Search

There is enough proof to believe that free-radical intermediates of anthracycline based anticancer agents are involved in different stages of drug action. Subtle therapeutic differences observed in the actions of different anthracyclines largely influence the mechanism of action of the drugs that distinguish one member from another. Redox properties control biological responses related either to the one-electron quinone/semiquinone couple or the two-electron quinone/quinone-dianion couple. Comproportionation also leads to generation of semiquinone. Hence, whatever the form of reduction of the quinone moiety, a substantial amount of semiquinone is eventually formed in the system. Immediately after formation, there is competition between natural radical-decay pathways and one-electron transfer reactions that generate the superoxide-radical anion. Prototropic properties control rate of radical decay while redox properties control rate of electron transfer to molecular oxygen. In aerated medium, semiquinone-radical anion and superoxide-radical anion co-exist while in de-aerated medium semiquinone-radical anion predominates. All the radicals are damaging to the biological system. Through this study, attempt was made to detect changes induced by the radicals on pyrimidine based nucleic acid bases and calf thymus DNA in aerated and de-aerated (Ar saturated) medium to know the mechanism by which Emodin, its Cu II /Mn II complexes might affect DNA. Semiquinone-radical anion was generated electrochemically maintaining a glassy carbon electrode at the first reduction potential of each compound. Since the chosen compound (Emodin), its complexes are analogues of anthracyclines, findings on them can be extrapolated to understand the differences in anticancer activity or of adverse drug reactions reported in an innumerable number of clinical studies related to anthracyclines where the difference in structure of different members is due to differences in the relative positioning of hydroxy groups on the hydroxy-9, 10-anthraquinone moiety of anthracyclines. The study helps to realize action of compounds of this class as anticancer agents., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Copper(II) forms a complex with sodium 1,4-dihydroxy-9,10-anthraquinone-2-sulphonate (sodium quinizarin-2-sulphonate, NaQSH(2)), an analogue of the core unit of anthracycline antibiotics used in the treatment of cancer. The 1:2 metal-ligand complex is formed in aqueous solution at neutral and acidic pH while in alkaline pH both 1:1 and 1:2 species are formed. The effective stability constant of the 1:2 metal-ligand complex is 9.64x10(16) while that of the 1:1 metal-ligand complex is 9.4x10(9). The 1:2 complex Cu(NaQSH)(2)(H(2)O)(2) was synthesized and characterized by different techniques in solid state and in solution. The complex Cu(NaQSH)(2)(H(2)O)(2) interacts with calf thymus DNA which was studied by fluorescence spectroscopy. The binding constant and site size for the interaction with DNA were determined.

Hydroxy-9,10-anthraquinones are structural analogues of anthracycline anticancer drugs showing similarity in physicochemical attributes, electrochemical behavior and biophysical interactions. 1,2-dihydroxy-9,10-anthraquinone (Q) and its complexes with Cu(II)/Ni(II) were studied for γ radiation induced modification of DNA in Chinese Hamster V79 cells. The amount of double stranded DNA remaining was ascertained by fluorometric analysis of DNA unwinding using ethidium bromide. Modification of double stranded DNA increased in the presence of Q and Cu(II)-Q when cells were irradiated (0-4.2 Gray). Ni(II)-Q was not that effective. Changing incubation time before recovery of DNA from cells there was evidence for DNA repair that was least for Cu(II)-Q treated cells. Minimum repair in case of Cu(II)-Q treated cells suggest the compound either assists radiation induced damage of agents responsible for repair or interacts with species like HO that assist in repair. Since a hydroxy-9,10-anthraquinone and its Cu(II) complex show radiosensitizing property, anthracyclines that contain a hydroxy-9,10-anthraquinone as the core moiety could also be tried as radiosensitizers in treating cancer. Graphical Abstract: .[Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]

