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Shweta Agarwal Dr. Ranjana Mehrotra Investigations on interaction mechanism of chloroethyl nitrosourea derivatives with nucleic acid: In silico and spectroscopic STUDIES THESIS SUBMITTED TO AcSIR FOR THE AWARD OF THE DEGREE OF Doctor of Philosophy In Biological Sciences By Shweta Agarwal Enrolment No: 10BB12A32008 Under the guidance of Dr. Ranjana Mehrotra Chief Scientist & Head Quantum Phenomena & Applications CSIR-NATIONAL PHYSICAL LABORATORY Dr. K.S. KRISHNAN MARG NEW DELHI-110012 INDIA AUGUST 2015 ABSTRACT Cancer is the second leading cause of death in the world after cardiovascular diseases. In spite of good advancements in diagnosis and treatment, there is still a lack of better remedial options for cancer treatment. Cancer develops, when normal cells (in a particular part of the body) begin to divide in an uncontrolled manner. Generally, transformation of a normal cell to cancerous cell is associated with DNA mutation and damage. At present, there are several regimes in use to combat cancer and majority of them involve the utilization of chemotherapy (the use of chemicals to destroy cancer cells). Despite inexorably significant role of chemotherapy in cancer cure and control, cytotoxic mechanisms of several chemotherapeutic agents are not well characterized. Many of these anticancer chemotherapeutic drugs target nucleic acids and auxiliary processes (such as replication, transcription and translation) in course of their cytotoxic action. Keeping this in view, researchers are constantly putting their efforts to elucidate the underlying anticancer mechanism of drugs at molecular level by investigating the interaction mode between nucleic acid and drugs. The information gathered from the outcome of such investigations is helpful in the establishment of a correlation between drug's molecular structure and its cytotoxicity. Furthermore, this knowledge would be instrumental in the detection of those structural modifications in a drug that could result in sequence/structure specific binding to their target (nucleic acid). This comprehension can be exploited in the rational designing and synthesis of new drugs, possessing better efficacy and reduced side effects, since non-specific binding restricts drug dose and regularity in cancer treatment. At last, it can be deduced that interaction studies are fundamental in unraveling the mystery of molecular recognition, in general, and nucleic acid binding, in particular. v Chapter 1, the introductory chapter, depicts aims and objectives of the present work. Chloroethyl nitrosoureas derivatives (CENUs) constitute one of the classes of alkylating antineoplastic agents, which possess immense importance and direct relevance in the treatment of brain tumors, lymphomas, malignant melanoma and various solid tumors. Antineoplastic action of CENUs is believed to involve the inhibition of DNA replication, RNA transcription and protein translation by means of alkylation of nitrogenous bases in DNA double helix. Despite of the availability of detailed structural/chemical knowledge about the alkylating agents in literature, there remain deficits in the understanding of CENUs-nucleic acid interaction in particular. Therefore, it is of great significance to elucidate the peculiarities of CENUs-nucleic acid complexation to comprehend their underlying cytotoxic action mechanism. In the present work, we aim to investigate the nucleic acid binding properties of chloroethyl nitrosourea derivatives, namely; nimustine, lomustine and semustine using molecular modeling and various spectroscopic techniques. Lomustine and semustine structurally differ from each other by single methyl group. Therefore, it is an interesting aspect to perform comparative exploration of nucleic acid binding features of these two, which is also demonstrated in work, presented here. Chapter 2 deals with the instrumentation and methodology used in the subsequent chapters of the thesis. Stock solution of nucleic acid (DNA and tRNA) were prepared in tris-HCl buffer (pH-7.4, 10 mM) and kept at 8 oC for 24 hours. The solutions were stirred at regular intervals to make sure the formation of homogenous nucleic acid solutions. The final concentration of DNA and tRNA stock solutions were measured spectrophotometrically using molar extinction coefficient of 6600 cm-1 M-1 and 9250 cm-1 M-1 respectively and calculated as 42 mM. Drug’s solutions of varying concentration were prepared by a series of dilutions of stock solution and mixed separately with stock DNA and tRNA solutions of constant concentration to attain different drug/DNA and drug/tRNA molar ratios. Vibrational [Fourier transform vi infrared spectroscopy (FTIR), surface enhanced Raman spectroscopy (SERS)], circular dichroism (CD) and absorption spectroscopic investigations were performed