Nucleic Acids: A Natural Target for Newly Designed Metal Chelate Based Drugs

Nucleic Acids: A Natural Target for Newly Designed Metal Chelate Based Drugs discusses how human diseases are becoming more costly to treat, along with updates on the resistance offered by disease-causing agents. The abundance of drugs in the market has provided great relief to patients, but side effects can destroy the immune system of the body. Patients need to boost their immune system, and at the same time cover expenses incurred to cure disease. Thus, a paradigm shift is needed to design a drug molecule with low cost and easy availability.

Metal complexes can be a great example of such a shift, as metal ions are components of biological molecules and can achieve good binding capability to specific targets while not allowing them to damage healthy cell system. Therefore, in this book, a comprehensive compilation of recent data is provided, including the structural elucidation of metal complexes by advanced techniques and the binding pattern of metal complexes with specific targets.

• Focuses on recent advances and methods adopted for generating new metal-based molecules and their interactions with biomolecules, especially nucleic acids
• Addresses challenges for developing new metal-based drugs
• Examines advances in optical techniques for the characterization of metal-based drugs

• Language: English
• Publisher: Academic Press
• Release date: Aug 20, 2023
• ISBN: 9780128205044

Book preview

Nucleic Acids

A Natural Target for Newly Designed Metal Chelate Based Drugs

Edited by

Irshad UL Haq Bhat

University of Bahrain, Bahrain

Zakia Khanam

Aligarh Muslim University, Aligarh, Uttar Pradesh, India

Table of Contents

Cover image

Title page

Copyright

Dedication

List of contributors

Abbreviations

Introduction

Chapter 1. Zinc complexes: Their interaction with nucleic acids and other biomolecular targets

1. Chemistry of zinc

2. Interaction of synthesized zinc complexes with nucleic acids

3. Methods of analysis

4. Interaction of zinc complexes with biomolecules

5. Conclusion

Chapter 2. Ruthenium complexes: An insight into their interactions with nucleic acids and biomolecules

1. Chemistry of ruthenium

2. Methods of synthesis

3. Methods of analysis

4. Uses of metal complexes

5. Limitations

6. Future prospects

7. Conclusions

Chapter 3. Nucleic acid interactions of copper complexes

1. Chemistry of copper

2. Methods of synthesis

3. Methods of analysis

4. Uses of metal complexes

5. Limitations

6. Future prospects

7. Conclusions

Chapter 4. Recent advances in iron complexes and their interaction with nucleic acids

1. Chemistry of iron

2. Methods of synthesis

3. Methods of analysis

4. Uses of metal complexes

5. Limitations

6. Future prospects

7. Conclusions

Chapter 5. Manganese complexes: Their interaction studies with nucleic acids and biomolecules

1. Chemistry of manganese

2. Methods of synthesis

3. Methods of analysis

4. Applications of manganese complexes

5. Limitations

6. Future prospects

7. Conclusion

Index

Copyright

Academic Press is an imprint of Elsevier

125 London Wall, London EC2Y 5AS, United Kingdom

525 B Street, Suite 1650, San Diego, CA 92101, United States

50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States

The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom

Copyright © 2023 Elsevier Inc. All rights reserved.

No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions.

This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein).

Notices

Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary.

Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility.

To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein.

ISBN: 978-0-12-820503-7

For information on all Academic Press publications visit our website at https://www.elsevier.com/books-and-journals

Publisher: Andre G. Wolff

Acquisitions Editor: Linda Versteeg-Buschman

Editorial Project Manager: Susan E. Ikeda

Production Project Manager: Sajana Devasi P. K.

Cover Designer: Miles Hitchen

Typeset by TNQ Technologies

Dedication

Dedicated to all contributors.

