Molecular complexes of some anthraquinone anti-cancer drugs: experimental and computational study

It is known that anti-cancer drugs target DNA in the cell. The mechanism of interaction of anti-cancer drugs with DNA is not fully understood. It is thought that the forces of interaction have some contribution from charge-transfer (CT) binding. The ability of some anthraquinones (AQs) anti-cancer drugs to form CT complexes with well-known electron donor molecules was investigated by NMR. The NMR spectroscopy has indicated the formation of CT complexes between 1,4-bis[[2-(dimethylamino) ethyl]amino]-5,8-dihydroxyanthracene-9,10-dione, (AQ4), and its des-hydroxylated equivalent 1,4-bis[[2-(dimethylamino) ethyl]amino]anthracene-9,10-dione, (AQ4H), as electron acceptors and pyrene (PY) and hexamethylbenzene (HMB) as electron donors. Association constants of the formed CT complexes were determined from the NMR data. AQ4 showed weaker electron accepting power than AQ4H, which could be easily explained on the basis of the electron donating nature of the two-hydroxyl groups. AQ4 and AQ4H have higher stability constant with PY than with HMB. This reflects the weaker interaction of the AQs with the latter, which is a direct effect of the six bulky methyl groups. Electronic absorption spectroscopy of the studied system was performed in chloroform and showed the absence of new absorption bands. The extent of interaction between AQs and donors has been computed using molecular mechanics and quantum mechanics. The computed values were compared with the experimental results of association constants.     

Amino-anthraquinone chromophores functionalised with 3-picolyl units: structures, luminescence, DFT and their coordination chemistry with cationic Re(I) di-imine complexes

The syntheses of four new ligands based upon 3-picolyl functionalised amino anthraquinone (AQ) chromophores are described via a one-pot reductive amination procedure giving the desired ligands L1-L4 (L1, 1-(3-picolylamino)anthracene-9,10-dione; L2, 1-hydroxy-4-(3-picolylamino)anthracene-9,10-dione; L3, 1,4-bis(3-picolylamino)anthracene-9,10-dione; L4, 1,5-bis(3-picolylamino)anthracene-9,10-dione). Each ligand was characterised in solution via(1)H and (13)C{(1)H} NMR, with three examples giving single crystal X-ray diffraction data. The structures confirmed the proposed formulations and also revealed the presence of intramolecular H-bonding between the quinone and secondary amine units. The electronic characteristics of the ligands were investigated using a combined experimental/theoretical approach, revealing that in each case absorption in the visible region constitutes significant charge transfer (CT) character, originating from N-(amine)-to-quinone transitions, and is solvent sensitive. Density functional theory (DFT) calculations also suggest that the position of amino-substitution at the AQ core influences the wavelength of the lowest energy feature, by modulation of the HOMO, rather than the LUMO energy. The coordination chemistry of the ligands was probed through reaction with fac-[Re(CO)(3)(di-imine)(MeCN)](BF(4)) where di-imine = 1,10-phenanthroline (phen) and 2,9-dimethyl-1,10-phenanthroline (dmp). Combined structural and spectroscopic studies confirmed that the ligands coordinate to Re(i) exclusively via the pyridyl units, however in the case of L3 only monometallic complexes were isolated. The optical properties of the complexes are dominated by AQ-centred (>425 nm) absorptions superimposed upon (1)MLCT features, as well as diimine-based intra-ligand (<350 nm) transitions. The luminescence properties of the complexes generally display dual emission, which was dependent upon the wavelength of sensitisation, with short-lived AQ fluorescence superimposed upon long-lived (3)MLCT phosphorescence.     

Tautomeric composition and tautomeric transformation sequence of 1,4-bis(alkylamino)anthraquinones

Compounds widely known as 1,4-bis(alkylamino)-9,10-anthraquinones are in fact neither individual substances nor substituted 9,10-anthraquinones but equilibrium mixtures of tautomers. Their aminoimine tautomeric transformations follow the sequence 4,9-bis(alkylamino)-1,10-anthraquinones ? 9-alkylamino-4-(alkylimino)-10-hydroxy-1,4-dihydroanthracen-1-ones ? N ¹,N ¹⁰-dialkyl-4,9-dihydroxy-1,10-dihydroanthracene-1,10-diimines.     

