DDR SUBPROJ 4: SYNTHESIS OF N-AMINOTETRAHYDROPYRIDINES AS ANTICANCER

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。这项拟议研究的目标是开发可用于治疗肺癌和结肠癌的有效化疗药物。非类固醇抗炎药(NSAIDs)，如阿司匹林、吡罗昔康和舒林酸在结肠癌中的作用已经在流行病学和动物研究中得到了很好的证明。越来越多的证据表明，NSAIDs对结肠癌的抑制作用是通过环氧合酶调节花生四烯酸代谢，进而抑制免疫应答。环氧合酶-2(COX-2)酶的高表达与多种人类肿瘤的恶变有关，包括结直肠癌、胃癌、食道癌、脑癌和肺癌。考虑到这一点，合理的假设是，诱导COX-2的化合物可能容易患癌症或炎症。我们早期发表的工作证实，我们合成的N-氨基甲酰基-1，2，3，6-四氢吡啶类似物是有效的非甾体抗炎药，具有很强的环氧合酶-1(COX-1)和环氧合酶-2(COX-2)抑制活性。可以对所建议的类似物进行测试，以制备与最活跃的类似物相关的一系列化合物。将进行结构活性分析，以研究取代基对分子物理化学性质的电子、空间和亲脂作用。

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.