Henderson Elizabeth D, Gangapuram Madhavi, Eyunni Suresh Kumar Vk, Redda Kinfe K, Wilson-Ardley Tiffany
College of Pharmacy and Pharmaceutical Sciences, Florida A & M University, Tallahassee, FL, USA.
Madridge J Pharm Res. 2019;3(1):52-59. doi: 10.18689/mjpr-1000109. Epub 2019 Mar 4.
Inflammation is believed to incite carcinogenesis by causing cell and genome damage. Tetrahydropyridines have gained significant synthetic interest because they constitute biologically active features of pharmaceutical agents. Previous tetrahydropyridines developed by our research group were effective in inhibiting inflammation. Since there is a relationship between inflammation and cancer, the objective of this manuscript is to expand our prior study to determine the anti-cancer activity of novel tetrahydropyridine analogs.
3-Ethylpyridine reacted with O-mesitylenesulfonylhydroxylamine to furnish N-amino-3-ethylpyridinium mesitylenesulfonate. The reaction of N-amino-3-ethylpyridinium mesitylenesulfonate with substituted acid chlorides gives the stable crystalline pyridinium ylides. A sodium borohydride reduction of ylides furnishes the target compounds, N-substituted [benzoylamino]-5-ethyl-1,2,3,6-tetrahydropyridines. The evaluation of these analogs cytotoxicity against Ishikawa, MCF-7, and MDA-MB-231 cell lines were determined after 72 hours of drug exposure employing CellTiter-Glo assay. To explore the interaction between the tetrahydropyridine derivatives and estrogen receptor alpha, SYBYL-X 2.1 was used to determine the best bioactive conformations of the tetrahydropyridine derivatives for the active site of the receptor.
Four novel N-substituted [benzoylamino]-5-ethyl-1,2,3,6-tetrahydropyridines were synthesized, purified, and characterized. The four tetrahydropyridine analogs exhibited some anti-cancer activity. Based on the molecular modeling studies, EH3 was expected to have the best antiproliferative activity due to having the highest docking score for ERα. However, EH2 had the best antiproliferative activity. Nevertheless, the biological screening and molecular modeling can provide insight to help with the design of more biologically active compounds as potential anti-cancer agents.
炎症被认为可通过导致细胞和基因组损伤来引发癌症。四氢吡啶因其构成药物的生物活性特征而引起了极大的合成兴趣。我们研究小组之前开发的四氢吡啶在抑制炎症方面具有成效。鉴于炎症与癌症之间存在关联，本论文的目的是扩展我们之前的研究，以确定新型四氢吡啶类似物的抗癌活性。
3 - 乙基吡啶与邻均三甲苯磺酰羟胺反应生成N - 氨基 - 3 - 乙基吡啶均三甲苯磺酸盐。N - 氨基 - 3 - 乙基吡啶均三甲苯磺酸盐与取代的酰氯反应生成稳定的结晶型吡啶叶立德。用硼氢化钠还原叶立德得到目标化合物N - 取代的[苯甲酰氨基]-5 - 乙基 - 1,2,3,6 - 四氢吡啶。在药物暴露72小时后，采用CellTiter - Glo检测法测定这些类似物对石川细胞系、MCF - 7细胞系和MDA - MB - 231细胞系的细胞毒性。为了探究四氢吡啶衍生物与雌激素受体α之间的相互作用，使用SYBYL - X 2.1来确定四氢吡啶衍生物与受体活性位点的最佳生物活性构象。
合成、纯化并表征了四种新型N - 取代的[苯甲酰氨基]-5 - 乙基 - 1,2,3,6 - 四氢吡啶。这四种四氢吡啶类似物表现出一定的抗癌活性。基于分子模拟研究，由于EH3对ERα的对接分数最高，预计其具有最佳的抗增殖活性。然而，EH2具有最佳的抗增殖活性。尽管如此，生物学筛选和分子模拟可为设计更具生物活性的潜在抗癌化合物提供思路。
