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

发现治疗困扰现代社会的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1万种候选化合物，发现计划的总成本可能接近5亿美元。以更便宜、更快、更高效的方式提供新药的压力意味着，化学家必须能够以高效的方式提供大量候选药物。用于实现这一点的技术之一是所谓的阵列化学，即以基质的形式制备化合物：例如，8种A类化合物同时与8种B类化合物反应，生成64种新化合物。这种方法有助于实现自动化，现在机器人合成器可以高效、自动地传递大部分化学物质。然而，目前这种数组方法有一个缺点。想象药物分子与其目标受体或酶的相互作用就像一把钥匙(药物)插在锁(受体/酶)中。在药物发现过程开始时，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)，用不同的取代基来装饰主干(对应于钥匙上不同排列的牙齿，钥匙上的牙齿是锁的代号)。因此，我们可以看出，主干和图案都很重要--如果锁是Chubb设计的，那么制作数百或数千把耶鲁钥匙是没有用的。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键的化学方法只允许化学家一次只对一种类型的主干进行工作。显然，有一种方法可以让我们同时改变我们制造的钥匙的类型，同时仍然保持改变钥匙上牙齿的图案的能力，这将使它们能够选择性地与所需的锁交互，这显然会更有效。我们如何才能做到这一点呢？这里进行的工作将开发一种新的方法来合成阵列，基于连杆的使用。这些小分子将允许我们以受控的方式将两个、三个或四个不同的商业组件连接在一起。一旦组分连接在一起，我们就可以通过让单独的组分一起反应形成环状分子来改变骨架的形状。例如，如果我们将三个组件A、B和C连接在一起，我们可以不使用主干，或者我们可以通过连接A到B、A到C或B到C来循环它。这四个可能的选项中的每一个都将具有非常不同的形状，因此为我们的药物发现提供了不同的主干，同时仍然能够改变A、B和C的性质(即钥匙的齿)。所有这一切的挑战是开发出将各种成分添加到关键部位的方法，这些方法足够温和，不会破坏我们将在循环过程中将成分连接在一起的基团，这也是目前拨款中将研究的内容。

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.