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A Commemorative Issue in Honor of Professor Nick Hadjiliadis: Metal Complex Interactions with Nucleic Acids and/or DNA

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Bioinorganic Chemistry".

Deadline for manuscript submissions: closed (31 May 2018) | Viewed by 65669

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editors

Dr. Christina N. Banti

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Guest Editor
Department of Chemistry, University of Ioannina, 45110 Ioannina, Greece
Interests: bioinorganic chemistry; evaluation of the anticancer properties of metal complexes by studying their interaction with intracellular molecules
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Sotiris Hadjikakou

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Guest Editor
Department of Chemistry, University of Ioannina, 451 10 Ioannina, Greece
Interests: crystal structure; structure determination; material characterization; structural chemistry; biological inorganic chemistry, antimicrobial compounds; antiproliferative compounds
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This special issue entitled "Metal complexes interactions with Nucleic acids and/or DNA" was inspired by Prof. Sotiris Hadjikakou, due to the contribution of Prof. Nick Hadjiliadis in the field of palladium or/and platinum/nucleic acids interactions. It will cover a selection of recent research and review articles in the field of Metal complexes interactions with Nucleic acids and/or DNA.

Metal complexes have long been recognized as critically important components of nucleic acid chemistry, both in regulation of gene expression and as promising therapeutic agents. The ability to recognize, to understand at the molecular level of how metal complexes interact with DNA has become an active research area at the interface between biological inorganic chemistry, molecular biology and medicine.

Arguably, the most prominent drug which contains a metal is cisplatin, the most widely used anti-cancer drug. The success of cisplatin in chemotherapy and the clarification of its mechanism of action through interaction with DNA has motivated a large number of studies on metal complexes interaction with nucleic acids or/and DNA. From the foregoing that the reader of this special issue will gain an appreciation of the real role of the interactions of metal complexes with nucleic acids or/and DNA in modern medicine.

This special issue on the "Metal complexes interactions with Nucleic acids and/or DNA" aims to provide an overview of this increasingly diverse field, presenting recent developments and the latest research with particular emphasis on metal-based drugs and metal ion toxicity.

Prof. Dr. Sotiris Hadjikakou
Dr. Christina N. Banti
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Biological inorganic chemistry
  • Metal complexes interactions with nucleic acids
  • Metal complexes interactions with DNA
  • Metal-based drugs
  • Platinum complexes anticancer agents
  • Non-platinum metal complexes anticancer agents

Published Papers (15 papers)

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Editorial

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3 pages, 161 KiB  
Editorial
Preface to “A Commemorative Issue in Honour of Professor Nick Hadjiliadis: Metal Complex Interactions with Nucleic Acids and/or DNA”
by Christina N. Banti and Sotiris K. Hadjikakou
Int. J. Mol. Sci. 2018, 19(12), 3815; https://doi.org/10.3390/ijms19123815 - 30 Nov 2018
Viewed by 1750
Abstract
This Special Issue of the International Journal of Molecular Science comprises a comprehensive study on "Metal Complex Interactions with Nucleic Acids and/or DNA". [...] Full article
(This article belongs to the Special Issue A Commemorative Issue in Honor of Professor Nick Hadjiliadis: Metal Complex Interactions with Nucleic Acids and/or DNA)

