Synthetic metallomolecules as agents for the control of DNA structure

This tutorial review summarises B-DNA structure and metallomolecule binding modes and illustrates some DNA structures induced by molecules containing metallic cations. The effects of aquated metal ions, cobalt amines, ruthenium octahedral metal complexes, metallohelicates and platinum complexes such as cis-platin are discussed alongside the techniques of NMR, X-ray crystallography, gel electrophoresis, circular dichroism, linear dichroism and molecular dynamics. The review will be of interest to people interested in both DNA structure and roles of metallomolecules in biological systems

Unusual DNA binding modes for metal anticancer complexes

DNA is believed to be the primary target for many metal-based drugs. For example, platinum-based anticancer drugs can form specific lesions on DNA that induce apoptosis. New platinum drugs can be designed that have novel modes of interaction with DNA, such as the trinuclear platinum complex BBR3464. Also it is possible to design inert platinum(IV) pro-drugs which are non-toxic in the dark, but lethal when irradiated with certain wavelengths of light. This gives rise to novel DNA lesions which are not as readily repaired as those induced by cisplatin, and provides the basis for a new type of photoactivated chemotherapy. Finally, newly emerging ruthenium(II) organometallic complexes not only bind to DNA coordinatively, but also by H-bonding and hydrophobic interactions triggered by the introduction of extended arene rings into their versatile structures. Intriguingly osmium (the heavier congener of ruthenium) reacts differently with DNA but can also give rise to highly cytotoxic organometallic complexes

DESIGN OF GRAPHENE-BASED SENSORS FOR NUCLEIC ACIDS DETECTION AND ANALYSIS

DNA (Deoxyribonucleic Acid) is the blueprint of life as it encodes all genetic information. In genetic disorder such as gene fusion, Copy Number Variation (CNV), and single nucleotide polymorphism, Nucleic acids such as DNA bases detection and analysis is used as the gold standard for successful diagnosis. Researchers have been conducting rigorous studies to achieve genome sequences at low cost while maintaining high accuracy and high throughput. A quick, accurate, and low-cost DNA detection approach would revolutionize medicine. Genome sequence helps to enhance people’s perception of inheritance, disease, and individuality. This research aims to improve DNA bases detection accuracy, and efficiency, and reduce the production cost, thus novel based sensors were developed to detect and identify the DNA bases. This work aims at first to develop specialized field effect transistors which will acquire real-time detection for different concentrations of DNA. The sensor was developed with a channel of graphite oxide between gold electrodes on a substrate of a silicon wafer using Quantumwise Atomistix Toolkit (ATK) and its graphical user interfaces Virtual Nanolab (VNL). The channel was decorated with trimetallic nanoclusters that include gold, silver, and platinum which have high affinity to DNA. The developed sensor was investigated by both simulation and experiment. The second aim of this research was to analyze the tissue transcriptome through DNA bases detection, thus novel graphene-based sensors with a nanopore were designed and developed to detect the different DNA nucleobases (Adenine (A), Cytosine (C), Guanine (G), Thymine (T)). This research focuses on the simulation of charge transport properties for the developed sensors. This work includes experimental fabrication and software simulation studies of the electronic properties and structural characteristics of the developed sensors. Novel sensors were modeled using Quantumwise Atomistix Toolkit (ATK) and its graphical user Interface Virtual Nanolab (VNL) where several electronic properties were studied including transmission spectrum and electrical current of DNA bases inside the sensor’s nanopore. The simulation study resulted in a unique current for each of the DNA bases within the nanopore. This work suggests that the developed sensors could achieve DNA sequencing with high accuracy. The practical implementation of this work represents the ability to predict and cure diseases from the genetic makeup perspective