Chlorination of 2,3,6-trialkyl-5,8-dihydroxy-1,4-naphthoquinones with HCl-MnO<Subscript>2</Subscript> in acetic acid. effective transformation of 2,3,6-trialkyl-2,3,7-trichloro-1,2,3,4-tetrahydronaphthalene-1,4-diones into 7-chloro-2,3,6-trialkyl-5,8-dihydroxy-1,4-naphthoquinones

Chlorination of 2,3,6-trialkyl-5,8-dihydroxy-1,4-naphthoquinones with HCl-MnO₂ in acetic acid gave a mixture of 7-chloro-2,3,6-trialkyl-5,8-dihydroxy-1,4-naphthoquinones and 2,3,7-trichloro-2,3,6-trialkyl-1,2,3,4-tetrahydronaphthalene-1,4-diones, the latter being formed via addition of the second chlorine molecule to monochloro derivatives. The reduction of 2,3,7-trichloro-2,3,6-trialkyl-1,2,3,4-tetrahydronaphthalene-1,4-diones with sodium dithionite in alkaline medium resulted in the formation of 7-chloro-2,3,6-trialkyl-5,8-dihydroxy-1,4-naphthoquinones in high yield.     

Etude des voies d'accès aux aminométhyl benzo[g]isoquinoléinediones-5,10. Mise en évidence d'une substitution anormale au cours de la réaction de Bischler-Napieralski en série diméthoxy-1,4 naphthalène

Under the conditions of the Bischler-Napieralski reaction the cyclization of 2-(1,4-dimethoxy and 1,4,8-trimethoxynaphthyl)ethylacetamides derivatives take place essentially at the 1 position by substitution of the 1-methoxy group. Nevertheless, 1-aminomethyl-9,10-azaanthraquinones are accessibles by condensation of 1-aminomethylisoquinoline-5,8-diones with a 1,4-diacetoxy-1,3-butadiene.     

Synthesis, characterisation and optical spectroscopy of platinum(II) di-ynes and poly-ynes incorporating condensed aromatic spacers in the backbone

A series of protected and terminal dialkynes with extended pi-conjugation through a condensed aromatic linker unit in the backbone, 1,4-bis(trimethylsilylethynyl)naphthalene, 1,4-bis(ethynyl)naphthalene, 9,10-bis(trimethylsilylethynyl)anthracene, 9,10-bis(ethynyl)anthracene, have been synthesized and characterized spectroscopically. The solid-state structures of and have been confirmed by single crystal X-ray diffraction studies. Reaction of two equivalents of the complex trans-[Ph(Et(3)P)(2)PtCl] with an equivalent of the terminal dialkynes 1,4-bis(ethynyl)benzene and, in (i)Pr(2)NH-CH(2)Cl(2), in the presence of CuI, at room temperature, afforded the platinum(II) di-ynes trans-[Ph(Et(3)P)(2)Pt-C[triple bond, length as m-dash]C-R-C[triple bond, length as m-dash]C-Pt(PEt(3))(2)Ph](R = benzene-1,4-diyl; naphthalene-1,4-diyl and anthracene-9,10-diyl ) while reactions between equimolar quantities of trans-[((n)Bu(3)P)(2)PtCl(2)] and under similar conditions readily afforded the platinum(II) poly-ynes trans-[-((n)Bu(3)P)(2)Pt-C[triple bond]C-R-C[triple bond]C-](n)(R = naphthalene-1,4-diyl and anthracene-9,10-diyl ). The Pt(II) diynes and poly-ynes have been characterized by analytical and spectroscopic methods, and the single crystal X-ray structures of and have been determined. These structures confirm the trans-square planar geometry at the platinum centres and the linear nature of the molecules. The di-ynes and poly-ynes are soluble in organic solvents and readily cast into thin films. Optical spectroscopic measurements reveal that the electron-rich naphthalene and anthracene spacers create strong donor-acceptor interactions between the Pt(II) centres and conjugated ligands along the rigid backbone of the organometallic polymers. Thermogravimetry shows that the di-ynes possess a somewhat higher thermal stability than the corresponding poly-ynes. Both the Pt(II) di-ynes and the poly-ynes exhibit increasing thermal stability along the series of spacers from phenylene through naphthalene to anthracene.     

