DDR SUBPROJ 4: SYNTHESIS OF N-AMINOTETRAHYDROPYRIDINES AS ANTICANCER

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The objective of the proposed research is to develop effective chemotherapeutic agents that can be utilized for the treatment of lung and colon cancers. The role of non steroidal anti-inflammatory agents (NSAIDs) such as aspirin, piroxicam, and sulindac in colon cancer has been well-documented in epidemiological and animal studies. Accumulating evidence indicates that the inhibition of colon tumor development by NSAIDs is mediated through the modulation of arachidonic acid metabolism via the cyclooxygenase enzymes, which in turn inhibit immune responsiveness. The increased expression of cyclooxygenase-2 (COX-2) enzyme has been reported to correlate with the malignant changes observed in a variety of human cancers, including colorectal, gastric, esophageal, brain, and lung tumors. With this in mind, it is reasonable to postulate that compounds that induce COX-2 could predipose to cancer or inflammation. Our earlier published work established that the N-aminocarbonyl-1,2,3,6-tetrahydropyridine analogs we synthesized were effective non steroidal anti-inflammatory agents with strong cyclooxygenae-1 (COX-1) and (COX-2) inhibitory activities. The proposed analogs can be tested so that a series of compounds related to the most active analogs could be prepared. Structure activity analysis to study the electronic, steric and lipophilic effects of substituents on the physicochemical properties of the molecule will be carried out.