Bioinorganic Chemistry

This book covers material that could be included in a one-quarter or one-semester course in bioinorganic chemistry for graduate students and advanced undergraduate students in chemistry or biochemistry. We believe that such a course should provide students with the background required to follow the research literature in the field. The topics were chosen to represent those areas of bioinorganic chemistry that are mature enough for textbook presentation. Although each chapter presents material at a more advanced level than that of bioinorganic textbooks published previously, the chapters are not specialized review articles. What we have attempted to do in each chapter is to teach the underlying principles of bioinorganic chemistry as well as outlining the state of knowledge in selected areas. We have chosen not to include abbreviated summaries of the inorganic chemistry, biochemistry, and spectroscopy that students may need as background in order to master the material presented. We instead assume that the instructor using this book will assign reading from relevant sources that is appropriate to the background of the students taking the course. For the convenience of the instructors, students, and other readers of this book, we have included an appendix that lists references to reviews of the research literature that we have found to be particularly useful in our courses on bioinorganic chemistry

Controlling platinum, ruthenium, and osmium reactivity for anticancer drug design

The main task of the medicinal chemist is to design molecules that interact specifically with derailed or degenerating processes in a diseased organism, translating the available knowledge of pathobiochemical and physiological data into chemically useful information and structures. Current knowledge of the biological and chemical processes underlying diseases is vast and rapidly expanding. In particular the unraveling of the genome in combination with, for instance, the rapid development of structural biology has led to an explosion in available information and identification of new targets for chemotherapy. The task of translating this wealth of data into active and selective new drugs is an enormous, but realistic, challenge. It requires knowledge from many different fields, including molecular biology, chemistry, pharmacology, physiology, and medicine and as such requires a truly interdisciplinary approach. Ultimately, the goal is to design molecules that satisfy all the requirements for a candidate drug to function therapeutically. Therapeutic activity can then be achieved by an understanding of and control over structure and reactivity of the candidate drug through molecular manipulation

Computational Study of Compounds with Biological Activity and their Interaction with Nano-Materials

In the last few decades, computer simulation became a potent tool to study experimental systems such as chemical reactions and adsorption mechanisms in more detail. Every day, developments in computers and computational software are made to increase the computational power to study more complex systems. In this thesis, computational methods were used to study the reactivity of two classes of compounds and their interaction with carbon-based materials; the two classes are platinum-based antitumor drugs and fluoroquinolones antimicrobials compounds. The hydrolysis reaction of cis-[Pt(PMe3)2(etga)], cis-[Pt(PMe3)2(3-Hfl)]+ containing ethyl gallate (etga) and 3-Hydroxyflavone(3-HFl), designed to try to limit the side effects of cisplatin, studied by means of density functional theory (DFT) calculations. The calculations showed that the activation energies are significantly lower than those calculated for cisplatin, with consequent high hydrolysis reaction rate that might make such complexes subject to fast degradation, causing potentially poor pharmacological activity; indeed, the complexes present lower cytotoxic activity compared to cisplatin. The complete mechanism of action (hydrolysis reaction, reaction with DNA bases and reaction with cysteine) of phenanthriplatin, a monofunctional platinum complex, was studied by means of DFT calculations. Moreover, a comparison between phenanthriplatin and cisplatin was made with the aim of understanding why phenanthriplatin presents a higher cytotoxicity activity compared to cisplatin. The hydrolysis reaction showed that phenanthriplatin\u2019s activation energy barrier is close to the energy barriers obtained for the first hydrolysis of cisplatin. The reaction with guanine is kinetically favoured in phenanthriplatin in respect to cisplatin. Finally, the reaction between phenanthriplatin and cysteine showed that such reaction is disadvantageous, both kinetically and thermodynamically, in phenanthriplatin in respect to cisplatin. This can explain why phenanthriplatin is more cytotoxic than cisplatin. The non-covalent interaction between graphene prototypes, new candidates as drugs delivery systems, and cisplatin were investigated through MP2 and DFT calculation. Different orientations of cisplatin in respect to the circumcoronene, one parallel and three perpendicular, were taken into account. The parallel orientation presents the highest value of interaction energy in vacuum. Finally, the introduction of the solvent does not drastically change the interaction energy profiles between cisplatin and circumcoronene. Thus, a favourable adsorption of cisplatin on graphene can be predicted. As regards the fluoroquinolones (FQ) antimicrobials compounds, the relative stability and photochemical behaviour of the different protonation states of CFX in gas phase and in water was studied by means of molecular dynamics simulations and DFT calculations. This work confirm the predominance of the zwitterionic form in water in respect to the neutral form. Finally, the protonation sequence was confirmed through the comparison with the crystalline structures found in the literature, through the calculation of the relative stability for such species and the calculated absorption UV-Vis spectra. Finally, the adsorption of both neutral and zwitterionic forms of CFX to the inner and outer surface of carbon nano-tubes (CNT) in vacuum and in water was studied through molecular dynamics simulations. The simulation results showed that CFX remains adsorbed to the surface of CNT both in vacuum and in water thanks to p-p interactions. Finally, the adsorption Gibbs free energy were carried out for the adsorbed zCFX and nCFX, finding out that adsorption is thermodynamically favoured. In conclusion, the use of computational chemistry can help to rationalize the experimental data and to investigate various mechanicistic hypothesis

