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Assistant Professor
B.S., Guru Nanak Dev University, Amritsar, India (1991-1994)
M.S., Guru Nanak Dev University, Amritsar, India (1994-1996)
Ph.D., University of Missouri-Columbia, Columbia, MO (1997-2003)
Postdoctoral Associate, The Ohio State University, Columbus, OH (2003-2005)
Email: sundeep@ksu.edu
Office Phone: 785-532-6660
Lab Phone: 785-532-6257
Fax: 785-532-6666
Rayat Group |
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Research Overview
Deamination of Catecholamine Neurotransmitters and Oxidative Stress in Parkinson’s Disease
Dopamine and norepinephrine are the catecholamine neurotransmitters in brain areas concerned with movement, emotional behavior, arousal, reward, and regulation of sleep and mood. The principal neuropathlogical feature of Parkinson’s disease is the selective and progressive degeneration of dopamine and norepinephrine-containing neurons as a result of oxidative stress. Oxidative stress could result from (1) the monoamine oxidase-mediated oxidation and autoxidation of catecholamines, which leads to the formation of cytotoxic quinones and reactive oxygen species (ROS), (2) the cysteinyl-catecholamine adducts, formed by the reaction of cysteine and quinones that also lead to the formation of ROS, (3) exposure to reactive nitrogen species (RNS) that leads to the formation of cytotoxic nitrated catecholamines and, (4) interaction of dopamine with cytotoxic and mutagenic agent glyoxal, which results in the production of toxic adducts.
The reactivity of these catecholamines towards various RNS has not been extensively studied. It is well known that dinitrogen trioxide N2O3, a RNS derived from nitric oxide, causes deamination of the exocyclic amino groups of DNA bases which has dire consequences on human body. The catecholamines, dopamine and norepinephrine, are also characterized by a primary amino group and what effect N2O3 might impose on these neurotransmitters is unknown. Nitrosative deamination of catecholamines represents a critical and yet unexplored pathway of neurodegeneration in PD. We will study the deamination of catecholamines under nitrosative stress to form the diazonium ions by experimental and theoretical methods. The possibility of the resulting diazonium ions to undergo adduct formation with various biomolecules such as DNA bases and amino acids will also be investigated in vitro and in vivo. We will also investigate toxicity of these adducts towards nerve cell models.
Synthesis and Biological Evaluation of Enyne-Carbodiimide Based Prodrugs for Cancer Therapy
Our objective is to develop novel DNA cleaving agents based on enyne-carbodiimides. We will synthesize first enyne-carbodiimide prodrugs for chemotherapy that could be selectively activated by irradiation to form biradicals in the target tissue. The biradicals so formed can abstract hydrogen atoms from the sugar-phosphate backbone of the DNA resulting in strand scission and ultimately in cytotoxicity.
The cycloaromatization of enyne-carbodiimides could proceed through the formation of a,3- benzofulvene or didehydrotoluene biradical depending on the nature of R1 and R2 groups. Despite the well-demonstrated ability of enyne-carbodiimides to form biradicals in solution, their DNA cleaving properties remain unexplored to date. One obvious reason involves the high reactivity of enyne-carbodiimides towards various biological nucleophiles, which restricts their use as potent DNA cleaving agents. Therefore, we will synthesize the enyne-carbodiimide prodrugs in which the carbodiimide functionality will be masked in a tetrazolin-5-thione ring structure. The enyne-tetrazolin-5-thiones could then be induced to undergo photochemical decomposition to free carbodiimides in the target tissue. Finally, we will test the ability of to cause DNA strand scission upon irradiation followed by incubation at various pHs and temperatures.
Selected Publications
- S. Rayat, M. Qian, and R. Glaser, Nitrosative cytosine deamination. An exploration of the chemistry emanating from deamination with pyrimidine ring-opening, Chem. Res. Tox. 2005, 18, 1211-1218.
- S. Rayat, Z. Wu, and R. Glaser, Nitrosative Guanine Deamination. Ab Initio Study of Deglycation of N-Protonated 5-Cyanoimino-4-Oxomethylene-4,5-Dihydroimidazoles, Chem. Res. Tox. 2004, 17, 1157-1169.
- S. Rayat, P. Majumdar, P. Tipton, and R. Glaser, 5-Cyanoimino-4-oxomethylene-4,5-dihydroimidazole and 5-Cyanoamino-4-imidazolecarboxylic Acid Intermediates in Nitrosative Guanosine Deamination. Evidence from 18O-Labeling Experiments, J. Am. Chem. Soc. 2004, 126, 9960-9969.
- B. Hodgen, S. Rayat and R. Glaser, Nitrosative Adenine Deamination: Facile Pyrimidine Ring-Opening in the Deamination of Adenine, Organic Letters, 2003, 5, 4077-4080.
- S. Rayat and R. Glaser, 4-Oxomethylene-5-Cyanoimino-4,5-Dihydroimidazole and Nitrosative Guanine Deamination. A Theoretical Study of Geometries, Electronic Structures and N-Protonation, J. Org. Chem. 2003, 68, 9882-9892.
- R. Glaser, S. Rayat, M. Lewis, M-. S. Son and S. Meyer, Theoretical Studies in DNA Base Deamination 2. Ab Initio Study of Linear, Unimolecular Dediazoniation Paths, J. Am. Chem. Soc. 1999, 121, 6108-6119.
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