Abstract：
Prolonged inflammation leads to the genesis of various inflammatory diseases such as atherosclerosis, cancer, inflammatory bowel disease, Alzheimer\'s, etc. The uncontrolled inflammatory response is characterized by the excessive release of pro-inflammatory mediators such as nitric oxide (NO), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), interleukin-1alpha (IL-1α), and inflammatory enzymes such as cyclooxygenase-2 (COX-2). Hence, the downregulation of these inflammatory mediators is an active therapy to control aberrant inflammation and tissue damage. To address this, herein, we present the rational design and synthesis of novel phytochemical entities (NPCEs) through strategic linker-based molecular hybridization of aromatic/heteroaromatic fragments with the labdane dialdehyde, isolated from the medicinally and nutritionally significant rhizomes of the plant Curcuma amada. To validate the anti-inflammatory potential, we employed a comprehensive in vitro study assessing its inhibitory effect on the COX-2 enzyme and other inflammatory mediators, viz., NO, TNF-α, IL-6, and IL-1α, in bacterial lipopolysaccharide-stimulated macrophages, as well as in-silico molecular modeling studies targeting the inflammation regulator COX-2 enzyme. Among the synthesized novel compounds, 5f exhibited the highest anti-inflammatory potential by inhibiting the COX-2 enzyme (IC50 = 17.67 ± 0.89 μM), with a 4-fold increased activity relative to the standard drug indomethacin (IC50 = 67.16 ± 0.17 μM). 5f also significantly reduced the levels of LPS-induced NO, TNF-α, IL-6, and IL-1α, much better than the positive control. Molecular mechanistic studies revealed that 5f suppressed the expression of COX-2 and pro-inflammatory cytokine release dose-dependently, which was associated with the inhibition of the NF-κB signaling pathway. This infers that the labdane derivative 5f is a promising lead candidate as an anti-inflammatory agent to further explore its therapeutic landscape.
摘要：
长时间的炎症导致各种炎症性疾病的发生，如动脉粥样硬化，癌症,炎症性肠病，老年痴呆症,等。不受控制的炎症反应的特征是促炎介质如一氧化氮（NO）的过度释放，肿瘤坏死因子-α（TNF-α），白细胞介素-6（IL-6），白细胞介素-1α（IL-1α），和炎症酶如环氧合酶-2(COX-2)。因此，这些炎症介质的下调是控制异常炎症和组织损伤的积极疗法。为了解决这个问题，在这里，我们提出了新的植物化学实体（NPCEs）的合理设计和合成，通过战略性的基于接头的分子杂交的芳香族/杂芳族片段与拉勃丹二醛，从植物姜黄的药用和营养上重要的根茎中分离。为了验证抗炎潜力，我们进行了一项全面的体外研究，评估其对COX-2酶和其他炎症介质的抑制作用，viz.,NO,TNF-α,IL-6和IL-1α，在细菌脂多糖刺激的巨噬细胞中，以及针对炎症调节因子COX-2酶的计算机分子建模研究。在合成的新化合物中，5f通过抑制COX-2酶表现出最高的抗炎潜力（IC50=17.67±0.89μM），活性相对于标准药物吲哚美辛增加4倍(IC50=67.16±0.17μM)。5f也显著降低了LPS诱导的NO的水平，TNF-α,IL-6和IL-1α，比阳性对照好得多。分子机制研究表明，5f剂量依赖性地抑制COX-2的表达和促炎细胞因子的释放，这与NF-κB信号通路的抑制有关。这推断labdane衍生物5f是作为抗炎剂的有希望的先导候选物,以进一步探索其治疗前景。