Isolation and characterisation of three new anthraquinone secondary metabolites from Symplocos racemosa

Three new anthraquinone secondary metabolites were isolated from Symplocos racemosa, a small tree of family symplocaceae. The structures of compounds (1–3) were elucidated to be 1,4-dihydroxy-6-(ethoxymethyl)-8-propylanthracene-9,10-dione (1), 1,4-dihydroxy-6-(hydroxymethyl)-8-butylanthracene-9,10-dione (2) and 1,4-dihydroxy-6-(hydroxymethyl)-8-propyl anthracene-9,10-dione (3) using their spectral data, i.e. through IR, UV, ¹H NMR, ¹³C NMR and two-dimensional (2D) NMR techniques including heteronuclear multiple quantum coherence, heteronuclear multiple bond correlation and correlation spectroscopy.     

Highly Efficient and Practical Syntheses of Lavendamycin Methyl Ester and Related Novel Quinolindiones

The novel 7-(N-formyl-, 7-(N-acetyl-, and 7-(N-isobutyrylamino)-2-methylquinoline-5,8-diones were synthesized in excellent overall yields in three steps via the nitration of the commercially available 8-hydroxy-2-methylquinoline followed by a reduction-acylation step and then oxidation. Acid hydrolysis of 7-(N-acetylamino)-2-methylquinoline-5,8-dione (14a) afforded the novel 7-aminoquinoline-5,8-dione 7 in excellent yields. Due to our efficient preparation of dione 14a, we now report a short and practical method for the total synthesis of the potent antitumor agent lavendamycin methyl ester (1b) with an excellent overall yield.     

An efficient synthesis of ([F]fluoropropyl)quinoline-5,8-diones by rapid radiofluorination-oxidative demethylation

Since many molecules bearing quinoline-5,8-dione or fused 1,4-quinone moieties possess a wide spectrum of biological activities, efficient methods for incorporation of fluorine-18 (F-18) into quinoline-5,8-diones have received considerable attention in positron emission tomography (PET) molecular imaging studies. In this paper, we describe an efficient synthetic route for the regioselective preparation of fluoropropyl-substituted quinoline-5,8-diones on the C3, C4, and C6 positions by tert-alcohol media fluorination, followed by oxidative demethylation of the corresponding dimethoxy compound using N-bromosuccinimide (NBS) in the presence of catalytic amounts of sulfuric acid. Moreover, F-18 labeled [¹⁸F]fluoropropylquinoline-5,8-diones [¹⁸F]21-23 were prepared from the corresponding mesylate precursors by a method of rapid and efficient one-pot, two-step reactions: radiofluorination using TBA [¹⁸F]F generated under no-carrier-added (NCA) conditions; oxidative demethylation, resulting in a 45% radiochemical yield of [¹⁸F]21-23 (decay-corrected) with a total synthesis time (including HPLC purification) of 75 min and high radiochemical purity (>99%), as well as high specific activity (∼230 GBq/μmol).     