List of contributors

Sayyed Jaheera Anwar,     Faculty of Science and Marine Environment, Universiti Malaysia Terengganu, Kuala Nerus, Terengganu, Malaysia

Masrat Bashir,     Department of Chemistry, Aligarh Muslim University, Aligarh, Uttar Pradesh, India

Irshad Ul Haq Bhat,     University of Bahrain, Bahrain

Imtiyaz Ahmad Mantoo,     Department of Chemistry, Aligarh Muslim University, Aligarh, Uttar Pradesh, India

Shazia Parveen,     Chemistry Department, Faculty of Science, Taibah University, Yanbu, Saudi Arabia

Sadiya,     Department of Chemistry, Aligarh Muslim University, Aligarh, Uttar Pradesh, India

Imtiyaz Yousuf,     Department of Chemistry, Aligarh Muslim University, Aligarh, Uttar Pradesh, India

Hanis Mohd Yusoff,     Advance Nano Materials (ANoMa) Research Group, Faculty of Science and Marine Environment, Universiti Malaysia Terengganu, Kuala Nerus, Terengganu, Malaysia

Abbreviations

2mq    2–mercapto–4(3H)–quinazolinone

2TU    2–thiouracil

4-mphen    4-methyl-1,10-phenanthroline

5′-GMP    guanosine 5′-monophosphate

6m2TU    6–methyl–2–thiouracil

8HQ    8-hydroxyquinoline

AFM    Atomic Force Microscopy

Am4Eotaz    N′-(3-ethyl-4-oxothiazolidin-2-ylidene)pyridine-2-carbohydrazonamide Am4Motaz

Arg    Arginine

As    Arsenic

ASC    ascididemin

Asp    Aspartic acid

AT    Adenine–thymine

ATP    Adenosine triphosphate

B    Boron

bbn    bis[4(4′-methyl-2,2′-bipyridyl)]-1; {n-alkane}

biphy    bipyridine

bipy    2,2′-bipyridine

bipyam    2,2′-dipyridylamine

bpg    4b,5,7,7a–tetrahydro–4b,7a–epiminomethanoimino–6H–imidazo[4,5–f][1,10] phenanthroline–6,13–dione

bpm    2,2′–bipyrimidine

BSA    bovine serum albumin

C    Carbon

CAPIP    (E)–2–(2–(furan–2–yl)vinyl)–1H–imidazo[4,5–f][1,10]phenanthroline

CD    circular dichroism

CEPIP    (E)–2–(4–fluorostyryl)–1H–imidazo[4,5–f][1,10]phenanthroline

CH2Cl2    dichloromethane

CHCl3    chloroform

Cl    Chlorine

Cl8HQ    5-chloro-8-hydroxyquinoline

Cp∗    pentamethyl cyclopentadienyl

CT DNA    Calf thymus DNA

CT    charge transfer

CV    Cyclic voltammetry

DACH    diaminocyclohexane

DAPI    4′,6-diamidino-2-phenylindole

dicnq    6,7–dicyanodipyrido[2,2-d:2′,3′–f]quinoxaline

dilc    diclofenac

DMF    dimethylformamide

dmp    2,9-dimethyl-1,10-phenanthroline

dmphen    4,7-dimethyl-1,10-phenanthroline

DNA    Deoxyribonucleic acid

Dppb    1,4–bis(diphenylphosphino)butane

Dppf    1,1′-bis(diphenylphosphino)ferrocene

dppz    dipyrido[3,2–a:2′,3′–c]phenazine

Dpq    dipyrido[3,2-f:2′,3′-h]quinoxaline

DpqQX    dipyrido[3,2-f:2′,3′-h]quinoxalino[2,3-b]quinoxaline

EPR    electron paramagnetic resonance

ESI    Electrospray ionization

ESI–MS    Electron spray ionization Mass spectroscopy

Et2O    diethyl ether

EtBr/EB    ethidium bromide

EtOH    ethanol

ɛmax    molar extinction coefficient

F    Fluorine

FAMP    2–(4–formylanthryl)imidazo–[4,5–f][1,10]phenanthroline

FES    Fluorescence emission spectroscopy

FID    fluorescent intercalator displacement

fip    2–ferrocenyl–1H–imidazo[4,5–f][1,10]–phenanthroline

FS-DNA    Fish DNA

GC    Guanine–cytosine

Gln    L-glutamine

Gua    guanine

HSA    human serum albumin

HS-DNA    herring sperm DNA

icip    2–(indeno[2,1-b]chromen–6–yl)–1H–imidazo[4,5–f]–[1,10]phenanthroline

IL    intraligand

Im    imidazole

imd    1-methylimidazole

KP1019    indazolium trans−[tetrachlorobis(1H−indazole)ruthenium(III)]

