Chemistry Cascades: Synthesis of prostratin analogues for evaluation against HIV

在医疗保健领域，没有什么比继续抗击艾滋病毒和艾滋病更大的挑战了。在这场战争中，我们希望从大自然中获得设计新疗法的灵感，因为天然产品往往具有复杂的分子结构，这些分子结构经过数千年的演变，成为生物靶标的选择性配体。例如，天然佛波醇酯是最有效的肿瘤促进剂之一，已被证明是研究癌症发生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，如非肿瘤促进的天然产品前列腺素，对潜伏的艾滋病毒具有活性，这一发现是这类化合物生物学中最令人兴奋的最新进展。事实上，Prostratin有望在耗尽病毒库的方法上取得重大进展，并在最近几年引起了极大的兴奋。在使用目前的治疗方法治疗艾滋病毒感染者后，潜伏的艾滋病毒病毒库仍然存在，从而阻止了病毒的消除。前列腺素的作用是将冬眠的艾滋病毒从静止的T细胞中冲洗出来，以便抗逆转录病毒药物可以攻击。不幸的是，在来源植物中发现的前列腺素水平非常低，而且获得这种天然产品的机会有限，减缓了其作为治疗剂的发展。这就提出了一个问题：如果我们不能从大自然中分离出我们需要的东西，我们能在实验室里高效地合成这些物质吗？不幸的是，使用目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，唯一报道的佛波醇的合成需要52个化学步骤！到目前为止，制备前列腺素的唯一尝试是从稀有的天然产品佛波醇开始。这不仅是供应问题的一个不令人满意的解决方案，而且像这样的自上而下的合成不利于分子内部的根本变化，我们对改变天然产品核心结构的影响知之甚少。从零开始开发一种高效的前列腺素合成方法是一个及时的挑战，将解决供应问题，并将使制备迫切需要但目前无法获得的前列腺素类似物成为可能。在这个项目中，我们将开发选择性反应，在此反应中，简单的起始材料将使用单一试剂在单一步骤中级联到复杂的分子中。级联反应不仅会让我们快速接触到目标，而且还会让我们控制正在建造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前列腺素和天然产物的类似物，这将被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允许化学家在未来设计合成时简化路线，从而缩短工艺并最大限度地减少浪费。科学界迫切需要在我们构建分子的方式上进行这样的改进。

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.