Examination of the distribution of the bioreductive drug AQ4N and its active metabolite AQ4 in solid tumours by imaging matrix-assisted laser desorption/ionisation mass spectrometry

AQ4N (banoxatrone) (1,4-bis-{[2-(dimethylamino-N-oxide)ethyl]amino}-5,8-dihydroxyanthracene-9,10-dione) is an example of a bioreductive prodrug in clinical development. In hypoxic cells AQ4N is reduced to the topoisomerase II inhibitor AQ4 (1,4-bis- {[2-(dimethylamino)ethyl]amino}-5,8-dihydroxyanthracene-9,10-dione). By inhibition of topoisomerase II within these hypoxic areas, AQ4N has been shown to sensitise tumours to existing chemo- and radiotherapy treatments. In this study the distribution of AQ4N and AQ4 in treated H460 human tumour xenografts has been examined by imaging matrix-assisted laser desorption/ionisation mass spectrometry. Images of the distribution of AQ4N and AQ4 have been produced that show little overlap. The distribution of ATP in the tumour xenografts was also studied as an endogenous marker of regions of hypoxia since concentrations of ATP are known to be decreased in these regions. The distribution of ATP was similar to that of AQ4N, i.e. in regions of abundant ATP there was no evidence of conversion of AQ4N into AQ4. This indicates that the cytotoxic metabolite AQ4 is confined to hypoxic regions of the tumour as intended.     

Photoionization studies on various quinones by an infrared laser desorption/tunable VUV photoionization TOF mass spectrometry

Photoionization and dissociative photoionization characters of six quinones, including 1,2-naphthoquinone (1,2-NQ), 1,4-naphthoquinone (1,4-NQ), 9,10-phenanthroquinone (PQ), 9,10-anthraquinone (AQ), benz[a]- anthracene-7,12-dione (BAD) and 1,2-acenaphthylenedione (AND) have been studied with an infrared laser desorption/tunable synchrotron vacuum ultraviolet (VUV) photoionization mass spectrometry (IR LD/VUV PIMS) technique. Mass spectra of these compounds are obtained at different VUV photon energies. Consecutive losses of two carbon monoxide (CO) groups are found to be the main fragmentation pathways for all the quinones. Detailed dissociation processes are discussed with the help of ab initio B3LYP calculations. Ionization energies (IEs) of these quinones and appearance energies (AEs) of major fragments are obtained by measuring the photoionization efficiency (PIE) spectra. The experimental results are in good agreement with the theoretical data.     

Synthesis of 1,2-bis(methoxyamino)cycloalkanes from alicyclic 1,2-bis(hydroxyamines)

Derivatives of 1,4-dihydroxypiperazine-2,3-dione were obtained by reaction of cis-1,2-bis(hydroxyamino)cycloalkanes with diethyl oxalate. Their alkylation with CH₂N₂ or Mel afforded 1,4-dimethoxypiperazine-2,3-diones. Hydrolysis of the latter gave 1,2-bis(methoxyamino)cycloalkanes.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 4, pp. 925–929, April, 1996.     

Aza-polycyclic aromatic hydrocarbons: 1—Elucidation of the regiochemistry of 1,2,3,4-tetrahydroazabenz-[a]anthracene-7,12-diones by long-range carbon–proton coupling constants

The ¹³C NMR spectra of 5,8-quinolinedione, 6-chloro-5,8-quinolinedione and 7-chloro-5,8-quinolinedione have been examined in detail. Utilization of long-range proton-carbon coupling constants have allowed the unambiguous identification of the regioisomeric 8-aza-1,2,3,4-tetrahydrobenz[a]anthracene-7,12-dione and 11-aza-1,2,3,4-tetrahydrobenz[a]anthracene-7,12-dione.     

Chelating, bridging, and chain structures within Ag(I) and Cu(I) complexes of bis(nicotinyloxy), bis(isonicotinyloxy), and bis(pyrimidine-5-carboxyloxy)-1,8-disubstituted anthraquinone ligands

Reaction of Ag(I) and Cu(I) [M(NCCH₃)₄]X (X = BF₄⁻ and PF₆⁻) salts with 1,8-bis(nicotinyloxy)anthracene-9,10-dione (1), 1,8-bis(isonicotinyloxy)anthracene-9,10-dione (2), and 1,8-bis(pyrimidine-5-carboxyloxy)anthracene-9,10-dione (3), yield new chelating and bridging complexes and two new coordination polymers. The bridging capabilities of ligands 1 and 2 have not been demonstrated before, and ligand 1, by itself, has the flexibility to produce either chelated or bridged structures and an unusual ladder coordination polymer. The tetradentate ligand 3 also produces a one-dimensional coordination polymer in the presence of one equivalent of Ag(I). All complexes have been characterized by X-ray crystallography.     

