Light MPEG Supports for the Synthesis of Arrays

为了发现新的药物，大量的化合物必须在生物筛选中进行筛选和测试。随着高通量筛选的出现，以快速，高效和具有成本效益的方式生产药物样化合物库的压力越来越大。这需要自动化。将化合物连接到固体载体上使它们易于通过机器处理，并且树脂结合的材料在合成中具有很大的用途，以便于纯化和允许自动化。它们作为固载试剂、催化剂和清除剂广泛应用于固相合成（SPS）和聚合物辅助有机合成（PAOS）中。不幸的是，固体载体具有几个严重的缺点：（a）从溶液相到固相的反应性降低，这影响SPS和PAOS两者。(b)在SPS中，有时在树脂上积聚不期望的产物，并且难以监测反应。(c)树脂是昂贵的，并且这对于PAOS是特别成问题的，因为在每个步骤中可以使用几种不同的树脂结合的材料，并且由于反应缓慢，经常使用过量的固体负载的材料。这些化学和经济问题限制了树脂的使用，并阻止了通过大规模SPS或PAOS再合成命中物（通过生物筛选鉴定为感兴趣的化合物）。我们建议使用低分子量的聚（乙二醇）单甲醚（MPEG）作为载体将克服这些问题。MPEG非常便宜，大规模生产，用于粘合剂，油漆，涂料，化妆品和家用产品。我们的目标是表明MPEG是合成化学家日常需求的最佳支持，并通过举例说明和利用其潜在优势来展示其作为阵列合成支持的潜力：（a）MPEG支持的化合物应可溶于大多数有机溶剂中，从而允许具有良好动力学优势的溶液相合成，从而需要更少当量的试剂。(b)使用二氧化硅和氧化铝上的固相萃取，从未聚乙二醇化的材料中纯化应该是简单的。(c)MPEG是非常便宜的，它应该有可能扩大再合成的命中使用原来的MPEG支持的合成。(d)使用所有标准技术，MPEG负载的化合物的表征应该是简单的，并且1H NMR光谱中的甲基信号可以用于评估纯度。因此，与固体支持的试剂不同，如果保存了MPEG支持的试剂，应该很容易检查它们是否仍然是好的。(e)正交纯化和回收系统（例如固体载体）可以与MPEG-负载的化合物一起使用，例如离子交换柱或清除剂树脂可以用于分离具有不同官能度的MPEG-负载的化合物，并且也可以使用树脂结合的试剂和催化剂。

In order to discover new drugs, large numbers of compounds have to be synthsized and tested in biological screens. With the advent of high throughput screening, the pressure is on to produce libraries of drug-like compounds in a quick, efficient and cost-effective way. This requires automation. Attaching compounds to solid supports makes them easy to handle by machines and resin-bound materials have found great use in synthesis for easing purification and allowing automation. They have been widely employed in solid-phase synthesis (SPS), and in polymer-assisted organic synthesis (PAOS) as solid-supported reagents, catalysts and scavengers. Unfortunately, solid supports have several serious drawbacks: (a) Reactivity is reduced on going from solution phase to solid phase, and this affects both SPS and PAOS. (b) In SPS, there is sometimes a build up of undesired products on resin and monitoring of reactions is difficult. (c) Resins are expensive, and this is particularly problematic for PAOS as several different resin-bound materials may be used in each step, and because of slow reaction, an excess of the solid-supported materials is often employed. These chemical and economic problems limit the use of resins and prevents the resynthesis of hits (compounds that are identified as interesting by the biological screen) by large-scale SPS or PAOS. We propose that using low molecular weight poly(ethyleneglycol)monomethyl ether (MPEG) as the support will overcome these problems. MPEG is extremely cheap and is produced on a massive scale for use in adhesives, in paints, coatings, cosmetics and household products. We aim to show that MPEG is the best support for the everyday needs of synthetic chemists, and to demonstrate its potential as a support in array synthesis by exemplifying and exploiting its potential advantages: (a) MPEG-supported compounds should be soluble in most organic solvents allowing solution-phase synthesis with the advantage of good kinetics so that fewer equivalents of reagents are necessary. (b) Purification from unPEGylated material should be straightforward using solid-phase extraction on silica and alumina. (c) MPEG is very cheap and it should be possible to scale-up resynthesis of hits using the original MPEG-supported synthesis. (d) Characterization of MPEG-supported compounds should be straightforward using all the standard techniques and the methyl signal in the 1H NMR spectra could be used to assess purity. Therefore, unlike solid-supported reagents, it should be easy to check whether MPEG-supported reagents are still good if they have been stored. (e) Orthogonal purification and recovery systems (e.g. solid supports) could be used with MPEG-supported compounds, e.g. ion-exchange columns or scavenger resins could be used to separate MPEG-supported compounds bearing different functionality, and resin-bound reagents and catalysts could also be used.