Département de Biologie Médicale et, Canada.
Département de Chimie, Biochimie et Physique, Université du Québec à Trois-Rivières, C.P. 500, Trois-Rivières, Québec G9A 5H7, Canada.
Eur J Med Chem. 2015;96:259-68. doi: 10.1016/j.ejmech.2015.04.026. Epub 2015 Apr 13.
Inflammation plays a crucial role in many types of cancer and is known to be involved in their initiation and promotion. As such, it is presently recognized as an important risk factor for several types of cancers such as bladder, prostate and breast cancers. The discovery of novel anti-inflammatory compounds can have a huge implication not only for the treatment of cancer but also as preventive and protective treatment modalities. We have recently identified a new compound (1) that presents interesting anti-inflammatory activity. In order to better understand its biological action, we have divided the molecule in its basic components and verified their respective contribution towards the anti-inflammatory response of the whole molecule. We have discovered that only the combination of the maleimide function together with the tert-butyloxycarbonylhydrazinamide function lead to important anti-inflammatory properties. The main derivative 1 can decrease the activating effects of INFγ or IL6 on human (hMϕs) macrophages by 38% or by 64% at a concentration of 10 μM as indicated by a decrease of STAT1 or STAT3 activation. The expression of pro-inflammatory markers CD40 and MHCII in INFγ stimulated hMϕs were reduced by 87% and 49%, respectively with a 3 h pretreatment of 1 at 10 μM. The cell motility assay revealed that 1 at 10 μM can reduce relative cell motility induced by IL6 by 92% in comparison with the untreated control hMϕ monolayers. Compound 1 reduced by 91% the inflammatory response induced by the cytokines (INFγ + TNFα) in the macrophage-like J774A.1 cells at a concentration of 25 μM, as measured by the detection of NO production with the Griess reagent. Furthermore, upon removal of the tert-butyloxycarbonyl protective group the unprotected derivative as a hydrochloride salt (1A) retains interesting anti-inflammatory activity and was found to be less toxic than the parent compound (1).
炎症在许多类型的癌症中起着至关重要的作用，并且已知其参与了癌症的起始和促进。因此，它目前被认为是几种癌症（如膀胱癌、前列腺癌和乳腺癌）的重要危险因素。发现新型抗炎化合物不仅对癌症的治疗具有重要意义，而且对预防和保护治疗方式也具有重要意义。我们最近发现了一种新的化合物（1），它具有有趣的抗炎活性。为了更好地了解其生物学作用，我们将分子分成其基本成分，并验证了它们各自对整个分子抗炎反应的贡献。我们发现，只有马来酰亚胺功能与叔丁氧基羰基肼酰胺功能的组合才会导致重要的抗炎特性。主要衍生物 1 在 10 μM 浓度下，通过降低 STAT1 或 STAT3 的激活，可使 INFγ 或 IL6 对人（hMϕs）巨噬细胞的激活作用分别降低 38%或 64%。1 在 10 μM 浓度下预处理 3 小时，可使 INFγ 刺激的 hMϕs 中促炎标志物 CD40 和 MHCII 的表达分别降低 87%和 49%。细胞迁移实验显示，与未经处理的对照 hMϕ 单层相比，1 在 10 μM 浓度下可使 IL6 诱导的相对细胞迁移减少 92%。在巨噬细胞样 J774A.1 细胞中，化合物 1 在 25 μM 浓度下可将细胞因子（INFγ+TNFα）诱导的炎症反应降低 91%，通过用 Griess 试剂检测 NO 生成来衡量。此外，在去除叔丁氧基羰基保护基后，未受保护的衍生物（1A）作为盐酸盐保留了有趣的抗炎活性，并且比母体化合物（1）的毒性更小。
