Site specific cross-linking of thio-nucleosides

Cancer is a devastating disease. Numerous drugs have been synthesised over the years aiming to cure cancer. Significant new advancements in anti-cancer therapy have been achieved over the past few years. This was made possible by the molecular level understanding of the cancer disease, which has led to the synthesis of various targeted drugs. The targets within the cancer cells are very limited for anti-cancer drug design because cancerous cells resemble normal cells in most of their molecular aspects. This makes it extremely difficult for cell specific incorporation of drugs or cell killing. So, alternative approaches have been followed for specific cell killing. However, such approaches are still at an early stage and a great deal of work needs to be done. Various DNA-targeted approaches, such as photo cross-linking and chemical cross-linking; have been developed for killing cancerous cells. These approaches have not completely solved the problem of specificity. Like traditional anti cancer drugs, these agents also indiscriminately cross-link DNA in both normal cells, cancerous cells leading to cell death. In this thesis, two modified nucleosides were chosen which can be incorporated into the DNA of the cells easily. These thio-modified nucleosides were proven to have more affinity towards the DNA of the cancerous cells. Such modified nucleosides have previously been exploited for anti-cancer activity, especially UVA cell killing. In this thesis the thio-modified nucleosides have been explored for their site specific cross-linking activity. The first modified nucleoside 4-thiothymidine was synthesised and reported in 1959. 4-Thiothymidine resembles thymidine, except for a modification at position 4 with sulphur instead of oxygen. Previous studies have shown that 4-thiothymidine behaves like thymidine when incorporated into the cells. Like thymidine, this is base-paired with adenine in DNA. In this thesis, at first the thiol group of 4-thiothymidine has been specifically activated by a stable and readily replaceable group. This group was then replaced by various thio-nucleophiles which lead to the cross-linking of the nucleoside. The standards of these cross-linked nucleosides were successfully synthesised and characterised. In the quest to improve specificity of incorporation into cancer cells a novel pro-drug, 4-thio-5-bromodeoxyuridine (S4-BrdU) was synthesised by members of our group in 2003. This nucleoside is another thymidine analogue which is modified by replacing oxygen at position 4 with sulphur and methyl at position 5 with bromine. The thiol group of S4-BrdU nucleoside was chosen for the purpose of cross-linking. Successful cross-linking of the nucleoside with various thiol nucleophiles has been explored. Firstly S4-BrdU was converted into a DNP derivative. The DNP was then replaced with mercaptoethanol, thioethanethiol and natural thiols such as cysteine (the only amino acid containing a thiol group in the molecule) and glutathione (a natural peptide which helps in detoxification pathways in the body). These cross-linked products have been characterised by various methods. After successfully cross-linking the nucleosides, oligomers containing 4-thiothymidine were synthesised. The oligomers were characterised and 4-thiothymidine was successfully incorporated into the oligomers

Gate Driver Circuit Design, PWM signal generation using FEZ Panda III and Arduino for Inverter

This paper presents the gate driver circuit design and PWM signal generation using FEZ panda III and Arduino boards for Inverter. FEZ panda III works on .net micro framework and all its programming, debugging features are available through Microsoft’s Visual studio whereas Arduino features are available through Arduino software. Inverters are used in various applications like in motor drives and solar and wind power applications. This paper is commenced by basic understanding of need of gate driver circuit for inverter and different types of PWM techniques for generating gate signals for inverter. Simulation of SPWM inverter in both open loop and closed loop operation is done and its respective gate voltage waveforms are studied and later hardware implementation of gate driver circuit using TLP250H IC is carried out and gate voltages at different duty cycles is studied with the help of FEZ Panda III and Arduino boards

Control Techniques for the Cascaded and Cross-switched Multilevel Inverter - A Comparison

Nowadays, the multilevel inverter has gained huge attention and has become more popularized in high voltage and high-power applications with low harmonics. As the number of output voltage increases, the harmonic content of the output voltage waveform decreases. In this paper, a comparison of cascaded H-bridge and cross-switched multilevel inverters for 7, 9, 15, 21 levels will be carried out. The different control techniques that will be used for carrying out comparisons are space vector pulse width modulation (SPVPWM), sinusoidal pulse width modulation (SPWM), and third harmonic injection pulse width modulation (THI-PWM) respectively. Here, the seven-level inverter is discussed mainly and can be extended to any number of levels

Gate Driver Circuit Design, PWM signal generation using FEZ Panda III and Arduino for Inverter

This paper presents the gate driver circuit design and PWM signal generation using FEZ panda III and Arduino boards for Inverter. FEZ panda III works on .net micro framework and all its programming, debugging features are available through Microsoft’s Visual studio whereas Arduino features are available through Arduino software. Inverters are used in various applications like in motor drives and solar and wind power applications. This paper is commenced by basic understanding of need of gate driver circuit for inverter and different types of PWM techniques for generating gate signals for inverter. Simulation of SPWM inverter in both open loop and closed loop operation is done and its respective gate voltage waveforms are studied and later hardware implementation of gate driver circuit using TLP250H IC is carried out and gate voltages at different duty cycles is studied with the help of FEZ Panda III and Arduino boards

Comparison of Control Techniques & Modeling of 15-level cross H Bridge Multilevel Inverter

This paper presents the simulation of a 15-level cross-H bridge multilevel inverter using control techniques like sinusoidal pulse width modulation and third harmonic injection pulse width modulation. This paper aims to enhance output voltage level using fewer switches and to decrease total harmonic distortion by improving overall efficiency. Compared to other inverter topologies cross H bridge topology uses a lesser number of switches and dc voltages. Analysis and simulation of 15-level cross H bridge MLI are performed and presented

On the non-parametric changepoint detection of flow regimes in cyclone Amphan

The Bay of Bengal was witness to a severe cyclone named Amphan during the summer of the year 2020. The National Institute of Ocean Technology (NIOT), INDIA moorings BD08 and BD09 happened to be in the vicinity of the cyclone. The highly instrumented mooring recorded near-surface meteorological parameters like wind speed, sea surface temperature, and near-surface pressure. This article explores the possibility of using a non-parametric algorithm to identify different flow regimes using a one-month long time-series data of the near-surface parameters. The changes in the structure of the time series signal were statistically segmented using an unconstrained non-parametric algorithm. The non-parametric changepoint method was applied to time series of near-surface winds, sea surface temperature, sea level pressure, air temperature and salinity and the segmentations are consistent with visual observations. Identifying different data segments and their simple parameterization is a crucial component and relating them to different flow regimes is useful for the development of parametrization schemes in weather and climate models. The segmentations can considerably simplify the parametrization schemes when expressed as linear functions. Moreover, the usefulness of non-parametric automatic detection of data segments of similar statistical properties shall be more apparent when dealing with relatively long time series data