Reductive activation of azido compounds for imaging and therapy

该项目将涉及激活细胞内的有机叠氮化合物（含有N3基团，可还原为胺NH 2基团），以产生可用于癌症成像，诊断或治疗的化合物。选择叠氮化合物是因为它们具有高稳定性和在细胞条件下对水解或氧化反应的抗性。将探索两种靶向激活产生癌症相关分子的方法：1）使用可以穿透组织的高能X射线（放射疗法）和2）使用癌性肿瘤内发现的缺氧条件。低氧（许多癌症的标志物）被定义为低氧浓度（通常<2%），与常氧（21%氧气，大气氧气压力，用于临床前测试）或低氧（组织常氧，取决于组织）相比。低氧条件下的激活是靶向癌组织而非正常组织的有效方式，因为低氧浓度在肿瘤中是常见的，特别是实体瘤。目前，X射线通常用于癌症治疗（用于放射治疗），因为它们能够渗透到体内，也是一种靶向方法。这两种活化方法将被单独或组合探索，以确定它们的作用机制，活化后是否产生不同的产物，以及每种途径引起的活化程度。上述条件将用于活化前药，前药定义为可以在体内转化为活性药物的分子。这些前药将是有机的或含金属的，例如铂或镧系元素络合物。有机前药将具有包括连接到目前批准用于癌症治疗的药物或连接到发荧光的系统（用于癌症成像）的叠氮基的结构。铂络合物广泛用于化疗（由于其与DNA反应导致细胞死亡的能力）-在该项目中，基于铂的叠氮化物前药将被活化以产生先前报道具有抗癌特性的络合物。镧系元素配合物（含镧至镥元素）具有发光特性，可用于癌症诊断成像。本项目的目标是合成含叠氮基的新型有机铂或镧系元素配合物，通过X射线或低氧条件激活，释放活性药物或提供癌症诊断信息。该项目属于EPSRC化学生物学、临床技术和医学成像研究领域的福尔斯。

This project will involve the activation of organic azide compounds (containing the N3 group, which can be reduced to the amine NH2 group) within cells to produce compounds which are useful for cancer imaging, diagnosis or treatment. Azides have been chosen due to their high stability and resistance to reaction under cell conditions by hydrolysis or oxidation.Two methods of targeted activation for the production of cancer-relevant molecules will be explored: 1) the use of high energy X-rays which can penetrate into tissues (radiotherapy) and 2) the use of hypoxic conditions found within cancerous tumours. Hypoxia (a marker of many cancers) is defined as low oxygen concentration (typically <2%), compared to normoxia (21% oxygen, atmospheric oxygen pressure, used for preclinical testing) or physoxia (tissue normoxia, which varies depending on the tissue). Activation under hypoxic conditions is an effective way to target cancerous tissues over normal tissues, as low oxygen concentrations are common in tumours, particularly solid tumours. X-rays are commonly used in cancer treatment currently (for radiotherapy) due to their ability to penetrate into the body and are also a targeted method. These two activation methods will be explored independently and in combination to determine their mechanisms of action, whether different products are produced following activation, and how much activation is caused by each pathway.The conditions described above will be used to activate prodrugs, defined as molecules which can be converted to active drugs within the body. These prodrugs will either be organic or metal-containing, such platinum or lanthanide complexes. The organic prodrugs will have structures which include the azide group connected to drugs which are currently approved for cancer treatment, or connected to systems which fluoresce (for use in cancer imaging). Platinum complexes are extensively used in chemotherapy (due to their ability to react with DNA to cause cell death) - in this project, platinum-based azide prodrugs will be activated to give complexes previously reported to have anticancer properties. Lanthanide complexes (containing elements from lanthanum to lutetium) are known to be luminescent and can be used in cancer imaging for diagnostic purposes.Overall, this project aims to synthesis novel organic, platinum- or lanthanide-containing complexes containing azide groups which can be activated by X-rays or under hypoxic conditions to release active drugs or provide diagnostic information on cancer. This project falls within the EPSRC research areas of chemical biology, clinical technology and medical imaging.