Research

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18 pages, 3500 KiB  
Article
Interactions Between Spermine-Derivatized Tentacle Porphyrins and The Human Telomeric DNA G-Quadruplex
by Navin C. Sabharwal, Jessica Chen, Joo Hyun (June) Lee, Chiara M. A. Gangemi, Alessandro D'Urso and Liliya A. Yatsunyk
Int. J. Mol. Sci. 2018, 19(11), 3686; https://doi.org/10.3390/ijms19113686 - 21 Nov 2018
Cited by 17 | Viewed by 4593
Abstract
G-rich DNA sequences have the potential to fold into non-canonical G-Quadruplex (GQ) structures implicated in aging and human diseases, notably cancers. Because stabilization of GQs at telomeres and oncogene promoters may prevent cancer, there is an interest in developing small molecules that selectively [...] Read more.
G-rich DNA sequences have the potential to fold into non-canonical G-Quadruplex (GQ) structures implicated in aging and human diseases, notably cancers. Because stabilization of GQs at telomeres and oncogene promoters may prevent cancer, there is an interest in developing small molecules that selectively target GQs. Herein, we investigate the interactions of meso-tetrakis-(4-carboxysperminephenyl)porphyrin (TCPPSpm4) and its Zn(II) derivative (ZnTCPPSpm4) with human telomeric DNA (Tel22) via UV-Vis, circular dichroism (CD), and fluorescence spectroscopies, resonance light scattering (RLS), and fluorescence resonance energy transfer (FRET) assays. UV-Vis titrations reveal binding constants of 4.7 × 106 and 1.4 × 107 M−1 and binding stoichiometry of 2–4:1 and 10–12:1 for TCPPSpm4 and ZnTCPPSpm4, respectively. High stoichiometry is supported by the Job plot data, CD titrations, and RLS data. FRET melting indicates that TCPPSpm4 stabilizes Tel22 by 36 ± 2 °C at 7.5 eq., and that ZnTCPPSpm4 stabilizes Tel22 by 33 ± 2 °C at ~20 eq.; at least 8 eq. of ZnTCPPSpm4 are required to achieve significant stabilization of Tel22, in agreement with its high binding stoichiometry. FRET competition studies show that both porphyrins are mildly selective for human telomeric GQ vs duplex DNA. Spectroscopic studies, combined, point to end-stacking and porphyrin self-association as major binding modes. This work advances our understanding of ligand interactions with GQ DNA. Full article
(This article belongs to the Special Issue A Commemorative Issue in Honor of Professor Nick Hadjiliadis: Metal Complex Interactions with Nucleic Acids and/or DNA)
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Graphical abstract