on free nucleic acid and CENUs-nucleic acid complexes at different molar ratios. In silico studies on drug-nucleic acid complexes were also carried out using AutoDock 4.2 software to get insight into the interaction site. Molecular docking and spectroscopic investigations on the binding properties of chloroethyl nitrosourea derivative; nimustine, lomustine and semustine with DNA duplex are detailed in Chapter 3. The spectral outcomes on nimustine-DNA adducts show that nimustine is a major groove-directed alkylating agent. Further analysis illustrates that interaction of nimustine occurs via guanine (C6=O6) and thymine (C4=O4) residues reactive sites located in DNA major groove. CD spectral results suggest the formation of an intermediate form of DNA during the transition from B- to C-form at local level after the formation of nimustine-DNA complexes, although globally, DNA remains in native B-form. Spectroscopic observations on lomustine- DNA complexes suggest that lomustine interacts via guanine (N7) and cytosine (C4) base residues along with slight binding to sugar-phosphate backbone of DNA duplex. Furthermore, formation of an intermediate stage (B-A-form) of DNA double helix after its interaction with lomustine was also noticed. In case of semustine-DNA complexation, initial interaction of semustine with thymine followed by dG-dC DNA cross-link formation is suggested, which further authenticates molecular modeling prediction. CD spectroscopic data indicates the formation of an intermediary form of DNA during the transition from B- to C-form locally after semustine-DNA complexation. Furthermore, DNA binding mechanism of semustine has been compared with that of lomustine. This suggests that lomustine has more prominent effect than semustine with respect to their interaction with DNA double helix. These findings may add further understanding about the cytotoxic action mechanism of chloroethyl nitrosourea derivatives at molecular level. vii Study of nature and mode of interaction of chloroethyl nitrosourea derivative; nimustine, lomustine and semustine with transfer RNA (tRNA) using various biophysical and spectroscopic techniques such as attenuated total reflection-Fourier transform infrared spectroscopy (ATR-FTIR), Fourier transform infrared difference spectroscopy, circular dichroism (CD) spectroscopy and UV-visible spectroscopy is illustrated in Chapter 4. In addition, molecular docking simulations were performed to predict the preferred orientation of CENUs binding to tRNA molecule, which further help in predicting the strength and site of interaction between the drug and tRNA moiety. Parameters involved in the complexation of CENUs with tRNA including binding affinities were studied in detail. FTIR spectral outcomes suggest that CENUs interact via guanine and cytosine residues of tRNA in addition to slight binding with its sugar-phosphate backbone, authenticating molecular modeling prediction. However, in case of nimustine-tRNA and semustine-tRNA complexes, primarily binding with uracil residue was observed as indicated by FTIR spectral analysis. This augments the possibility of groove-directed alkylation as their anticancer action mechanism. CD spectroscopic data signifies no conformational change in native A-form of tRNA after its complexation with CENUs. Furthermore, UV-visible studies affirm weak type of binding of CENUs with tRNA. These findings may further contribute in the development of RNA targeting chemotherapeutic agents. Chapter 5 includes conclusions of the experimental observations and analysis along with the concluding remarks and future perspectives. Mechanistic understanding of cytotoxicity, exerted by the drugs, is vital to comprehend the molecular basis of their action and subsequent to improve their binding specificity & efficacy. In this perspective, explication of structural-conformational aspects of binding phenomenon with correlation of structure-function relationship becomes significant. Thereby, much attention has been paid towards the investigations of DNA and RNA recognizing agents that particularly target their structural components and can be developed as therapeutics. viii Chapter 5 CHAPTER 5 Conclusions and Future Perspectives ““Research is to see what everybody else has seen, and to think, what nobody else has thought” -Albert Szent-Gyorgi Conclusions Mechanistic explication of cytotoxicity, exerted by chemotherapeutic agents, is essential to comprehend the molecular basis of their action and subsequent to improve their specificity & efficacy. In this perspective, understanding of structural- conformational aspects of binding phenomenon, correlation of structure-function relationship, thermodynamics properties, nitrogenous base sequence selectivity and linkage between ligand geometry become
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