Synthetic Analogues of the Actinomycin, Quinamycin and Nogalamycin Groups of Antitumour Antibiotics

常见的实体瘤是癌症死亡的主要原因，其治疗的主要困难是耐药性问题。例如，许多患有肺癌、乳腺癌或结肠癌的患者对药物治疗反应良好，他们的肿瘤最初会消退，但后来又会以积极的耐药性形式出现。在这种情况下，不可避免的结果是肿瘤通过药物治疗而生长，患者最终屈服并死亡。这也是治疗成人漏血和非霍奇金淋巴瘤的常见情况。耐药性的根本原因是癌细胞的遗传不稳定性，这导致肿瘤是异质的，使得几乎不可避免的是，癌细胞将出现对治疗的抗性。耐药机制有很多，其中一些是特定药物类型所特有的，一些是渗透性屏障，一些涉及细胞死亡生物化学的遗传失调。破坏耐药性的一种方法是使用作用机制新颖的药物，从而挑战肿瘤设计新的防御。在这里，我们试图开发一类天然存在的抗肿瘤抗生素的合成类似物，其作用机制是不寻常的，但由于所涉及的化学困难，尚未被药物化学家开发。这些抗生素通过与DNA结合并抑制基因转化为蛋白质的过程中的第一步而起作用。我们已经设计了化学上可接近的化合物，我们的初步工作表明，这些化合物模拟了天然抗生素的DNA结合和生物学特性。拟议的工作将使我们能够评估这类新药物是否具有实验性抗肿瘤活性，特别是在耐药肿瘤中。

The principal difficulty in the treatment of the common solid tumours that cause the majority of cancer deaths is the problem of drug resistance. For example, many patients with cancer of the lung, breast or colon respond well to drug treatment with their tumours initially regressing, only to return later in an aggressive drug-resistant form. In this event, the inevitable outcome is that the tumour grows through drug treatment and the patient eventually succumbs and dies. This is also a familiar scenario in the treatment of adults with leakaemias and non-Hodgkins lymphomas. The underlying cause of drug resistance is the genetic instability of cancer cells which results in tumours that are heterogeneous, making it almost inevitable that a cancer cell will arise that is resistant to treatment. There are many mechanisms of resistance, some of which are peculiar to particular drug types, some are permeability barriers and some involve genetic deregulation of the biochemistry of cell death. One way of subverting resistance is by the use of drugs whose mechanism of action is novel so that the tumour is challenged to devise a new defense. Here, we are attempting to develop synthetic analogues of a class of naturally- occurring antitumour antibiotic whose mechanism of action is unusual but which has not been exploited by medicinal chemists because of the difficulty of the chemistry involved. These antibiotics work by binding to DNA and inhibiting the first step in the process whereby genes are turned into proteins. We have designed compounds that are chemically accessible that our preliminary work suggests mimic the DNA-binding and biological properties of the natural antibiotics. The proposed work will enable us to evaluate whether this new class of agent has experimental antitumour activity, particularly amongst drug-resistant tumours.