Computational Study of Compounds with Biological Activity and their Interaction with Nano-Materials

In the last few decades, computer simulation became a potent tool to study experimental systems such as chemical reactions and adsorption mechanisms in more detail. Every day, developments in computers and computational software are made to increase the computational power to study more complex systems. In this thesis, computational methods were used to study the reactivity of two classes of compounds and their interaction with carbon-based materials; the two classes are platinum-based antitumor drugs and fluoroquinolones antimicrobials compounds. The hydrolysis reaction of cis-[Pt(PMe3)2(etga)], cis-[Pt(PMe3)2(3-Hfl)]+ containing ethyl gallate (etga) and 3-Hydroxyflavone(3-HFl), designed to try to limit the side effects of cisplatin, studied by means of density functional theory (DFT) calculations. The calculations showed that the activation energies are significantly lower than those calculated for cisplatin, with consequent high hydrolysis reaction rate that might make such complexes subject to fast degradation, causing potentially poor pharmacological activity; indeed, the complexes present lower cytotoxic activity compared to cisplatin. The complete mechanism of action (hydrolysis reaction, reaction with DNA bases and reaction with cysteine) of phenanthriplatin, a monofunctional platinum complex, was studied by means of DFT calculations. Moreover, a comparison between phenanthriplatin and cisplatin was made with the aim of understanding why phenanthriplatin presents a higher cytotoxicity activity compared to cisplatin. The hydrolysis reaction showed that phenanthriplatin\u2019s activation energy barrier is close to the energy barriers obtained for the first hydrolysis of cisplatin. The reaction with guanine is kinetically favoured in phenanthriplatin in respect to cisplatin. Finally, the reaction between phenanthriplatin and cysteine showed that such reaction is disadvantageous, both kinetically and thermodynamically, in phenanthriplatin in respect to cisplatin. This can explain why phenanthriplatin is more cytotoxic than cisplatin. The non-covalent interaction between graphene prototypes, new candidates as drugs delivery systems, and cisplatin were investigated through MP2 and DFT calculation. Different orientations of cisplatin in respect to the circumcoronene, one parallel and three perpendicular, were taken into account. The parallel orientation presents the highest value of interaction energy in vacuum. Finally, the introduction of the solvent does not drastically change the interaction energy profiles between cisplatin and circumcoronene. Thus, a favourable adsorption of cisplatin on graphene can be predicted. As regards the fluoroquinolones (FQ) antimicrobials compounds, the relative stability and photochemical behaviour of the different protonation states of CFX in gas phase and in water was studied by means of molecular dynamics simulations and DFT calculations. This work confirm the predominance of the zwitterionic form in water in respect to the neutral form. Finally, the protonation sequence was confirmed through the comparison with the crystalline structures found in the literature, through the calculation of the relative stability for such species and the calculated absorption UV-Vis spectra. Finally, the adsorption of both neutral and zwitterionic forms of CFX to the inner and outer surface of carbon nano-tubes (CNT) in vacuum and in water was studied through molecular dynamics simulations. The simulation results showed that CFX remains adsorbed to the surface of CNT both in vacuum and in water thanks to p-p interactions. Finally, the adsorption Gibbs free energy were carried out for the adsorbed zCFX and nCFX, finding out that adsorption is thermodynamically favoured. In conclusion, the use of computational chemistry can help to rationalize the experimental data and to investigate various mechanicistic hypothesis