inducing Activity

The attack of a thiolate ion on the trisulfide unit of natural calicheamicin γ (1) activates it to form a diradical, which then attacks DNA. Thioacetate 2 is even more readily activated—under mildly basic conditions caused by OH- ions—and likewise exhibits extremely interesting biological properties.

Redox-controlled Bergman cycloaromatizations. Designed enediynes with DNA-cleaving properties and antitumor activity

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTRedox-controlled Bergman cycloaromatizations. Designed enediynes with DNA-cleaving properties and antitumor activityK. C. Nicolaou, A. Liu, Z. Zeng, and S. McCombCite this: J. Am. Chem. Soc. 1992, 114, 24, 9279–9282Publication Date (Print):November 1, 1992Publication History Published online1 May 2002Published inissue 1 November 1992https://doi.org/10.1021/ja00050a006RIGHTS & PERMISSIONSArticle Views436Altmetric-Citations73LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (498 KB) Get e-Alerts Get e-Alerts

Design, synthesis, and study of simple monocyclic conjugated enediynes. The 10-membered ring enediyne moiety of the enediyne anticancer antibiotics

Following the discovery of the enediyne anticancer antibiotics, investigations were initiated directed toward the design, synthesis, and study of simple monocyclic conjugated enediynes. In this article the synthesis of the parent 10-membered ring enediyne found in the enediyne natural products and its properties are described. In addition to the parent hydrocarbon 27, the synthetic methodology developed based on the Ramberg-Blcklund reaction delivers a series of higher ring homologs (17-22) and the water soluble version of the 10-membered ring compound 47. Molecular mechanics calculations on these systems led to a number of geometrical parameters which correlated well with their tendencies to undergo the Bergman cycloaromatization reaction. Kinetic studies on the Bergman cycloaromatization of the 10-membered ring enediynes 27 and 47 led to the following thermodynamic values: 27, energy of activation (E,) = 23.8 kcal/mol, AG* (37 C) = 24.6 kcal/mol; 47, energy of activation (E,) = 31.5 kcal/mol, AG' (37 C) = 24.8 kcal/mol. The designed enediyne 47 showed potent DNA-cleaving properties becoming the first synthetic molecule to mimic the action of the naturally occurring enediynes in this regard.

Ten‐Membered Ring Enediynes with Remarkable Chemical and Biological Profiles

The large effects of minimal structural variations are demonstrated by enediynes 1. At 50 °C the cis isomer cyclizes much faster (t1/2 = 4 h) than the trans isomer (t1/2 = 22 h). The carbonate derivative of trans-l is stable even for several hours at 100 °C. The exploration of the chemistry of cyclic enediynes is prompted by their DNA-cleaving properties.

Design and synthesis of 1-thia-3,8-diyn-5-ene systems with DNA-cleaving properties related to the neocarzinostatin chromophore

1-Thia-3,8-diyn-5-ene compounds 5–10, which are derivatives of the parent compound 1 are synthesized in a short step with high stability; these compounds show DNA-cleaving activity under basic conditions in the absence of any additives.