Electrochemical behavior of the anticancer drug doxorubicin hydrochloride was studied using cyclic voltammetry in aqueous medium using Hepes buffer (pH~7.4). At this pH, doxorubicin hydrochloride undergoes a reversible two-electron reduction with E1/2 value -665 ± 5 mV (versus Ag/AgCl, saturated KCl). Depending on scan rates, processes were either quasireversible (at low scan rates) or near perfect reversible (at high scan rates). This difference in behavior of doxorubicin hydrochloride with scan rate studied over the same potential range speaks of differences in electron transfer processes in doxorubicin hydrochloride. Attempt was made to identify and understand the species involved using simulation. The information obtained was used to study the interaction of doxorubicin hydrochloride with calf thymus DNA. Cathodic peak current gradually decreased as more calf thymus DNA was added. The decrease in cathodic peak current was used to estimate the interaction of the drug with calf thymus DNA. Nonlinear curve fit analysis was applied to evaluate the intrinsic binding constant and site size of interaction that was compared with previous results on doxorubicin hydrochloride-DNA interaction monitored by cyclic voltammetry or spectroscopic techniques [ABSTRACT FROM AUTHOR]

Hydroxy-9,10-anthraquinones resemble anthracycline-based anticancer drugs. By varying the pH of the solution, the proton dissociation constants of 1,2,5,8-tetrahydroxy-9,10-anthraquinone (THAQ) were determined. Interaction of THAQ with calf thymus DNA (ct DNA) was studied by UV-Vis spectroscopy to determine the overall binding constant and site size of interaction. The binding constant values (~104) for THAQ interacting with ct DNA at different pH were an order less than that known for anthracyclines. From knowledge of the overall binding constants at different pH values and the first pK of THAQ, the contribution of each form (neutral and monoanionic) towards overall binding with ct DNA could be obtained under physiological conditions. Hence, knowing the contributions of the neutral and monoanionic forms, it now becomes possible to know the overall binding constant for an interaction of THAQ with ct DNA at any pH. The calculated parameters help in understanding the role of the negative charge on the monoanionic form during interaction and suggests suitable chemical modifications that could prevent the development of such negative charges. This could lead to an increase in binding of THAQ to ct DNA. The study also helps to recognize the importance of sugar units in anthracycline anticancer drugs in DNA interaction. Copyright © 2011 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Anthracyclines are broad-spectrum antibiotics that are used against several human cancers. Hydroxy-9,10-anthraquinone compounds closely resemble anthracycline antibiotics from a structural and functional viewpoint. High cost and aspects of toxicity introduce limitations on its use. On complex formation the toxicities of anthracyclines decrease. A close analogue is sodium 1,4-dihydroxy-9,10-anthraquinone-2-sulphonate (AS), which is a comparatively cheaper molecule and resembles a good number of anthracycline derivatives. It forms a complex with CuII, [Cu(AS)2]. The complex interacts with calf thymus DNA that was studied by UV/Vis spectroscopy and cyclic voltammetry. The experimental data obtained from the two techniques was analyzed for binding constant and size of the binding site. These results not only corroborate each other but also justify earlier data obtained using fluorescence spectroscopy. An important aspect to this study was that nonlinear curve fitting, which is usually applied for analyzing DNA interaction using fluorescence and absorption spectroscopy, was used for the first time to analyze the interaction of the complex with DNA using cyclic voltammetry by monitoring the change in the reduction peak current ( Ip). The DNA binding data provides an insight into a probable mode of action of the hydroxy-9,10-anthraquinones within cells as modification of DNA that leads to cell death is an important aspect in cancer research. [ABSTRACT FROM AUTHOR]

