The mechanism by which tumor formation and cancer causation occurs pertains to public health, and it is an area is of great interest to many, including Mahesh K. Lakshman, Associate Professor of Chemistry at The Graduate Center and City College. Polycyclic aromatic hydrocarbons (PAHs) as a class are produced by activities in a modern society and, due to their ubiquitous presence in the environment on automobile exhaust, in the products of diesel fuel combustion, in products of the incomplete combustion of refuse, in components of cigarette smoke exposure to them is inevitable. Many PAHs pose a severe health risk to humans and are implicated in the process of tumorigenesis.
Based on the metabolic fate of any PAH and the DNA alkylation mechanism, a complex set of 16 DNA adducts are produced from any hydrocarbon. Since the tumor-forming ability is implicitly and directly related to the intracellular enzymatic recognition/repair of the damaged DNA, DNA sequences (such as ras and tumor suppressor genes) containing site-specific carcinogen modification are valuable probes for studying tumorigenesis. Therefore the development of approaches to the chemical syntheses of DNA with carcinogen lesions is an important focus of Professor Lakshman's work. Carcinogen-modified DNA can be used to probe structure in relation to biology/biochemistry on a comparative basis. The development of new, highly stereo and regioselective synthesis methods is part of the research program. Once the research has given a detailed understanding of how the tumor is initiated, possible therapeutics can be developed.
In another area of his research, also linked to nucleoside and DNA modification, Prof. Lakshman has focussed on the development and application of metal-mediated reactions, and he is studying the palladium mediated C-N and C-C bond forming reactions of nucleosides. These studies have shown that such catalysis is very effective for the synthesis of N6 and N2 modified deoxyadenosine and deoxyguanosine analogs, as well as of hydrophobic nucleosides that contain aryl units linked directly to the C-6 and C-2 positions of the purine. He is directing further research in this area towards the development of novel nucleoside paradigms that have a wide variety of uses, ranging from therapeutic agents to enzyme-DNA interaction evaluators.
Professor Lakshman's research has been funded by the National Cancer Institute (NIH) and the National Science Foundation. In addition, he is the co-PI for an NSF grant for the acquisition of a Circular Dichroism Spectrophotometer; and is the PI of an NSF grant that led to acquisition of a 500 MHz NMR spectrometer. Both of these instruments will enhance the quality of research programs at City College and CUNY.