Anti tumour agents from natural products - new approaches to targeting ultra potent analogues of the duocarmycins

杀死分裂细胞的分子被称为细胞毒性药物，仍然是临床上使用的抗癌化疗药物的支柱。问题是这些化合物毒性很大。它们会杀死体内的所有分裂细胞，因此会对已经病得很重的患者产生可怕的、令人衰弱的副作用。在过去的二十年里，设计新药物的重点已经转向两种主要方法，以试图减少这些副作用-要么针对肿瘤特定的途径，要么通过靶向细胞毒药物，使它们只在所需的作用部位发挥作用。这两种方法都取得了一些成功。在前一种情况下，名为曲妥珠单抗(商标为Herceptin)的抗体是众所周知的，并用于乳腺癌的治疗。它针对的是一种名为Her2的受体，该受体在一些肿瘤细胞表面高度过度表达，因此该药物对这些肿瘤具有选择性。同样，激酶抑制剂甲磺酸伊马替尼(Gleevec或Glivec)针对慢性髓系白血病的一种蛋白质，现在用于治疗这种疾病。这些化合物在蛋白质水平上选择性地杀死细胞。如果我们可以在基因水平上针对超强效药物，那么在任何蛋白质产生之前，会发生什么？我们最近开发了一种方法，利用固相合成来快速生成雌激素活性最强的天然产物双霉素的类似物，并正在研究基于这些分子的抗体药物结合物(ADCs)和蛋白质靶向的开发。然而，我们现在的目标是调查其他潜在的目标方法。这涉及到通过将双霉素结合到与特定双链DNA序列结合的选择性分子中来选择性地靶向特定的基因，并有可能关闭特定的基因。这些药物被称为地塞米松类似物或“发夹状聚酰胺”。虽然已经研究了通过连接物简单地将多卡霉素类似物连接到基因选择剂上，但随着我们方法的发展，将多卡霉素掺入到聚酰胺中只是成为一个现实的命题。通过选择性DNA烷基化关闭特定基因的能力将是开发靶向药物的有力途径，并将有助于识别在包括癌症在内的疾病治疗中具有潜力的新分子。

Molecules that kill cells that divide, known as cytotoxic drugs, are still the backbone of clinically used chemotherapeutic agents against cancer. The problem is that these compounds are very toxic. They kill all dividing cells in the body and so lead to horrendous and debilitating side effects in patients that are already very ill. In the last twenty years, the focus for the design of new agents has switched to two main approaches in order to try to curtail these side effects - either targeting tumour specific pathways or through targeting of cytotoxic agents so that they only exert their effects at the desired site of action. Both approaches have met with some success. In the former case, the antibody called trastuzumab (trade name herceptin) is well known and is used in the treatment of breast cancer. It targets a receptor called Her2, which is highly over-expressed on the surface of some tumour cells and therefore the agent is selective for those tumours. Similarly, the kinase inhibitor imatinib mesylate (gleevec or glivec) targets a protein in chronic myeloid leukaemia and is now used in the treatment of this disease. These compounds kill cells in a selective way at the protein level. What if we could target ultrapotent drugs at the level of genes, so before any protein has been produced? We have recently developed methodology to rapidly generate analogues of the estremely potent natural products the duocarmycins using solid phase synthesis and are investigating the development of antibody drug conjugates (ADCs) and protein targeting based upon these molecules. However, there are other potential targeting methodologies that we now aim to investigate. This involves the selective targeting of particular genes via the incorporation of duocarmycins into selective molecules that bind to particular sequences of double stranded DNA and have the potential to turn off particular genes. These are called distamycin analogues or "hairpin polyamides". While simply attaching a duocarmycin analogue to a gene selective agent by a linker has been studied, the incorporation of the duocarmycin into the polyamide has only become a realistic proposition with the development of our approach. The ability to turn off particular genes through selective DNA alkylation will be a powerful approach to the development of targeted agents and will help in the identification of new molecules with potential in the treatment of disease, including cancer.