Anthracycline drugs show anticancer activity, an ability to inhibit DNA replication and RNA transcription but are costly. This study attempts to see if cheaper hydroxy-9,10-anthraquinones (1,2,4-trihydroxy-9,10-anthraquinone) that structurally resemble anthracyclines mimic its biological interactions and whether it can be a suitable substitute. Proton dissociation at 298 K for THA, pK1 = 4.82 ± 0.05 (phenolic OH at C2) and particularly pK2 = 9.22 ± 0.05 (phenolic OH at C1 and C4) closely resemble those of the anthracyclines. THA undergoes a single step two-electron reduction in aqueous media (pH 7.36) having E1/2 = −0.69 V and two successive single-electron reduction in DMF having E1/2 values −0.70 V and −1.06 V, respectively. CV data showed quasi-reversible nature of THA in aqueous media. E1/2 values of THA were comparable to anthracycline drugs suggesting similarity in redox behavior. Binding studies of THA to ct DNA using UV-Vis and fluorescence spectroscopy were analyzed. Intrinsic binding constant and site size of interaction were (4.80 ± 0.2) × 104 M−1 and (5.96 ± 0.3) bases, respectively. THA, approximately three to five times weaker in binding ct DNA than anthracycline anticancer drugs suggests a role for sugar moieties present in anthracyclines. Anti-leukemic activity studies of THA on cultured MOLT-4 cell lines were performed and apoptosis measured by MTT assay. Result indicates THA to be a potent inducer of apoptosis in MOLT-4 cell line having an IC50 value of 33.8 µM. THA therefore possesses anti-leukemic activity that is comparable to anthracyclines on P388 leukemia and the study reveals that 1,2,4-trihydroxy-9,10-anthraquinone to be a suitable substitute to the costlier anthracyclines. Copyright © 2011 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The anthracycline drugs adriamycin and daunorubicin, efficient in the treatment of various human cancers, form strong intercalation complexes with DNA. The therapeutic efficacy and toxicity of such anticancer drugs are governed by biochemical reactions of the core dihydroxy-9,10-anthraquinone unit. The high cost and toxic side effects of anthracycline drugs limit their use in cancer therapy. For a few decades, efforts have been made to find cheap, less toxic yet efficient analogues of anthracyclines. This work on 1,4-dihydroxy-9,10-anthraquinone (QH), a simple analogue of the anthracyclines, was carried out to compare its biochemical properties with anthracyclines. UV-Vis and fluorescence spectroscopic methods were used to analyze interaction of the compound with calf thymus DNA. The data were used to evaluate the binding constant and site size. [ABSTRACT FROM AUTHOR]

The anthracycline drugs, adriamycin and daunorubicin, efficient in the treatment of various human cancers, form strong intercalation complexes with DNA. The therapeutic efficiency and toxic properties of the drugs are associated with electron transfer processes, which correlate well with the redox behaviour of the compounds. Sodium 1,4-dihydroxy 9,10-anthraquinone-2-sulphonate (sodium quinizarin-2-sulphonate, NaLH2) (Na-Qz-2S) is a molecule that resembles anthracycline drugs and has a simpler structure in comparison to these drugs. Two electrons in the course of chemical action reduce this molecule like the anthracyclines. Electrochemical methods were used to identify this process. UV-Vis and fluorescence spectroscopy were used to analyse binding of the compound to calf thymus DNA. The binding constant and site size were evaluated for Na-Qz-2S and the same compared to that of the anthracyclines. Such comparisons are essential in order to understand whether the simpler hydroxy-anthraquinones can be a substitute for anthracycline drugs in cancer chemotherapy. Copyright © 2009 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Hydroxy-9,10-anthraquinones are cheaper alternatives to anthracycline drugs. They closely resemble anthracycline drugs both from a structural and functional viewpoint. Electrochemical behavior of the Ni(II) complex (Na2[Ni(NaLH)2Cl2].2H2O) of sodium 1,4-dihydroxy-9,10-anthraquinone-2-sulphonate (NaLH2), analogue of the core unit of anthracycline anticancer drugs, was studied at physiological pH using cyclic voltammetry. The Ni(II) complex of sodium 1,4-dihydroxy-9,10-anthraquinone- 2-sulphonate undergoes diffusion-controlled one-electron reduction that enables performing an electrochemical study on the interaction of the complex with calf thymus DNA. The complex was titrated with increasing concentrations of DNA, and the reduction peak for the unbound complex helped in evaluating binding parameters. Analysis of binding data using nonlinear curve fit in a cyclic voltammetry experiment is the first such attempt. The paper evaluates site size of interaction that also serves as a means to determine stoichiometry of complex formation, between a metal ion and ligand from a DNA interaction study, probably a first of its kind. [ABSTRACT FROM AUTHOR]