15 pages, 2087 KiB  
Article
CoII(Chromomycin)2 Complex Induces a Conformational Change of CCG Repeats from i-Motif to Base-Extruded DNA Duplex
by Yu-Wen Chen, Roshan Satange, Pei-Ching Wu, Cyong-Ru Jhan, Chung-ke Chang, Kuang-Ren Chung, Michael J. Waring, Sheng-Wei Lin, Li-Ching Hsieh and Ming-Hon Hou
Int. J. Mol. Sci. 2018, 19(9), 2796; https://doi.org/10.3390/ijms19092796 - 17 Sep 2018
Cited by 9 | Viewed by 3588
Abstract
We have reported the propensity of a DNA sequence containing CCG repeats to form a stable i-motif tetraplex structure in the absence of ligands. Here we show that an i-motif DNA sequence may transition to a base-extruded duplex structure with a GGCC tetranucleotide [...] Read more.
We have reported the propensity of a DNA sequence containing CCG repeats to form a stable i-motif tetraplex structure in the absence of ligands. Here we show that an i-motif DNA sequence may transition to a base-extruded duplex structure with a GGCC tetranucleotide tract when bound to the (CoII)-mediated dimer of chromomycin A3, CoII(Chro)2. Biophysical experiments reveal that CCG trinucleotide repeats provide favorable binding sites for CoII(Chro)2. In addition, water hydration and divalent metal ion (CoII) interactions also play a crucial role in the stabilization of CCG trinucleotide repeats (TNRs). Our data furnish useful structural information for the design of novel therapeutic strategies to treat neurological diseases caused by repeat expansions. Full article
(This article belongs to the Special Issue A Commemorative Issue in Honor of Professor Nick Hadjiliadis: Metal Complex Interactions with Nucleic Acids and/or DNA)
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21 pages, 5201 KiB  
Article
Cellular Pharmacology of Palladinum(III) Hematoporphyrin IX Complexes: Solution Stability, Antineoplastic and Apoptogenic Activity, DNA Binding, and Processing of DNA-Adducts
by Georgi Momekov, Iva Ugrinova, Evdokia Pasheva, Daniela Tsekova and Galina Gencheva
Int. J. Mol. Sci. 2018, 19(8), 2451; https://doi.org/10.3390/ijms19082451 - 19 Aug 2018
Cited by 4 | Viewed by 3753
Abstract
Two paramagnetic PdIII complexes of hematoporphyrin IX ((7,12-bis(1-hydroxyethyl)-3,8,13,17-tetramethyl-21H-23H-porphyn-2,18-dipropionic acid), Hp), namely a dinuclear one [PdIII2(Hp-3H)Cl3(H2O)5]·2PdCl2, Pd1 and a mononuclear metalloporphyrin type [PdIII(Hp-2H)Cl(H2O)]·H2 [...] Read more.
Two paramagnetic PdIII complexes of hematoporphyrin IX ((7,12-bis(1-hydroxyethyl)-3,8,13,17-tetramethyl-21H-23H-porphyn-2,18-dipropionic acid), Hp), namely a dinuclear one [PdIII2(Hp-3H)Cl3(H2O)5]·2PdCl2, Pd1 and a mononuclear metalloporphyrin type [PdIII(Hp-2H)Cl(H2O)]·H2O, Pd2 have been synthesized reproducibly and isolated as neutral compounds at different reaction conditions. Their structure and solution stability have been assayed by UV/Vis and EPR spectroscopy. The compounds researched have shown in vitro cell growth inhibitory effects at micromolar concentration against a panel of human tumor cell lines. A DNA fragmentation test in the HL-60 cell line has indicated that Pd1 causes comparable proapoptotic effects with regard to cisplatin but at substantially higher concentrations. Pd1 and cisplatin form intra-strand guanine bis-adducts as the palladium complex is less capable of forming DNA adducts. This demonstrates its cisplatin-dissimilar pharmacological profile. The test for efficient removal of DNA-adducts by the NER synthesis after modification of pBS plasmids with either cisplatin or Pd1 has manifested that the lesions induced by cisplatin are far better recognized and repaired compared those of Pd1. The study on the recognition and binding of the HMGB-1 protein to cisplatin or Pd1 modified DNA probes have shown that HMG proteins are less involved in the palladium agent cytotoxicity. Full article
(This article belongs to the Special Issue A Commemorative Issue in Honor of Professor Nick Hadjiliadis: Metal Complex Interactions with Nucleic Acids and/or DNA)
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13 pages, 2590 KiB  
Article
Optical Properties of Silver-Mediated DNA from Molecular Dynamics and Time Dependent Density Functional Theory
by Esko Makkonen, Patrick Rinke, Olga Lopez-Acevedo and Xi Chen
Int. J. Mol. Sci. 2018, 19(8), 2346; https://doi.org/10.3390/ijms19082346 - 09 Aug 2018
Cited by 7 | Viewed by 4469
Abstract