Synthese von Plectranthonen,diterpenoiden Phenanthren-1,4-chinonen

Synthesis of Plectranthons, Diterpenoid Phenanthrene-1,4-diones The following phenanthrene-1,4-diones have been synthesized by using the photocyclization of the corresponding highly substituted stilbenes as the key step: 3-hydroxy-5,7,8-trimethyl-2-(prop-2-enyl)phenanthrene-1,4-dione ( 1 ), (RS)-, (R)-, and (S)-2-[3-hydroxy-5,7,8-trimethyl-1,4-dioxophenanthren-2-yl]-1-methylethyl acetate ( 2 , 31 , and 32 , resp.), 3-hydroxy-7,8-dimethyl-2-(prop-2-enyl)phenanthrene-1,4-dione ( 3 ), 3-hydroxy-7,8,10-tri-methyl-2-(prop-2-enyl)phenanthrene-1,4-dione ( 4 ), 5,7,8-trimethyl-2-(prop-2-enyl)phenanthrene-1,4-dione ( 17 ), and 3-hydroxy-2-methylphenanthrene-1,4-dione ( 42 ). The quinones 1 and 3 proved to be identical with the recently isolated plectranthons A and C. Compounds 2 , 31 , and 32 exhibited the same UV/VIS, IR, ¹H-NMR and mass spectra as natural plectranthon B , but had different melting points. This might be due either to crystal modifications or to diastereoisomerism caused by the helical structure of the phenanthrene-1,4-dione skeleton. The spectral data of synthetic 4 were not compatible with those of natural plectranthon D for which structure 4 had been proposed based mainly on ¹H-NMR arguments concerning the chemical shifts of H? C(9) and H? C(10) in 1–3. Extensive ¹H-NMR investigations have now revealed that the currently stated assignments of the H? C(9)/ H? C(10) AB system have to be reversed for highly substituted phenanthrene-1,4-diones: in the model compounds 2-methylphenanthrene-1,4-dione (41) and 2, H? C(10) resonates al lower field as expected (peri-position), whereas in the highly substituted congeners 1 , 2 , 3 , 31 , and 32 , H? C(9) is shifted paramagnetically, a fact which had lead to the erroneous assignment of structure 4 for natural plectranthon D .     

Polyfunctional macroheterocycles

The reaction of 1-[1,2-bis(carbomethoxy)ethyl]aziridine with ethane-1,2-dithiol leads to 1.8-bis[1,2-bis(carbomethoxy)ethylamino]-3,6-dithiaoctane. Condensation with phthalic and terephthalic acid dichloride gives 9,10-benzo-8, 11-dioxo-7,12-bis[1,2-bis(carbomethoxy)ethyl]-1,4-dithia-7,12-diazacyclotetradec-9-ene and 9,12-benzo-8,13-dioxo-7,14-bis[1,2-bis(carbomethoxy)ethyl]-1,4-dithia-7,14-diazacyclohexadeca-9,12-diene, respectively, while condensation with formaldehyde gives 7,9,18,20-tetrakis[1,2-bis(carbomethoxy)ethyl]-1,4,12,15-tetrathia-7,9,18.29-tetraazacyclodocosane. The corresponding disulfone is formed in the oxidation of 9,10-benzo-8,11-dioxo-7,12-bis[1,2-bis(carbomethoxy) ethyl]-1,4-dithia-7,12-diazacyclotetradec-9-ene with 30% hydrogen peroxide.See [1] for Communication 1.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1563–1565, November, 1988.     

