Light MPEG Supports for the Synthesis of Arrays

为了发现新的药物，必须合成大量的化合物并在生物筛选中进行测试。随着高通量筛选技术的出现，以快速、高效和经济的方式生产类药物化合物文库的压力越来越大。这需要自动化。将化合物附着在固体支架上使它们易于由机器处理，树脂结合材料在合成中有很大的用途，可以简化纯化和实现自动化。它们作为固相合成（SPS）和聚合物辅助有机合成（PAOS）中的固体载体试剂、催化剂和清除剂被广泛应用。不幸的是，固体支架有几个严重的缺点：(a)从溶液相到固相的反应性降低，这对SPS和PAOS都有影响。(b)在SPS中，有时树脂上积聚不需要的产物，监测反应是困难的。(c)树脂昂贵，这对聚丙烯酸酯来说尤其成问题，因为每一步都可能使用几种不同的树脂结合材料，而且由于反应缓慢，经常使用过多的固体支撑材料。这些化学和经济问题限制了树脂的使用，并阻碍了大规模SPS或PAOS重新合成hit（通过生物筛选确定为有趣的化合物）。我们建议采用低分子量的聚乙二醇单甲醚（MPEG）作为载体来克服这些问题。MPEG非常便宜，并且大规模生产，用于粘合剂、油漆、涂料、化妆品和家用产品。我们的目标是证明MPEG是合成化学家日常需要的最佳支持，并通过举例说明和利用其潜在优势来证明其作为阵列合成支持的潜力：(a) MPEG支持的化合物应该可溶于大多数有机溶剂，允许具有良好动力学优势的溶液相合成，因此需要较少的当量试剂。(b)从未聚乙二醇化的材料中提纯应使用二氧化硅和氧化铝的固相萃取直接。(c) MPEG非常便宜，应该可以使用原始的MPEG支持的合成来扩大点击的再合成。(d)使用所有标准技术表征mpeg支持的化合物应该是简单的，1H NMR光谱中的甲基信号可以用来评估纯度。因此，与固体载体的试剂不同，mpeg载体的试剂如果储存起来，应该很容易检查是否仍然良好。(e)正交纯化和回收系统（如固体载体）可用于mpeg负载化合物，如离子交换柱或清除剂树脂可用于分离具有不同功能的mpeg负载化合物，也可使用树脂结合试剂和催化剂。

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.