We report a combined quantum mechanics/molecular mechanics (QM/MM) molecular dynamics and time-dependent density functional (TDDFT) study of metal-mediated deoxyribonucleic acid (M-DNA) nanostructures. For the Ag + -mediated guanine tetramer, we found the maug-cc-pvdz basis set to be sufficient for calculating electronic circular dichroism [...] Read more.
We report a combined quantum mechanics/molecular mechanics (QM/MM) molecular dynamics and time-dependent density functional (TDDFT) study of metal-mediated deoxyribonucleic acid (M-DNA) nanostructures. For the Ag + -mediated guanine tetramer, we found the maug-cc-pvdz basis set to be sufficient for calculating electronic circular dichroism (ECD) spectra. Our calculations further show that the B3LYP, CAM-B3LYP, B3LYP*, and PBE exchange-correlation functionals are all able to predict negative peaks in the measured ECD spectra within a 20 nm range. However, a spurious positive peak is present in the CAM-B3LYP ECD spectra. We trace the origins of this spurious peak and find that is likely due to the sensitivity of silver atoms to the amount of Hartree–Fock exchange in the exchange-correlation functional. Our presented approach provides guidance for future computational investigations of other Ag + -mediated DNA species. Full article
(This article belongs to the Special Issue A Commemorative Issue in Honor of Professor Nick Hadjiliadis: Metal Complex Interactions with Nucleic Acids and/or DNA)
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18 pages, 1821 KiB  
Article
Binding of Organometallic Ruthenium Anticancer Complexes to DNA: Thermodynamic Base and Sequence Selectivity
by Suyan Liu, Aihua Liang, Kui Wu, Wenjuan Zeng, Qun Luo and Fuyi Wang
Int. J. Mol. Sci. 2018, 19(7), 2137; https://doi.org/10.3390/ijms19072137 - 23 Jul 2018
Cited by 10 | Viewed by 4547
Abstract
Organometallic ruthenium(II) complexes [(η6-arene)Ru(en)Cl][PF6] (arene = benzene (1), p-cymene (2), indane (3), and biphenyl (4); en = ethylenediamine) are promising anticancer drug candidates both in vitro and in vivo. In [...] Read more.
Organometallic ruthenium(II) complexes [(η6-arene)Ru(en)Cl][PF6] (arene = benzene (1), p-cymene (2), indane (3), and biphenyl (4); en = ethylenediamine) are promising anticancer drug candidates both in vitro and in vivo. In this paper, the interactions between ruthenium(II) complexes and 15-mer single- and double-stranded oligodeoxynucleotides (ODNs) were thermodynamically investigated using high performance liquid chromatography (HPLC) and electrospray ionization mass spectroscopy (ESI-MS). All of the complexes bind preferentially to G8 on the single strand 5′-CTCTCTT7G8T9CTTCTC-3′ (I), with complex 4 containing the most hydrophobic ligand as the most reactive one. To the analogs of I (changing T7 and/or T9 to A and/or C), complex 4 shows a decreasing affinity to the G8 site in the following order: -AG8T- (K: 5.74 × 104 M−1) > -CG8C- > -TG8A- > -AG8A- > -AG8C- > -TG8T- (I) ≈ -CG8A- (K: 2.81 × 104 M−1). In the complementary strand of I, the G bases in the middle region are favored for ruthenation over guanine (G) bases in the end of oligodeoxynucleotides (ODNs). These results indicate that both the flanking bases (or base sequences) and the arene ligands play important roles in determining the binding preference, and the base- and sequence-selectivity, of ruthenium complex in binding to the ODNs. Full article
(This article belongs to the Special Issue A Commemorative Issue in Honor of Professor Nick Hadjiliadis: Metal Complex Interactions with Nucleic Acids and/or DNA)
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18 pages, 3349 KiB  
Article
Poly Organotin Acetates against DNA with Possible Implementation on Human Breast Cancer
by George K. Latsis, Christina N. Banti, Nikolaos Kourkoumelis, Constantina Papatriantafyllopoulou, Nikos Panagiotou, Anastasios Tasiopoulos, Alexios Douvalis, Angelos G. Kalampounias, Thomas Bakas and Sotiris K. Hadjikakou
Int. J. Mol. Sci. 2018, 19(7), 2055; https://doi.org/10.3390/ijms19072055 - 14 Jul 2018
Cited by 27 | Viewed by 3708
Abstract
Two known tin-based polymers of formula {[R3Sn(CH3COO)]n} where R = n-Bu– (1) and R = Ph– (2),were evaluated for their in vitro biological properties. The compounds were characterized via their physical properties [...] Read more.