Leu    Leucine

L-Phe    L-phenylalaninate

LysH    protonated L-lysinate

MALDI–MS    matrix–assisted laser desorption–ionization

Me2bpy    4,4′–dimethyl–2,2′–bipyridine

MeCN    methylcyanine

Mef    mefenamic acid

MeOH    methanol

MG    methyl green

MIm    2-mercapto-1-methylimidazole anion

MLCT    metal-to-ligand charge transfer

mmi    mercapto–1–methyl–imidazole

Mn    Manganese

Mn-SOD    manganese superoxide dismutase

MnTBAP    manganese(iii) 5,10,15,20-tetrakis(4-benzoic acid)-porphyrin

MnTE-2-PyP5+    Mn(III) meso-tetrakis (4-carboxylatophenyl)porphyrin

MnTnBuOE-2-PyP5+    Mn(III) meso-tetrakis(N-n-butylpyridinium-2-yl)porphyrin

MOFs    metal-organic frameworks

mpca    6–mercaptopyridine–3–carboxylic acid

MS    Mass spectrometry

MSEB    (2-(1-(2-hydroxyethyl)-4,5-diphenyl-1H-imidazole-2-yl) (4-bromophenol)

N    Nitrogen

N′-(3-methyl-4-oxothiazolidin-2-ylidene)pyridine-2-carbohydrazonamide

NAMI−A    imidazolium trans−[tetrachloro−(dimethylsulfoxide)imidazole ruthenium(III)]

nap    naproxen

NMR    Nuclear magnetic resonance

N-p-NBHA    N-p-naphthylbenzohydroxamato

NSAIDs    nonsteroidal antiinflammatory drugs

O    Oxygen

Oh    Octahedral

O-VEDH2    N,N′-bis(O-vanillinidene)ethylenediamine

P    Phosphorous

PBIP    2–(4–bromophenyl)imidazo[4,5–f]1,10–phenanthroline

PCS    pyridine-2-carboxaldehyde-semicarbazone

phe    phenylalanine

PHEHAT    1,10–phenanthrolino[5,6-b]–1,4,5,8,9,12–hexaazatriphenylene

Phen    1,10-phenanthroline

pocl    2–(5–chlorofuran–2–yl)imidazo[4,5–f][1,10]phenanthroline

poi    2–(5–5–iodofuran–2–yl)imidazo[4,5–f][1,10]phenanthroline

poly(A)    polyadenylic acid

ppbm    2-(pyridin-2-yl)-1-(pyridin-3-ylmethyl)- 1H-benzo[d]imidazole

PPh3    Triphenylphosphine

ppn    2,4–diaminopyrimido [5,6-b]dipyrido [2,3–f:2′,3′–h]quinoxaline

pta    1,3,5–triaza–7–phosphatricyclo–[3.3.1.1]decane or 1,3,5–triaza–7–phosphaadamantane

py-phen    pyrazino[2,3f][1,10]phenanthroline

pytri    2–(1-R–1H–1,2,3–triazol–4–yl)pyridine

pzta    pyrazin-2-yl)-1,3,5-triazine-2,4-diamine

RAPTA−C    Ru(η⁶ −p−cymene)Cl2(pta)

