Hagos Ghenet K, Abdul-Hay Samer O, Sohn Johann, Edirisinghe Praneeth D, Chandrasena R Esala P, Wang Zhiqiang, Li Qian, Thatcher Gregory R J
Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60612, USA.
Mol Pharmacol. 2008 Nov;74(5):1381-91. doi: 10.1124/mol.108.046664. Epub 2008 Aug 1.
Nonsteroidal anti-inflammatory drugs (NSAIDs) have shown promise in colorectal cancer (CRC), but they are compromised by gastrotoxicity. NO-NSAIDs are hybrid nitrates conjugated to an NSAID designed to exploit the gastroprotective properties of NO bioactivity. The NO chimera ethyl 2-((2,3-bis(nitrooxy)propyl)disulfanyl)benzoate (GT-094), a novel nitrate containing an NSAID and disulfide pharmacophores, is effective in vivo in rat models of CRC and is a lead compound for design of agents of use in CRC. Preferred chemopreventive agents possess 1) antiproliferative and 2) anti-inflammatory actions and 3) the ability to induce cytoprotective phase 2 enzymes. To determine the contribution of each pharmacophore to the biological activity of GT-094, these three biological activities were studied in vitro in compounds that deconstructed the structural elements of the lead GT-094. The anti-inflammatory and antiproliferative actions of GT-094 in vivo were recapitulated in vitro, and GT-094 was seen to induce phase 2 enzymes via the antioxidant responsive element. In the variety of colon, macrophage-like, and liver cell lines studied, the evidence from structure-activity relationships was that the disulfide structural element of GT-094 is the dominant contributor in vitro to the anti-inflammatory activity, antiproliferation, and enzyme induction. The results provide a direction for lead compound refinement. The evidence for a contribution from the NO mimetic activity of nitrates in vitro was equivocal, and combinations of nitrates with acetylsalicylic acid were inactive.
非甾体抗炎药（NSAIDs）在结直肠癌（CRC）治疗中显示出前景，但会受到胃肠毒性的影响。NO-NSAIDs是与NSAID结合的杂化硝酸盐，旨在利用NO生物活性的胃肠保护特性。新型硝酸盐2-((2,3-双(硝基氧基)丙基)二硫烷基)苯甲酸乙酯（GT-094）是一种含有NSAID和二硫键药效基团的新型硝酸盐，在CRC大鼠模型体内有效，是CRC治疗用药物设计的先导化合物。优选的化学预防剂具有1）抗增殖和2）抗炎作用以及3）诱导细胞保护II相酶的能力。为了确定每个药效基团对GT-094生物活性的贡献，在体外对解构先导化合物GT-094结构元件的化合物进行了这三种生物活性的研究。GT-094在体内的抗炎和抗增殖作用在体外得到重现，并且发现GT-094通过抗氧化反应元件诱导II相酶。在所研究的多种结肠、巨噬细胞样和肝细胞系中，构效关系的证据表明，GT-094的二硫键结构元件在体外对抗炎活性、抗增殖和酶诱导起主要作用。这些结果为先导化合物的优化提供了方向。体外硝酸盐的NO模拟活性贡献的证据不明确，硝酸盐与乙酰水杨酸的组合无活性。
