BACKGROUND Colchicine is routinely used for its anti-inflammatory properties to treat gout and Familial Mediterranean fever. More recently, it was also shown to be of therapeutic benefit for another group of diseases in which inflammation is a key component, namely, cardiovascular disease. Whilst there is considerable interest in repurposing this alkaloid, it has a narrow therapeutic index and is associated with undesirable side effects and drug interactions. We, therefore, developed a derivatives of colchicine that preferentially target leukocytes to increase their potency and diminish their side effects. The anti-inflammatory activity of the colchicine derivatives was tested in experimental models of neutrophil activation by the etiological agent of gout, monosodium urate crystals (MSU). METHODS Using a rational drug design approach, the structure of colchicine was modified to increase its affinity for βVI-tubulin, a colchicine ligand preferentially expressed by neutrophils and other immune cells. The ability of the colchicine analogues with the predicted highest affinity for βVI-tubulin to dampen neutrophil responses to MSU was determined with in vitro assays that measure MSU-induced production of ROS, release of IL-1 and IL-8, and the increase in the concentration of cytoplasmic calcium. The anti-inflammatory property of the derivatives was assessed in the air pouch model of MSU-induced inflammation in mice. RESULTS The most effective compound generated, CCI, is more potent than colchicine in all the in vitro assays. It inhibits neutrophil responses to MSU in vitro at concentrations 10-100-fold lower than colchicine. Similarly, in vivo, CCI inhibits the MSU-induced recruitment of leukocytes at a 10-fold lower concentration than colchicine when administered prior to or after MSU. CONCLUSIONS We provide evidence that colchicine can be rendered more potent atinhibiting MSU-induced neutrophil activation and inflammation using a rational drug design approach. The development of compounds such as CCI will provide more efficacious drugs that will not only alleviate gout patients of their painful inflammatory episodes at significantly lower doses than colchicine, but also be of potential therapeutic benefit for patients with other diseases treated with colchicine.

中文翻译：

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秋水仙碱的针对性和更有效，抗炎衍生物的发展：对痛风的影响。

背景技术秋水仙碱因其抗炎特性而被常规用于治疗痛风和家族性地中海热。最近，它也显示出对另一组疾病的治疗益处，在另一组疾病中，炎症是关键成分，即心血管疾病。尽管人们对重新利用这种生物碱有极大的兴趣，但它的治疗指数很窄，并且与不良副作用和药物相互作用有关。因此，我们开发了秋水仙碱的衍生物，该衍生物优先靶向白细胞以增加其效力并减少其副作用。在痛风病原体尿酸单钠晶体（MSU）的病原体激活的实验模型中，对秋水仙碱衍生物的抗炎活性进行了测试。方法采用合理的药物设计方法，秋水仙碱的结构被修饰以增加其对βVI-微管蛋白的亲和力，βVI-微管蛋白是嗜中性粒细胞和其他免疫细胞优先表达的秋水仙碱配体。用体外测定法测定了预测的对βVI-微管蛋白具有最高亲和力的秋水仙碱类似物抑制中性粒细胞对MSU的反应的能力，这些测定方法可测量MSU诱导的ROS产生，IL-1和IL-8的释放以及MCU的增加。细胞质钙的浓度。在MSU诱导的小鼠的气袋模型中评估了衍生物的抗炎特性。结果在所有体外测定中，生成的最有效化合物CCI比秋水仙碱更有效。它在体外抑制中性粒细胞对MSU的反应，其浓度比秋水仙碱低10-100倍。同样，在体内 当在MSU之前或之后施用时，CCI抑制MSU诱导的白细胞募集的浓度比秋水仙碱低10倍。结论我们提供证据表明，使用合理的药物设计方法，秋水仙碱可以更有效地抑制MSU诱导的中性粒细胞活化和炎症。诸如CCI之类的化合物的开发将提供更有效的药物，这些药物不仅可以以比秋水仙碱低得多的剂量减轻痛风患者的疼痛性炎症发作，而且对于患有秋水仙碱治疗的其他疾病的患者具有潜在的治疗益处。结论我们提供证据表明，使用合理的药物设计方法，秋水仙碱可以更有效地抑制MSU诱导的中性粒细胞活化和炎症。诸如CCI之类的化合物的开发将提供更有效的药物，这些药物不仅可以以比秋水仙碱低得多的剂量减轻痛风患者的疼痛性炎症发作，而且对患有秋水仙碱治疗的其他疾病的患者具有潜在的治疗益处。结论我们提供证据表明，使用合理的药物设计方法，秋水仙碱可以更有效地抑制MSU诱导的中性粒细胞活化和炎症。诸如CCI之类的化合物的开发将提供更有效的药物，这些药物不仅可以以比秋水仙碱低得多的剂量减轻痛风患者的疼痛性炎症发作，而且对患有秋水仙碱治疗的其他疾病的患者具有潜在的治疗益处。