RAPTA−T    Ru(η⁶ −C6H5Me) (pta)Cl2

RNA    Ribonucleic acid

ROS    reactive oxygen species

rRNA    ribosomal RNA

Ru    Ruthenium

S    Sulfur

SA    serum albumin

Salen(tBu)H2    N,N′-bis(3,5-di-t-butylsalicylidene)-1,2-diamino-2-methylpropane

SarGly    sarcosine-glycine peptide

Ser    Serine

Si    Silicon

TAP    1,4,5,8–tetraazaphenanthrene

tatp    1,4,8,9–tetra–aza–triphenylene

TEM    Transmission Electron Microscopy

Terp    4′-(3,4,5-trimethoxyphenyl)-2,2′:6′,2′-terpyridine

THF    tetrahydrofuran

Topo I    type I topoisomerases

Topo II    type II topoisomerases

Topo    topoisomerase

TOPRIM    topoisomerase-primase

Tp    terephthalate

tRNA    transfer RNA

trp    L-tryptophan

tzdt    1,3–thiazolidine–2–thione

Uv–vis    Ultraviolet visible

WDLs    water-derived ligands

XAS    X-ray Absorption Spectroscopy

λmax    absorbance maximum

Introduction

The use of a variety of ligands in the chelation process has led to the discovery of thousands of metal-based complexes of biological importance. The nucleic acids are a primary target for these metal complexes and have been immensely studied by scientists. The book chapters from different authors have revealed the importance of metal complexes by compiling the extensive data collected from various search engines. The chemistry of metal, synthetic procedures, and interactive modes of zinc, ruthenium, copper, iron, and magnesium complexes have been compiled. This book can work as a reference material for students as well as researchers at different levels by presenting cutting-edge research for metal-based drug designers to study the interaction of metal complexes with nucleic acids.

Chapter 1: Zinc complexes

Their interaction with nucleic acids and other biomolecular targets

Imtiyaz Yousuf, Masrat Bashir, Imtiyaz Ahmad Mantoo, and Sadiya     Department of Chemistry, Aligarh Muslim University, Aligarh, Uttar Pradesh, India

Abstract

Transition metal ions on account of their unique features, viz., variable oxidation states, physiologically tuneable redox states, wide range of geometries and coordination numbers, and their ability to form vast number of coordination complexes, offer an excellent platform for the design of therapeutic metallodrugs. Although, the field of metal-based therapy against various diseased states gained momentum after the spectacular discovery of cisplatin, an anticancer metallodrug. Cisplatin has shown phenomenal anticancer activity against solid malignancies, but its clinical use has been limited due to its severe toxicity and resistance issues. This has shifted the focus to metal ions that are less toxic and have potential to exert promising therapeutic activity. Metal complexes of late 3d-metal ions, viz., Co(II), Cu(II), and Zn(II), have been exploited successfully against numerous diseased states as such metal ions are essential in maintaining the daily state of heath when administered within physiologic levels. Moreover, the physiologic excess or deficiency of these metal ions has direct implication on the prevalence of many diseases. Zinc is an essential metal element required for the development and growth of the human body and is essentially part of plethora of metalloenzymes of physiologic importance. Many Zn(II)-based complexes have been synthesized and screened for their biomedical properties including neurodegenerative, antimicrobial, anticancer, anti-inflammatory, and antidiabetic disease, etc. Thus, in the present book chapter, we provide a detailed description of the interaction studies of numerous potential zinc complexes derived from diverse ligand scaffolds with various biomolecular targets. The interaction studies of drugs with nucleic acids and albumin proteins is crucial in the determination of the mechanistic pathway of drug action and designing of more efficient and targeted specific drugs with fewer side effects.

Keywords

Albumin proteins; Experimental methods; Metallodrugs; Nucleic acids interaction; Zn(II) complexes