Two known tin-based polymers of formula {[R3Sn(CH3COO)]n} where R = n-Bu– (1) and R = Ph– (2),were evaluated for their in vitro biological properties. The compounds were characterized via their physical properties and FT-IR, 119Sn Mössbauer, and 1H NMR spectroscopic data. The molecular structures were confirmed by single-crystal X-Ray diffraction crystallography. The geometry around the tin(IV) ion is trigonal bi-pyramidal. Variations in O–Sn–O···Sn′ torsion angles lead to zig-zag and helical supramolecular assemblies for 1 and 2, respectively. The in vitro cell viability against human breast adenocarcinoma cancer cell lines: MCF-7 positive to estrogens receptors (ERs) and MDA-MB-231 negative to ERs upon their incubation with 1 and 2 was investigated. Their toxicity has been studied against normal human fetal lung fibroblast cells (MRC-5). Compounds 1 and 2 exhibit 134 and 223-fold respectively stronger antiproliferative activity against MDA-MB-231 than cisplatin. The type of the cell death caused by 1 or 2 was also determined using flow cytometry assay. The binding affinity of 1 and 2 towards the CT-DNA was suspected from the differentiation of the viscosity which occurred in the solution containing increasing amounts of 1 and 2. Changes in fluorescent emission light of Ethidium bromide (EB) in the presence of DNA confirmed the intercalation mode of interactions into DNA of both complexes 1 and 2 which have been ascertained from viscosity measurements. The corresponding apparent binding constants (Kapp) of 1 and 2 towards CT-DNA calculated through fluorescence spectra are 4.9 × 104 (1) and 7.3 × 104 (2) M−1 respectively. Finally, the type of DNA binding interactions with 1 and 2 was confirmed by docking studies. Full article
(This article belongs to the Special Issue A Commemorative Issue in Honor of Professor Nick Hadjiliadis: Metal Complex Interactions with Nucleic Acids and/or DNA)
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16 pages, 5344 KiB  
Article
Multi-Acting Mitochondria-Targeted Platinum(IV) Prodrugs of Kiteplatin with α-Lipoic Acid in the Axial Positions
by Salvatore Savino, Cristina Marzano, Valentina Gandin, James D. Hoeschele, Giovanni Natile and Nicola Margiotta
Int. J. Mol. Sci. 2018, 19(7), 2050; https://doi.org/10.3390/ijms19072050 - 14 Jul 2018
Cited by 14 | Viewed by 4021
Abstract
Platinum(II) drugs are activated intracellularly by aquation of the leaving groups and then bind to DNA, forming DNA adducts capable to activate various signal-transduction pathways. Mostly explored in recent years are Pt(IV) complexes which allow the presence of two additional ligands in the [...] Read more.
Platinum(II) drugs are activated intracellularly by aquation of the leaving groups and then bind to DNA, forming DNA adducts capable to activate various signal-transduction pathways. Mostly explored in recent years are Pt(IV) complexes which allow the presence of two additional ligands in the axial positions suitable for the attachment of other cancer-targeting ligands. Here we have extended this strategy by coordinating in the axial positions of kiteplatin ([PtCl2(cis-1,4-DACH)], DACH = Diaminocyclohexane) and its CBDCA (1,1-cyclobutanedicarboxylate) analogue the antioxidant α-Lipoic acid (ALA), an inhibitor of the mitochondrial pyruvate dehydrogenase kinase (PDK). The new compounds (cis,trans,cis-[Pt(CBDCA)(ALA)2(cis-1,4-DACH)], 2, and cis,trans,cis-[PtCl2(ALA)2(cis-1,4-DACH)], 3), after intracellular reduction, release the precursor Pt(II) species and two molecules of ALA. The Pt residue is able to target DNA, while ALA could act on mitochondria as activator of the pyruvate dehydrogenase complex, thus suppressing anaerobic glycolysis. Compounds 2 and 3 were tested in vitro on a panel of five human cancer cell lines and compared to cisplatin, oxaliplatin, and kiteplatin. They proved to be much more effective than the reference compounds, with complex 3 most effective in 3D spheroid tumor cultures. Notably, treatment of human A431 carcinoma cells with 2 and 3 did not determine increase of cellular ROS (usually correlated to inhibition of mitochondrial PDK) and did not induce a significant depolarization of the mitochondrial membrane or alteration of other morphological mitochondrial parameters. Full article
(This article belongs to the Special Issue A Commemorative Issue in Honor of Professor Nick Hadjiliadis: Metal Complex Interactions with Nucleic Acids and/or DNA)
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17 pages, 6164 KiB  
Article
Syntheses, Crystal Structures, and Antitumor Activities of Copper(II) and Nickel(II) Complexes with 2-((2-(Pyridin-2-yl)hydrazono)methyl)quinolin-8-ol
by Qi-Yuan Yang, Qian-Qian Cao, Qi-Pin Qin, Cai-Xing Deng, Hong Liang and Zhen-Feng Chen
