New Synthesis-Enabling Reactions and Reaction Cascades for the Discovery and Production of Potential Anti-Cancer Compounds

除了外科医生的刀和放射治疗，化疗是最有效的武器之一，特别是对小细胞肺癌等无法手术和侵袭性的癌症。到目前为止，癌症仍然比有效的药物多得多，仍然需要有效的抗癌治疗，既有选择性又有效力。临床上使用的大多数现有药物都是天然来源的，或者是这些天然产品的人造类似物。这些(通常)具有细胞毒性的天然产物被寄主有机体用作自卫手段，几千年来，它们在对抗捕食者的行动模式上已经演变成既有效又有选择性的。一个很好的例子是紫杉醇[紫杉醇]，最初是从太平洋红豆杉中分离出来的，目前用于治疗肺癌、卵巢癌和乳腺癌。如果天然产物能够以可持续的方式大规模收获，或者在实验室通过发酵技术产生，那么就可以开发出有效的、适销对路的药物。如果这是不可能的，剩下的唯一选择就是通过化学合成过程进行生产。然而，这些目标分子往往具有如此复杂的三维结构，以至于传统的一步一锅化学合成方法变得如此冗长，以至于只能获得毫克量。这一问题可以通过战略性地实施新的合成来解决，使反应能够实现，并且从适当和容易获得的起始材料的反应级联进入化学路线。与传统方法的30-40步相比，这些方法可以在大约15步的时间内构建复杂的靶分子。只需大约15个步骤就可以获得复杂的分子，这意味着这些分子(和类似物的库)现在可以快速制造出来，甚至可能达到克级。此外，可以访问大量部分类似于天然产品的后期中间体，并将其转化为结构简化的天然产品类似物的库。这种合成能力可能会使首次进行彻底的生物学评估，并建立强大的结构/活性关系，这些关系可以反馈到合成循环中，潜在地导致化合物具有增强的生物活性，并最终导致有吸引力的候选药物。在过去的三年里，我们的团队一直致力于发现和开发新的不对称催化剂，新的强大的催化剂使能合成方法，并与这一建议最相关，新催化剂和多催化剂使能的反应级联序列。反应级联在合成方面非常强大，因为它们允许在单个容器中发生一系列成键反应，从而构建了复杂性并最大化了效率。通过对原料和催化剂的合理选择，可以在一次有效的操作中产生先进的中间体。在五年的研究期间，我们希望显著扩展这些初步研究开辟的研究范围，开发新的催化剂合成方法和反应级联反应，并将研究结果应用于一些复杂的生物活性生物碱天然产物的全合成。在合作的头三年，我们希望开发新的化学和策略，导致短期和有效的立体选择性全合成瑞香素D和甘露糖胺A(及其类似物，用于生物评价和合成孔径雷达)。

Alongside the surgeon's knife and radiotherapy, chemotherapy is one of the most effective weapons especially on inoperable and aggressive cancers such as small cell lung cancer. To date there are still many more cancers than effective medicines and there remains the need for effective anti-cancer treatments that are both selective and potent. The majority of the existing drugs in clinical use are of natural origin or are man made analogues of these natural products. These (often) cytotoxic natural products are employed by the host organism as a means of self-defense and over millennia have evolved to be both potent and selective in their modes of action against predators. An excellent example is paclitaxel [taxol] first isolated from the pacific yew tree and currently used in the treatment of lung, ovarian and breast cancers. If the natural product can be harvested on scale and in a sustainable fashion, or be created by fermentation techniques in the laboratory, then an effective marketable drug can be developed. When this is not possible the only remaining option is to manufacture through the process of chemical synthesis. However, these target molecules often possess such complex three dimensional structures that the traditional, one-step, one-pot chemical synthesis approaches become so lengthy that only milligram quantities can be obtained. This problem maybe overcome by the strategic implementation of new synthesis enabling reactions and reaction cascades into chemical routes from appropriate and readily available starting materials. These can allow the construction of the complex target molecules in around 15 steps, compared with 30-40 steps using traditional approaches. Accessing complex molecules in around 15 steps means that these molecules (and libraries of analogues) may now be made at speed and possibly on gram scale. In addition, large quantities of late stage intermediates resembling in part the natural product can be accessed and converted into libraries of structurally simplified natural product analogues. Such synthesis capability may allow thorough biological evaluation for the first time and the creation of powerful structure / activity relationships that can be fed back into the synthesis cycle, potentially resulting in compounds with enhanced biological activity, and eventually lead to attractive drug candidates. Our group has been engaged over the past 3 years in the discovery and development of new asymmetric catalysts, new powerful catalyst-enabled synthetic methodology and most relevant to this proposal, new catalyst and multi-catalyst enabled reaction cascade sequences. Reaction cascades are powerful in synthesis as they allow a series of bond-forming reactions to occur in a single vessel / thus building complexity and maximizing efficiency. By judicious choice of starting materials and catalysts, advanced intermediates can be created in one efficient operation. During the five year Fellowship we wish to significantly expand the lines of research opened up by these preliminary studies, develop new catalyst enabled synthetic methodology and reaction cascades, and apply the findings to the total synthesis of a number of complex bioactive alkaloid natural products. For the first three years of the fellowship we wish to develop new chemistry and strategies leading to the short and effective stereoselective total synthesis of both daphniyunnine D and manzamine A (and their analogues for biological evaluation and the development of SAR).