Quinalizarin, an analogue of anthracycline anticancer agents, is an anticancer agent itself. A CuII complex was prepared and characterized by elemental analysis, UV-Vis & IR spectroscopy, mass spectrometry, EPR and DFT. The intention behind the preparation of the complex was to increase cellular uptake, compare its binding with DNA against that of quinalizarin, modulation of semiquinone formation, realization of human DNA topoisomerase I & human DNA topoisomerase II inhibition and observation of anticancer activity. While the first two attributes of complex formation lead to increased efficacy, decrease in semiquinone generation could results in a compromise with efficacy. Inhibition of human DNA topoisomerase makes up this envisaged compromise in free radical activity since the complex shows remarkable ability to disrupt activities of human DNA topoisomerase I and II. The complex unlike quinalizarin, does not catalyze flow of electrons from NADH to O 2 to the extent known for quinalizarin. Hence, decrease in semiquinone or superoxide radical anion could make modified quinalizarin [as CuII complex] less efficient in free radical pathway. However, it would be less cardiotoxic and that would be advantageous to qualify it as a better anticancer agent. Although binding to calf thymus DNA was comparable to quinalizarin, it was weaker than anthracyclines. Low cost of quinalizarin could justify consideration as a substitute for anthracyclines but the study revealed IC 50 of quinalizarin/CuII-quinalizarin was much higher than anthracyclines or their complexes. Even then, there is a possibility that CuII-quinalizarin could be an improved and less costly form of quinalizarin as anticancer agent. Synopsis: A CuII complex of quinalizarin was prepared with the intention of increasing cellular uptake, study binding with DNA, modulate formation of semiquinone and check for inhibition of human DNA topoisomerase I and II to correlate observed anticancer activity. Low cost of quinalizarin justifies its consideration as a substitute for anthracyclines. [Display omitted] • Quinalizarin (THAQ), an analogue of anthracyclines, is active pharmacologically. • Complex formation modulates generation of free radicals that affect its mechanism of action. • The complex is an efficient inhibitor of topoisomerase enzymes, crucial for drug action. • Interaction of [CuII(THAQ) 2 (H 2 O) 2 ] with topoisomerase was realized by molecular docking. • THAQ, the acetylated form, shows more efficacy on ALL MOLT 4 cells than [CuII(THAQ) 2 (H 2 O) 2 ]. [ABSTRACT FROM AUTHOR]

pK a of a compound is crucial for determining the contributions of different forms of it towards overall binding with DNA. Hence it is important to use correct pK a values in DNA interaction studies. This study takes a look at the importance of pK a values to realize binding of compounds with DNA. Since pK a of a compound determined in the presence of DNA is quite different from that determined in its absence hence, presence of different forms of a compound during interaction with DNA is different from that realized if the determination of pK a is done in normal aqueous solution in absence of DNA. Hence, calculations determining contributions of different forms of a compound interacting with DNA are affected accordingly. Two simple analogues of anthracyclines, alizarin and purpurin, were used to investigate the influence DNA has on pK a values. Indeed, they were different in presence of DNA than when determined in normal aqueous solution. pK a1 for alizarin and purpurin determined in the absence and presence of calf thymus DNA were used in equations that determine contributions of two forms (neutral and anionic) towards overall binding with DNA. The study concludes that correct pK a values, determined correctly i.e. under appropriate conditions, must be used for DNA binding experiments to evaluate contributions of individual forms. [ABSTRACT FROM AUTHOR]