Int. J. Mol. Sci. 2018, 19(7), 1874; https://doi.org/10.3390/ijms19071874 - 26 Jun 2018
Cited by 25 | Viewed by 3862
Abstract
Two transition metal complexes with 2-((2-(pyridin-2-yl)hydrazono)methyl)quinolin-8-ol (L), [Cu(L)Cl2]2 (1) and [Ni(L)Cl2]·CH2Cl2 (2), were synthesized and fully characterized. Complex 1 exhibited high in vitro antitumor activity against SK-OV-3, MGC80-3 and HeLa cells [...] Read more.
Two transition metal complexes with 2-((2-(pyridin-2-yl)hydrazono)methyl)quinolin-8-ol (L), [Cu(L)Cl2]2 (1) and [Ni(L)Cl2]·CH2Cl2 (2), were synthesized and fully characterized. Complex 1 exhibited high in vitro antitumor activity against SK-OV-3, MGC80-3 and HeLa cells with IC50 values of 3.69 ± 0.16, 2.60 ± 0.17, and 3.62 ± 0.12 μM, respectively. In addition, complex 1 caused cell arrest in the S phase, which led to the down-regulation of Cdc25 A, Cyclin B, Cyclin A, and CDK2, and the up-regulation of p27, p21, and p53 proteins in MGC80-3 cells. Complex 1 induced MGC80-3 cell apoptosis via a mitochondrial dysfunction pathway, as shown by the significantly decreased level of bcl-2 protein and the loss of Δψ, as well as increased levels of reactive oxygen species (ROS), intracellular Ca2+, cytochrome C, apaf-1, caspase-3, and caspase-9 proteins in MGC80-3 cells. Full article
(This article belongs to the Special Issue A Commemorative Issue in Honor of Professor Nick Hadjiliadis: Metal Complex Interactions with Nucleic Acids and/or DNA)
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11 pages, 1364 KiB  
Article
Palladacyclic Conjugate Group Promotes Hybridization of Short Oligonucleotides
by Madhuri Hande, Sajal Maity and Tuomas Lönnberg
Int. J. Mol. Sci. 2018, 19(6), 1588; https://doi.org/10.3390/ijms19061588 - 28 May 2018
Cited by 11 | Viewed by 3991
Abstract
Short oligonucleotides with cyclopalladated benzylamine moieties at their 5′-termini have been prepared to test the possibility of conferring palladacyclic anticancer agents sequence-selectivity by conjugation with a guiding oligonucleotide. Hybridization of these oligonucleotides with natural counterparts was studied by UV and CD (circular dichroism) [...] Read more.
Short oligonucleotides with cyclopalladated benzylamine moieties at their 5′-termini have been prepared to test the possibility of conferring palladacyclic anticancer agents sequence-selectivity by conjugation with a guiding oligonucleotide. Hybridization of these oligonucleotides with natural counterparts was studied by UV and CD (circular dichroism) melting experiments in the absence and presence of a competing ligand (2-mercaptoethanol). Cyclopalladated benzylamine proved to be strongly stabilizing relative to unmetalated benzylamine and modestly stabilizing relative to an extra A•T base pair. The stabilization was largely abolished in the presence of 2-mercaptoethanol, suggesting direct coordination of Pd(II) to a nucleobase of the complementary strand. In all cases, fidelity of Watson-Crick base pairing between the two strands was retained. Hybridization of the cyclopalladated oligonucleotides was characterized by relatively large negative enthalpy and entropy, consistent with stabilizing Pd(II) coordination partially offset by the entropic penalty of imposing conformational constraints on the flexible diethylene glycol linker between the oligonucleotide and the palladacyclic moiety. Full article
(This article belongs to the Special Issue A Commemorative Issue in Honor of Professor Nick Hadjiliadis: Metal Complex Interactions with Nucleic Acids and/or DNA)
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22 pages, 6252 KiB  
Article
Design, Synthesis, and Biological Evaluation of Benzimidazole-Derived Biocompatible Copper(II) and Zinc(II) Complexes as Anticancer Chemotherapeutics
by Mohamed F. AlAjmi, Afzal Hussain, Md. Tabish Rehman, Azmat Ali Khan, Perwez Alam Shaikh and Rais Ahmad Khan
Int. J. Mol. Sci. 2018, 19(5), 1492; https://doi.org/10.3390/ijms19051492 - 16 May 2018
Cited by 29 | Viewed by 4791
Abstract
Herein, we have synthesized and characterized a new benzimidazole-derived “BnI” ligand and its copper(II) complex, [Cu(BnI)2], 1, and zinc(II) complex, [Zn(BnI)2], 2, using elemental analysis and various spectroscopic techniques. Interaction of complexes 1 and 2 with the [...] Read more.