1. Chemistry of zinc

Zinc is a transition metal with atomic and mass numbers 30 and 65.38 a.m.u., respectvely, exists in several isotopic forms of masses 66, 67, 68, and 70. Zinc is a malleable, ductile, bluish-white metal element with electronic configuration of [Ar] 4s², 3d¹⁰. Transition metals on account of their distinctive properties, including variable oxidation states, tuneable redox chemistry, lesser toxicity, and target specificity with the biomolecules, offer an excellent platform for the design of therapeutic metallodrugs (Galani et al., 2014; Haghdoost et al., 2018; Santini et al., 2014). Moreover, transition metals form an enormous number of coordination complexes with a diverse range of organic ligands due to a wide range of geometries and coordination numbers that often modulate their kinetic (rates of ligand exchange) and thermodynamic reactivity with the targeted biomolecules (Khare et al., 2021; Psomas & Kessissoglou, 2013). To date, diverse inorganic complexes have been identified as efficient diagnostic and therapeutic agents. Although, the field of metal-based therapy against various diseased states gained momentum after the successful clinical intervention of cisplatin and other platinum dugs against cancer, which opened new prospects for the design of metallodrugs with potential biomedical applications (Mjos & Orvig, 2014). Platinum metallodrugs have shown phenomenal success against various cancers with more than 50% of patients being treated with platinum-based therapy (Olszewski & Hamilton, 2010; Wang & Guo, 2013). However, the issue of systematic toxicity, constrained therapeutic window, and drug resistance exhibited by platinum-based drugs has shifted the focus toward the development of non-platinum complexes (Jung & Lippard, 2007; Wilson & Lippard, 2014). With an aim of achieving lower toxicity, improved selectivity, and better activity, many late 3d-metal complexes especially Zn(II)-based complexes have been successfully exploited. Zinc is an essential trace element responsible for the development and growth in various forms of life and hence has a considerable therapeutic effect against several diseased states (Maywald & Rink, 2022). Zinc is the most prominent trace metal and has the potential to bind with more than 300 metalloenzymes. It is generally coordinated to sulfur, nitrogen, or oxygen of amino acid residues to facilitate any cellular actions regarding this metal like transport and trafficking, which happen due to uninterrupted exchange of the metal from donor to acceptor ligands (Yaman et al., 2005). The occurrence of zinc is vital for the survival of cells and tissue protection, particularly cellular, production, differentiation, apoptosis, invulnerability, and reproduction (Zhu et al., 2017). It is involved in the synthesis and repair of DNA, as the primary element of binding proteins of DNA has an important function in the genetic message translation and transcription factor purpose, which plays a significant role in examining the cell metabolism and providing protection against oxidation damage (Valko et al., 2016). For an average adult, the regular intake of 8–11 mg is recommended, which regulates its presence of around 3 gm in the individual, mainly confined in muscles, liver, testicles, and brain (Connie & Christine, 2009, p. 151). To avoid the toxic effects caused by the excess or deficiency of metal, the optimum amount of intracellular zinc is mainly controlled by the homeostasis processes depending on the activity of specific transporters like ZIP and ZnT proteins (Wessels et al., 2017). However, zinc imbalance is usual, and its nutritional deficiency can cause breakage in the strands of DNA and oxidative differences that elevate the chances of cancer growth (Skrajnowska & Bobrowska-Korczak, 2019; Ames & Wakimoto, 2002). Unusual variations in the metabolism of Zn may result in neurocognitive disorders and the CNS diseases (Szewczyk et al., 2011), so its leveling is crucial (Davies et al., 2010).

Apart from being an essential cofactor having a catalytic and structural role in an excess of enzymes, its complexes are also employed as drugs (Carrigan & Poulter, 2003). Additionally, it was reported in various literatures that numerous zinc complexes exhibit remarkable biologic activities, viz., anti-Alzheimer (Vasto et al., 2008), anticonvulsant (d’Angelo et al., 2008), antimicrobial (Riduan & Zhang, 2021), antitumor (Pellei et al., 2021), anti-inflammatory (Psomas, 2020), and antidiabetic disease (Chukwuma et al., 2020). It is also found to be beneficial in minimizing cardio- and hepatotoxicity that are triggered by some anticancer drugs (Wang et al., 2022).

