The Linchpin Strategy in the Array Synthesis of Diverse Bioactive Ligand Scaffolds

发现治疗现代社会疾病的新药对化学家来说是一个巨大的挑战。对于每一种进入临床使用的药物，都需要制造和测试大约10，000种候选化合物，发现计划的总成本可能接近5亿美元。以更便宜、更快和更有效的方式提供新药的压力意味着化学家必须能够以有效的方式提供大量的候选药物。其中一种技术是所谓的阵列化学，其中化合物以基质形式制备：例如，八种A型化合物与八种B型化合物同时反应，产生六十四种新化合物。这种方法有助于自动化，现在这种化学物质的大部分可以通过机器人合成器有效和自动地提供。然而，这种阵列方法有一个缺点。想象一下药物分子与其靶受体或酶的相互作用就像一把钥匙（药物）插入一把锁（受体/酶）。在药物发现过程的开始，我们有锁，但没有钥匙。化学家就像锁匠一样，会拿一把主干（一把空白钥匙），用不同的取代基（对应于钥匙上编码锁的牙齿的不同排列）来装饰主干。因此，我们可以看到，主干和图案都很重要--如果锁是丘布设计的，那么制作成百上千把耶鲁钥匙是没有好处的。然而，到目前为止，大多数用于阵列合成大量化合物作为潜在关键的化学方法只允许化学家一次研究一种类型的骨架。显然，更有效的是有一种方法，允许我们同时改变我们制造的钥匙的类型，同时仍然保留改变钥匙上的齿的图案的能力，这将允许它们选择性地与所需的锁相互作用。我们如何才能做到这一点？在这里进行的工作将开发一种新的方法来合成的阵列，基于使用的关键。这些是小分子，可以让我们以可控的方式将两种、三种或四种不同的市售成分结合在一起。一旦这些成分连接在一起，我们就可以改变骨架的形状，方法是让各个成分反应在一起，形成环状分子。例如，如果我们将三个组分A、B和C在关键点上连接在一起，我们可以让主链单独存在，或者我们可以通过将A连接到B、A连接到C或B连接到C来使它环化。这四种可能的选择中的每一种都将具有非常不同的形状，因此为我们的药物发现钥匙提供了不同的骨干，并且仍然能够改变A，B和C的性质（即钥匙的牙齿）。所有这些的挑战是开发将各种组分添加到关键的方法，这些方法足够温和，不会破坏我们将用于在环化中将组分连接在一起的基团，这就是当前拨款中将要研究的内容。

The discovery of new drugs to treat diseases afflicting modern society is a huge challenge for chemists. For every drug that enters clinical usage, it is necessary to make and test around 10,000 candidate compounds, and total costs for the discovery programme can approach 500 million. The pressure to deliver new drugs in a cheaper, faster and more efficient manner means that chemists have to be able to deliver large numbers of drug candidates in an efficient manner. One of the techniques used to do this is so-called array chemistry, where compounds are prepared in a matrix form: for example, eight compounds of type A are simultaneously reacted with eight compounds of type B to deliver sixty four new compounds. Such an approach lends itself to automation and much of this chemistry can now be delivered efficiently and automatically by robotic synthesisers. However, there is a drawback to this array approach as it stands. Imagine the interaction of the drug molecule with its target receptor or enzyme as being like a key (the drug) fitting in a lock (the receptor/enzyme). At the start of the drug discovery process, we have the lock but no key. The chemist, like a locksmith, would take a backbone (a blank key) and decorate the backbone with different substituents (corresponding to the different arrangements of teeth on the key which code for the lock). We can therefore see that both the backbone AND the pattern are important - it is no good making hundreds or thousands of Yale keys if the lock is a Chubb design. However, until now most chemical methods for the array synthesis of large numbers of compounds as potential keys only allow chemists to work on one type of backbone at a time. It would clearly be more efficient to have a method that allows us to simultaneously vary the type of keys we make whilst still retaining the ability to alter the patterns of the teeth on the key, which will allow them to selectively interact with the desired lock . How can we achieve this?The work undertaken here will develop a new method for the synthesis of arrays, based on the use of linchpins . These are small molecules which will allow us to join together two, three or four different commercially available components in a controlled manner. Once the components are linked together, we can change the shape of the backbone by getting the individual components to react together to form ring-shaped molecules. For example, if we joined three components A, B and C together on the linchpin, we could leave the backbone alone, or we could cyclise it by joining A to B, A to C, or B to C. Each of these four possible options will have a very different shape, and hence gives us different backbones to our keys for drug discovery, as well as still being able to vary the nature of A, B and C (ie the teeth of the key). The challenge in all of this is developing methods for addition of the various components to the linchpin which are mild enough not to destroy the groups that we will use to join the components together in the cyclisation, and this is what will be studied in the current grant.