Herein, we have synthesized and characterized a new benzimidazole-derived “BnI” ligand and its copper(II) complex, [Cu(BnI)2], 1, and zinc(II) complex, [Zn(BnI)2], 2, using elemental analysis and various spectroscopic techniques. Interaction of complexes 1 and 2 with the biomolecules viz. HSA (human serum albumin) and DNA were studied using absorption titration, fluorescence techniques, and in silico molecular docking studies. The results exhibited the significant binding propensity of both complexes 1 and 2, but complex 1 showed more avid binding to HSA and DNA. Also, the nuclease activity of 1 and 2 was analyzed for pBR322 DNA, and the results obtained confirmed the potential of the complexes to cleave DNA. Moreover, the mechanistic pathway was studied in the presence of various radical scavengers, which revealed that ROS (reactive oxygen species) are responsible for the nuclease activity in complex 1, whereas in complex 2, the possibility of hydrolytic cleavage also exists. Furthermore, the cytotoxicity of the ligand and complexes 1 and 2 were studied on a panel of five different human cancer cells, namely: HepG2, SK-MEL-1, HT018, HeLa, and MDA-MB 231, and compared with the standard drug, cisplatin. The results are quite promising against MDA-MB 231 (breast cancer cell line of 1), with an IC50 value that is nearly the same as the standard drug. Apoptosis was induced by complex 1 on MDA-MB 231 cells predominantly as studied by flow cytometry (FACS). The adhesion and migration of cancer cells were also examined upon treatment of complexes 1 and 2. Furthermore, the in vivo chronic toxicity profile of complexes 1 and 2 was also studied on all of the major organs of the mice, and found them to be less toxic. Thus, the results warrant further investigations of complex 1. Full article
(This article belongs to the Special Issue A Commemorative Issue in Honor of Professor Nick Hadjiliadis: Metal Complex Interactions with Nucleic Acids and/or DNA)
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12 pages, 3835 KiB  
Article
Binding Interactions of Zinc Cationic Porphyrin with Duplex DNA: From B-DNA to Z-DNA
by Tingxiao Qin, Kunhui Liu, Di Song, Chunfan Yang, Hongmei Zhao and Hongmei Su
Int. J. Mol. Sci. 2018, 19(4), 1071; https://doi.org/10.3390/ijms19041071 - 04 Apr 2018
Cited by 10 | Viewed by 5029
Abstract
Recognition of unusual left-handed Z-DNA by specific binding of small molecules is crucial for understanding biological functions in which this particular structure participates. Recent investigations indicate that zinc cationic porphyrin (ZnTMPyP4) is promising as a probe for recognizing Z-DNA due to its characteristic [...] Read more.
Recognition of unusual left-handed Z-DNA by specific binding of small molecules is crucial for understanding biological functions in which this particular structure participates. Recent investigations indicate that zinc cationic porphyrin (ZnTMPyP4) is promising as a probe for recognizing Z-DNA due to its characteristic chiroptical properties upon binding with Z-DNA. However, binding mechanisms of the ZnTMPyP4/Z-DNA complex remain unclear. By employing time-resolved UV-visible absorption spectroscopy in conjunction with induced circular dichroism (ICD), UV-vis, and fluorescence measurements, we examined the binding interactions of ZnTMPyP4 towards B-DNA and Z-DNA. For the ZnTMPyP4/Z-DNA complex, two coexisting binding modes were identified as the electrostatic interaction between pyridyl groups and phosphate backbones, and the major groove binding by zinc(II) coordinating with the exposed guanine N7. The respective contribution of each mode is assessed, allowing a complete scenario of binding modes revealed for the ZnTMPyP4/Z-DNA. These interaction modes are quite different from those (intercalation and partial intercalation modes) for the ZnTMPyP4/B-DNA complex, thereby resulting in explicit differentiation between B-DNA and Z-DNA. Additionally, the binding interactions of planar TMPyP4 to DNA were also investigated as a comparison. It is shown that without available virtual orbitals to coordinate, TMPyP4 binds with Z-DNA solely in the intercalation mode, as with B-DNA, and the intercalation results in a structural transition from Z-DNA to B-ZNA. These results provide mechanistic insights for understanding ZnTMPyP4 as a probe of recognizing Z-DNA and afford a possible strategy for designing new porphyrin derivatives with available virtual orbitals for the discrimination of B-DNA and Z-DNA. Full article
(This article belongs to the Special Issue A Commemorative Issue in Honor of Professor Nick Hadjiliadis: Metal Complex Interactions with Nucleic Acids and/or DNA)
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Review