Rigid Scaffolds: Synthesis of 2,6-Bridged Piperazines with Functional Groups in all three Bridges

The activity of pharmacologically active compounds can be increased by presenting a drug in a defined conformation, which fits exactly into the binding pocket of its target. Herein, the piperazine scaffold was conformationally restricted by substituted C₂- or C₃-bridges across the 2- and 6-position. At first, a three-step, one-pot procedure was developed to obtain reproducibly piperazine-2,6-diones with various substituents at the N-atoms in high yields. Three strategies for bridging of piperazine-2,6-diones were pursued: 1. The bicyclic mixed ketals 8-benzyl-6-ethoxy-3-(4-methoxybenzyl)-6-(trimethylsilyloxy)-3,8-diazabicyclo[3.2.1]octane-2,4-diones were prepared by Dieckmann analogous cyclization of 2-(3,5-dioxopiperazin-2-yl)acetates. 2. Stepwise allylation, hydroboration and oxidation of piperazine-2,6-diones led to 3-(3,5-dioxopiperazin-2-yl)propionaldehydes. Whereas reaction of such an aldehyde with base provided the bicyclic alcohol 9-benzyl-6-hydroxy-3-(4-methoxybenzyl)-3,9-diazabicyclo[3.3.1]nonane-2,4-dione in only 10 % yield, the corresponding sulfinylimines reacted with base to give N-(2,4-dioxo-3,9-diazabicyclo[3.3.1]nonan-6-yl)-2-methylpropane-2-sulfinamides in >66 % yield. 3. Transformation of a piperazine-2,6-dione with 1,4-dibromobut-2-ene and 3-halo-2-halomethylprop-1-enes provided 3,8-diazabicyclo[3.2.1]octane-2,4-dione and 3,9-diazabicyclo[3.3.1]nonane-2,4-dione with a vinyl group at the C₂- or a methylene group at the C₃-bridge, respectively. Since bridging via sulfinylimines and the one-pot bridging with 3-bromo-2-bromomethylprop-1-ene gave promising yields, these strategies will be exploited for the synthesis of novel receptor ligands bearing various substituents in a defined orientation at the carbon bridge     

The synthesis of 6,9-difluorobenzo[g]quinoline-5,10-dione. Displacements of the fluorides by diamines which lead to 6,9-bis[(aminoalkyl)amino]benzo[g]quinoline-5,10-diones

The synthesis of 6,9-difluorobenzo[g]quinoline-5,10-dione ( 3b ) is described. Facile ipso substitutions of the fluorides from 3b by diamines readily yield the corresponding 6,9-bis[(aminoalkyl)amino]benzo-[g]quinoline-5,10-diones 2 . The analogue 2d has been synthesized by side arm modifications of dione 8a .     

The aza-analogues of 1,4-naphthoquinones are potent substrates and inhibitors of plasmodial thioredoxin and glutathione reductases and of human erythrocyte glutathione reductase

Various aza-analogues of 1,4-naphthoquinone and menadione were prepared and tested as inhibitors and substrates of the plasmodial thioredoxin and glutathione reductases as well as the human glutathione reductase. The replacement of one to two carbons at the phenyl ring of the 1,4-naphthoquinone core by one to two nitrogen atoms led to an increased oxidant character of the molecules in accordance with both the redox potential values and the substrate efficiencies. Compared to the 1,4-naphthoquinone and menadione, the quinoline-5,8-dione 1 and both quinoxaline-5,8-diones 5 and 6 behaved as the most efficient subversive substrates of the three NADPH-dependent disulfide reductases tested. Modulation of these parameters was observed by alkylation of the aza-naphthoquinone core.     

Synthesis of benzo[f]isoindole-4,9-diones

A synthesis of benzo[f]isoindole-4,9-diones 1 is presented starting from the reaction of 2,3-bis(bromomethyl)-1,4-dimethoxynaphthalene 15 with primary amines affording 2,3-bis(aminomethyl)-1,4-dimethoxynaphthalenes 14, which could be converted by CAN-mediated oxidation in one step to benzo[f]isoindole-4,9-diones 1. An alternative synthesis of benzo[f]isoindole-4,9-diones 1 starts from 2,3-bis(bromomethyl)-1,4-naphthoquinone 9 via 2,3-dihydrobenzo[f]isoindoles 10 which spontaneously oxidize.