• CoII & CoIII complexes of alizarin were prepared to compare efficacy with anthracyclines. • Structure of CoIII complex was obtained by computation based on spectroscopic evidence. • Biophysical interaction of complexes with DNA was done by varying pH and ionic strength. • Complexes bind DNA better than alizarin; decrease O2·− formation during electron transfer. • Interaction with ROS due to CoII –alizarin was detected in cell lines by the H2DCFDA assay. • Complexes more effective on SIHA cells than HepG2 cells; far less cytotoxic to normal cells. A coordination compound of CoII with alizarin was prepared to see if it resembles various activities that are reported for anthracyclines as anticancer agents. Alizarin, which has a comparatively simpler structure than anthracyclines, contain the same hydroxy-9,10-anthraquinone as found in anthracyclines. Hence, if tried in cancer chemotherapy, it is expected to show some advantages related to cost and for all those reasons that become applicable in using a relatively simpler compound. However, to be acceptable, it must show comparable efficacy as known for anthracyclines. Like anthracyclines, alizarin forms the semiquinone radical anion that generates superoxide radical anion, responsible for cardiotoxicity. Complex formation decreases generation of superoxide, that was verified by an enzyme assay that might help to decrease toxic side effects. Although hydroxy-9,10-anthraquinones (here alizarin), resemble anthracyclines, biophysical and/or biochemical interactions of the former at the cellular level are less efficient than the latter. Besides, under physiological conditions alizarin is anionic. Hence, increase in pH affects DNA binding adversely. The prepared complex, which is anionic, when it has CoII and neutral when CoIII, binds DNA better than alizarin under varying conditions of ionic strength and pH. Since reactive oxygen species are present in cells, there is a high probability that the CoII complex could either completely or partially convert to CoIII. The CoIII species would then manifest in several biological responses affecting the growth of cells. Experiments pertaining to ROS were performed on three human cell lines (SIHA, HepG2, WI 38) that suggest a shift in mechanism for the complex/complexes from that known for anthracyclines or hydroxy-9,10-anthraquinones. An expected loss in efficacy due to decreased semiquinone formation is compensated by the CoII/CoIII couple owing to the metal ion being present in two oxidation states in cellular medium thus promoting cytotoxicity. The CoII/CoIII complex tried on cells reveal several attributes that enable it/them to overcome some of the shortcomings of alizarin to become comparable to anthracyclines. [Display omitted] [ABSTRACT FROM AUTHOR]

The study attempts to find out if a MnII complex of 1,2-dhydroxy-9,10-anthraquinone (a simple analogue of anthracyclines) match the efficacy of established drugs. The complex was synthesized, characterized by spectroscopic techniques. Structure was obtained by computational methods. Biophysical interaction with DNA under varying conditions of pH and ionic strength and the ability of the complex to modulate ROS was investigated. Attributes of complex formation and performance on cancer cells permit drug prospecting. Alizarin (DHA), a simple analogue of the anthracycline core was used to form a complex with MnII to see if the complex matches the efficacy of anthracyclines. It was characterized by spectroscopic techniques, mass spectrometry and TGA. In the absence of a single crystal, the structure was obtained by computational techniques. Interaction of the complex with DNA at different ionic strength and pH was compared with anthracyclines to see if it addresses some of the shortcomings of hydroxy-9,10-anthraqunones in general and DHA in particular when compared to anthracyclines. Increased affinity of the complex towards DNA and that its binding constant values do not decrease with increase in pH or decrease in ionic strength of the medium are positive attributes of complex formation. This is significant since cancer patients often experience fluctuation of pH and ionic strength in body fluids during treatment that affect efficacy of drugs. The complex decreases the flow of electrons from NADH to molecular oxygen owing to decreased semiquinone formation; a fact important for controlling cardiotoxicity. Experiments on ROS depletion in HeLa, Hep G2 and WI 38 lung fibroblast cells by the H 2 DCFDA assay suggests a shift in mechanism for the complex from that of DHA. Loss in efficacy due to decrease in semiquinone formation by the complex is made up by other attributes of complex formation that eventually promote cytotoxicity. Compounds were tried on HeLa, Hep G2 and WI 38 lung fibroblast cells. An effort was made to correlate aspects of semiquinone formation, ROS generation and interaction with DNA with results obtained on two cancer cell lines and a normal cell line. [ABSTRACT FROM AUTHOR]