Synthesis and Biology of Prostanoids

前列腺素类化合物是一类重要的局部前列腺素样化学信使，在哺乳动物组织中具有多种生物学活性。一些合成的前列腺素（PG）类似物是“十亿美元”的药物，例如拉坦前列素，其用于治疗青光眼。然而，由于这些复杂的分子不能从天然来源中分离出足够的量，它们必须以相当高的成本合成（20个步骤）。我们已经开发了一个显着更短的路线，这类化合物（7个步骤），并证明了一个克规模的合成PGF 2 α 6，这可以大大降低成本的制造三尖杉酯碱。我们现在计划扩大这种化学反应的范围。正如Corey内酯已用于制备其他前列腺素类化合物一样，我们相信我们的关键烯醛中间体，用于合成前列腺素PGF 2 α，甚至可以更有效地获得所有其他前列腺素类化合物。因此，我们计划制备每类前列腺素的关键成员，从而证明其获得整个前列腺素家族的潜力。许多前列腺素是高度不稳定的（前列环素，血栓烷），所以我们将制备稳定的氟化类似物。我们将证明在PGF 2 α的合成中使用的关键烯醛中间体的能力，以获得剩余的前列腺素类在一个显着更短的步骤数比以前报道的。这项提议不仅寻求更有效地制备这些重要分子，而且还寻求研究我们制造的分子的药理学特性。为此，我们将使用人血小板，这是基本止血所必需的，但也在血栓形成和心血管疾病中发挥重要作用。我们将确定氟化前列环素类似物和贝前列素9对各种功能性血小板反应和细胞内信号传导途径的抗血小板作用，并将其与研究充分的PGI 2类似物伊洛前列素的作用进行比较。当血小板被激活时，它们也释放TxA 2，TxA 2进一步激活并招募血小板到生长的血栓中。将测定TxA 2类似物11/12对血小板功能和细胞内信号传导途径的药理学性质，并直接与TxA 2类似物U46619进行比较。由于血小板在心血管疾病中的重要作用，有血栓形成事件风险的患者常规处方抗血小板药物，这些药物干扰血小板功能的扩增。一线治疗是阿司匹林，一种通过阻断环氧合酶活性来抑制血小板中TxA 2产生的药物。然而，它的使用与不期望的副作用如胃病和胃溃疡相关，因为它抑制所有前列腺素类的产生。因此，我们在这里建议通过开发一种靶向TxA 2本身的人源化抗体药物来去除血栓烷A2。这种方法的优点是，副作用的可能性显着降低，因为我们没有阻止其他前列腺素类的生产机制。因此，通过显着缩短的途径生产不同类别的前列腺素类的关键成员不仅会导致临床和学术相关的前列腺素类的更有效的生产，而且还有助于开发治疗心血管疾病的新的抗血栓形成方法。

Prostanoids, consisting of prostaglandins, prostacyclins, and thromboxanes are an important class of local hormone-like chemical messengers, which are responsible for a diverse range of biological activities in mammalian tissues. Some synthetic analogues of prostaglandins (PG) are 'billion dollar' drugs e.g. latanoprost, which is used to treat glaucoma. However, since these complex molecules cannot be isolated from natural sources in sufficient quantities, they have to be synthesised (20 steps) at considerable cost. We have developed a dramatically shorter route to this class of compounds (7 steps) and demonstrated a gram scale synthesis of PGF2alpha 6, which could substantially reduce the cost of manufacture of prostaglandins. We now plan to broaden the reach of this chemistry. Just as the Corey lactone has been used to prepare other prostanoids, we believe that our key enal intermediate, used in the synthesis of the prostaglandin PGF2alpha, is even better placed to access all of the other prostanoids more efficiently. We therefore plan to prepare key members of each class of prostanoids thereby demonstrating its potential to access the whole family of prostanoids. Many of the prostanoids are highly unstable (prostacyclins, thromboxanes) and so we will prepare fluorinated analogues that are stable. We will demonstrate the power of the key enal intermediate used in the synthesis of PGF2alpha to access the remaining prostanoids in a substantially shorter number of steps than has been previously reported. This proposal not only seeks to prepare these important molecules more efficiently but it also seeks to study the pharmacological properties of the molecules we make. For this, we will use human platelets, which are essential for primary haemostasis but also play an important role in thrombosis and cardiovascular disease. We will determine the anti-platelet effects of the fluorinated prostacyclin analogue and beraprost 9 on various functional platelet responses and intracellular signalling pathways and compare this to the effect of the well-studied PGI2 analogue iloprost. When platelets become activated, they also release TxA2, which further activates and recruits platelets to the growing thrombus. The pharmacological properties of the TxA2 analogues 11/12 on platelet functional and intracellular signalling pathways will be determined and directly compared to the TxA2 analogue U46619. Due to the important role of platelets in cardiovascular disease, patients at risk of thrombotic events are routinely prescribed anti-platelet drugs that interfere with the amplification of platelet function. The first line of treatment is aspirin, a drug that inhibits TxA2 production in platelets by blocking cyclooxygenase activity. However, its use is associated with undesirable adverse effects such as gastropathies and gastric ulcers, as it inhibits the production of all prostanoids. We therefore propose here to remove the agent, thromboxane A2 as it is produced, by developing a humanised antibody-based drug that targets TxA2 itself. The advantages of this approach are that the likelihood of side effects is significantly reduced, as we are not blocking mechanisms for the production of other prostanoids. The production of key members of the different classes of prostanoids through a dramatically shorted route will therefore not only result in more efficient production of clinically and academically relevant prostanoids, but also facilitate the development of novel anti-thrombotic approaches in the treatment of cardiovascular disease.