Zinc derivatives have advantages over other metal-based drugs in terms of lower toxicity and minimal side effects. The chemical and physical uniqueness of zinc makes it different from the remaining first row transition metals, which is the main reason behind its pervasive occurrence in biologic systems. The redox inactive dicationic Zn²+ ion is diamagnetic and a strong Lewis acid (vulnerable to the rapid interchange of ligands), and it stabilizes several coordination geometries (Vallee & Auld, 1990; Suchomski et al., 2012; Chen & Wang, 2020). The charge and steric hindrance of the ligands make it extremely flexible to coordination geometries, which permits the interchange between different coordination geometries, where tetrahedral is the most preferred one in proteins. Being a Lewis acid, the nitrogen binding site of histidine amino acid residue is favored followed by the sulfur of cysteine, oxygen of glutamate/aspartate, and also carbonyl oxygen of glutamate/aspartate, hydroxyl oxygen of tyrosine, and carbonyl oxygen of peptide bond (Haas & Franz, 2009; Barone et al., 2013). On account of possessing diverse geometries and coordination numbers, Zn can coordinate with the binding site of N, O, S, etc., of various ligands (pyridine-based systems and terpyridine, diamine systems and quinoline, and imidazole-based systems, etc.) (Porchia et al., 2020; Banerjee & Chakravarty, 2015). Nevertheless, it forms stable chelates complexes with the ligands of N and O donors (Maret & Li, 2009).

Many studies revealed that the damage of Zn homeostasis leads to its participation in acquiring various cancer diseases. The chelation therapy and the application of ionophore ligands are employed to attain the appropriate zinc concentration in the case of zinc excessiveness and its deficiency respectively (Zhang et al., 2019). Zinc complexes have attracted a lot of attention as potential novel anticancer metal-based drugs compared with other metal (II) complexes. Zinc complexes have been taken into consideration as Zn²+ ion is notably nontoxic at heavier doses in comparison with other metals like Hg, Cu, Fe, etc. (Ye et al., 2020). Furthermore, zinc complexes promote the activation of Lewis acid owing to rapid exchange of ligands that lead in playing a role in the hydrolytic catalysis reactions, for example, cleavage and hydrolysis of deoxyribonucleic acid (DNA) possessing anticancer activity (Parkin, 2004). Zinc complexes consist of photosensitive systems, for instance, phthalocyanines, that have been employed as photosensitizer agents in photodynamic therapy. In contrast with other potential metals, zinc is highly coordinated to phthalocyanines, resulting in superior photochemical and chemical properties (Al Mousawi et al., 2017; Yavuz et al., 2018).

2. Interaction of synthesized zinc complexes with nucleic acids

DNA is the prime intracellular target of anticancer drugs that are currently in clinical use or under clinical trials (Skok et al., 2019). DNA consists of four nucleobases, viz., adenine (A), guanine (G), cytosine (C), and thymine (T), which are planar aromatic derivatives of purine (A and G) and pyrimidine (C and T). The phosphodiester bond (which joins 3′ end of one sugar to the 5′ end of another) binds together the adjacent nucleotides in the polymeric chain. As a result, lengthy, single-stranded polyanionic chains with a well-defined directionality (often specified in the 5′ to 3′ direction) are created, and these chains essentially make up the fundamental structure of nucleic acid (Kanvah et al., 2010). Many biologic activities, such as recombination, replication, transcription, and chromosomal segregation during meiosis and mitosis, depend on recognition of specific DNA sequences of various molecules. Similar interactions exist in other processes, including DNA repair, DNA lesions caused by radiation and carcinogens, and the mechanism of action of various antineoplastic agents. Additionally, DNA is typically the main intracellular target of anticancer drugs (Havelka et al., 2007), so it is crucial to understand the various ways how drugs attach to DNA to design novel, effective DNA-targeted medications with solid therapeutic profiles. Furthermore, understanding the chemical reactions that take place between small molecules and DNA is crucial for predicting the potential physiologic and/or therapeutic implications of such interactions (Haq, 2002).

It is generally known that DNA can adopt several conformations that are determined both logically and macroscopically by various structural characteristics rather than existing in a single three-dimensional (3D) structure (Fig. 1.1) (Miyahara et al., 2013). Although both