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13 pages, 3735 KiB  
Review
DNA Modified with Boron–Metal Cluster Complexes [M(C2B9H11)2]—Synthesis, Properties, and Applications
by Agnieszka B. Olejniczak, Barbara Nawrot and Zbigniew J. Leśnikowski
Int. J. Mol. Sci. 2018, 19(11), 3501; https://doi.org/10.3390/ijms19113501 - 07 Nov 2018
Cited by 27 | Viewed by 3837
Abstract
Together with tremendous progress in biotechnology, nucleic acids, while retaining their status as “molecules of life”, are becoming “molecular wires”, materials for the construction of molecular structures at the junction between the biological and abiotic worlds. Herein, we present an overview of the [...] Read more.
Together with tremendous progress in biotechnology, nucleic acids, while retaining their status as “molecules of life”, are becoming “molecular wires”, materials for the construction of molecular structures at the junction between the biological and abiotic worlds. Herein, we present an overview of the approaches for incorporating metal centers into nucleic acids based on metal–boron cluster complexes (metallacarboranes) as the metal carriers. The methods are modular and versatile, allowing practical access to innovative metal-containing DNA for various applications, such as nucleic acid therapeutics, electrochemical biosensors, infrared-sensitive probes, and building blocks for nanoconstruction. Full article
(This article belongs to the Special Issue A Commemorative Issue in Honor of Professor Nick Hadjiliadis: Metal Complex Interactions with Nucleic Acids and/or DNA)
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18 pages, 1419 KiB  
Review
Modulating Chemosensitivity of Tumors to Platinum-Based Antitumor Drugs by Transcriptional Regulation of Copper Homeostasis
by Yu-Hsuan Lai, Chin Kuo, Macus Tien Kuo and Helen H. W. Chen
Int. J. Mol. Sci. 2018, 19(5), 1486; https://doi.org/10.3390/ijms19051486 - 16 May 2018
Cited by 35 | Viewed by 4785
Abstract
Platinum (Pt)-based antitumor agents have been effective in treating many human malignancies. Drug importing, intracellular shuffling, and exporting—carried out by the high-affinity copper (Cu) transporter (hCtr1), Cu chaperone (Ato x1), and Cu exporters (ATP7A and ATP7B), respectively—cumulatively contribute to the chemosensitivity [...] Read more.
Platinum (Pt)-based antitumor agents have been effective in treating many human malignancies. Drug importing, intracellular shuffling, and exporting—carried out by the high-affinity copper (Cu) transporter (hCtr1), Cu chaperone (Ato x1), and Cu exporters (ATP7A and ATP7B), respectively—cumulatively contribute to the chemosensitivity of Pt drugs including cisplatin and carboplatin, but not oxaliplatin. This entire system can also handle Pt drugs via interactions between Pt and the thiol-containing amino acid residues in these proteins; the interactions are strongly influenced by cellular redox regulators such as glutathione. hCtr1 expression is induced by acute Cu deprivation, and the induction is regulated by the transcription factor specific protein 1 (Sp1) which by itself is also regulated by Cu concentration variations. Copper displaces zinc (Zn) coordination at the zinc finger (ZF) domains of Sp1 and inactivates its DNA binding, whereas Cu deprivation enhances Sp1-DNA interactions and increases Sp1 expression, which in turn upregulates hCtr1. Because of the shared transport system, chemosensitivity of Pt drugs can be modulated by targeting Cu transporters. A Cu-lowering agent (trientine) in combination with a Pt drug (carboplatin) has been used in clinical studies for overcoming Pt-resistance. Future research should aim at further developing effective Pt drug retention strategies for improving the treatment efficacy. Full article
(This article belongs to the Special Issue A Commemorative Issue in Honor of Professor Nick Hadjiliadis: Metal Complex Interactions with Nucleic Acids and/or DNA)
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29 pages, 2368 KiB  
Review
The Interaction of the Metallo-Glycopeptide Anti-Tumour Drug Bleomycin with DNA
by Vincent Murray, Jon K. Chen and Long H. Chung
Int. J. Mol. Sci. 2018, 19(5), 1372; https://doi.org/10.3390/ijms19051372 - 04 May 2018
Cited by 41 | Viewed by 7533
Abstract
The cancer chemotherapeutic drug, bleomycin, is clinically used to treat several neoplasms including testicular and ovarian cancers. Bleomycin is a metallo-glycopeptide antibiotic that requires a transition metal ion, usually Fe(II), for activity. In this review, the properties of bleomycin are examined, especially the [...] Read more.
The cancer chemotherapeutic drug, bleomycin, is clinically used to treat several neoplasms including testicular and ovarian cancers. Bleomycin is a metallo-glycopeptide antibiotic that requires a transition metal ion, usually Fe(II), for activity. In this review, the properties of bleomycin are examined, especially the interaction of bleomycin with DNA. A Fe(II)-bleomycin complex is capable of DNA cleavage and this process is thought to be the major determinant for the cytotoxicity of bleomycin. The DNA sequence specificity of bleomycin cleavage is found to at 5′-GT* and 5′-GC* dinucleotides (where * indicates the cleaved nucleotide). Using next-generation DNA sequencing, over 200 million double-strand breaks were analysed, and an expanded bleomycin sequence specificity was found to be 5′-RTGT*AY (where R is G or A and Y is T or C) in cellular DNA and 5′-TGT*AT in purified DNA. The different environment of cellular DNA compared to purified DNA was proposed to be responsible for the difference. A number of bleomycin analogues have been examined and their interaction with DNA is also discussed. In particular, the production of bleomycin analogues via genetic manipulation of the modular non-ribosomal peptide synthetases and polyketide synthases in the bleomycin gene cluster is reviewed. The prospects for the synthesis of bleomycin analogues with increased effectiveness as cancer chemotherapeutic agents is also explored. Full article
(This article belongs to the Special Issue A Commemorative Issue in Honor of Professor Nick Hadjiliadis: Metal Complex Interactions with Nucleic Acids and/or DNA)
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