Chemistry Cascades: Synthesis of prostratin analogues for evaluation against HIV

在保健领域，没有什么比继续防治艾滋病毒和艾滋病更大的挑战了。在这场战争中，我们在设计新疗法时向大自然寻求灵感，因为天然产物通常具有复杂的分子结构，这些结构已经进化了数千年，可以作为生物靶点的选择性配体。例如，天然存在的佛波醇酯是最有效的肿瘤促进剂之一，并已被证明是研究致癌作用和开发预防方法的有用的“小分子”工具。与佛波醇相关的天然化合物，如非肿瘤促进天然产物prostratin，对潜伏的HIV有活性的发现是这类化合物生物学中最令人兴奋的最新发展。事实上，prostratin有望在耗尽病毒库的方法上取得重大进展，近年来引起了极大的兴奋。潜伏的HIV病毒库在使用当前疗法治疗HIV感染患者后持续存在，从而阻止病毒的消除。Prostratin的功能是将“冬眠”的HIV从休眠的T细胞中冲洗出来，这样抗逆转录病毒药物就可以攻击它。不幸的是，在来源植物中发现的prostratin水平非常低，而且这种天然产物的获取有限，减缓了它作为治疗剂的发展。这就提出了一个问题：如果我们不能从自然界中分离出我们需要的物质，我们能在实验室中有效地合成这些物质吗？不幸的是，使用当前最先进的合成工具很难制备与佛波醇相关的天然产品。事实上，唯一报道的佛波醇合成需要52个化学步骤！迄今为止，制备prostratin的唯一尝试是从稀缺的天然产物佛波醇开始。这不仅是供应问题的一个不满意的解决方案，而且像这样的“自上而下”的合成并不能促进分子内部的根本变化，而且我们对修改天然产物核心结构的影响知之甚少。从零开始有效合成prostratin的发展是一个及时的挑战，将解决供应问题，并将允许制备prostratin的类似物，迫切需要，但目前无法获得。在这个项目中，我们将开发选择性反应，其中简单的起始材料“级联”通过复杂的分子在一个步骤中，使用单一的试剂。级联反应不仅使我们能够快速接近目标，而且还使我们能够控制正在构建的分子的形状或立体化学。开发的新合成工具将使我们能够首次合成prostratin和这种天然产物的类似物，这将证明是防治艾滋病毒和艾滋病的宝贵武器。此外，我们创造的新合成方法将使化学家在未来设计合成时能够简化路线，从而缩短流程并最大限度地减少浪费。科学界迫切需要改进我们构建分子的方式。

In the field of healthcare, there are few greater challenges than the continuing fight against HIV and AIDS. In this war, we look to nature for inspiration in the design of new therapeutics as natural products often have complex molecular architectures that have evolved over millennia to act as selective ligands for biological targets. For example, naturally occuring phorbol esters are amongst the most potent of tumour promoters and have proved useful 'small molecule' tools for the study of carcinogenesis and the development of methods for its prevention. The discovery that natural compounds related to phorbol, such as the non-tumour promoting natural product prostratin, are active against latent HIV is the most exciting recent development in the biology of this compound class. In fact, prostratin promises a major advance in approaches to deplete viral reservoirs and has caused significant excitement in recent years. Latent HIV viral reservoirs persist after treatment of HIV-infected patients using current therapies, thus preventing elimination of the virus. Prostratin functions by flushing 'hibernating' HIV out of resting T-cells so that antiretroviral drugs can attack.Unfortunately, the levels of prostratin found in the source plants is very low and limited access to the natural product has slowed its development as a therapeutic agent. This poses the question: if we can't isolate what we need from nature, can we synthesise these substances efficiently in the laboratory? Unfortunately, natural products related to phorbol are very difficult to prepare using the current state-of-the-art synthetic tools. In fact, the only reported synthesis of phorbol took 52 chemical steps! The only attempt to prepare prostratin to date has started from the scarce natural product phorbol. Not only is this an unsatisfactory solution to the supply problem, but a 'top-down' synthesis such as this does not facilitate fundamental changes to the interior of the molecule and we learn little about the effect of modifying the natural product's core structure. The development of an efficient synthesis of prostratin from scratch is a timely challenge and will address the issue of supply and will allow the preparation of analogues of prostratin that are urgently needed but are currently unobtainable.In this project we will develop selective reactions in which simple starting materials 'cascade' through to complex molecules in a single step, using a single reagent. Not only will the cascade reactions grant us rapid access to the targets but they will also allow us to control the shape, or stereochemistry, of the molecule under construction. The new synthetic tools developed will allow us to carry out the first synthesis of prostratin and analogues of the natural product that will prove valuable weapons in the fight against HIV and AIDS. In addition, the new synthetic methods we create will allow chemists to streamline routes when designing syntheses in the future, thus shortening processes and minimising waste. Such improvements in the way we build molecules are urgently needed by the scientific community.