Chemical synthesis of illudalic acid analogs for stimulant use disorder

项目摘要 这个以本科生为中心的项目的目标是开发化学合成的创新， 生产用于兴奋剂使用障碍的新型治疗先导化合物。 兴奋剂使用障碍影响着数百万美国人。涉及兴奋剂的过量死亡人数增加 近年来，他们在COVID-19大流行期间激增，特别是在与 阿片类药物滥用目前还没有FDA批准的治疗兴奋剂使用障碍的药物，但蛋白酪氨酸 D型磷酸酶受体（PTPRD）已被鉴定为重要的治疗靶点。遗传 研究表明PTPRD表达水平越高，物质滥用和成瘾倾向越大， 降低PTPRD活性可减少小鼠的可卡因寻找行为。因此，PTPRD抑制剂提供了潜在的 开发治疗兴奋剂使用障碍的新途径。 天然产物伊鲁达酸是一种有效的PTPRD抑制剂。本文报道了衣草酸的化学合成方法。 因此，一种被称为7-BIA的简化类似物成为靶向的先导化合物 PTPRD。7-BIA比伊鲁达酸更容易合成，但效力较低。艾露达酸（和 7-BIA）被假定可逆地结合在PTPRD催化结构域中，暴露反应性二醛，并且 然后共价连接到关键的半胱氨酸残基，不可逆地阻断PTPRD活性。 报道了衣草酸类似物的合成方法。初步结果建立了收敛的5步合成 本发明提供了一种新的方法，该方法使用最长线性序列（longest linear sequence，LLS）来测定衣草酸，而现有方法需要16-20个线性步骤。的 这里的关键步骤是[4+2]苯并环化以组装完全取代的芳烃核心和碳框架。 本科生将开发的方法和相关的综合和后期阶段的方法 - 将被称为“illudalogs”的illudalic酸类似物官能化。将评价化合物的PTPRD 抑制活性和选择性，以及作为阳性对照的衣草酸和7-BIA。这样做的理由 目前的研究成果是，基于衣鲁达酸的PTPRD抑制剂可用于兴奋剂使用障碍的药物治疗。 三个互补的目标集中在：（1）发展illudalogs的合成化学，包括晚期- 阶段功能化和新的苯环化：（2）建立和维护合成化合物库 用于构效关系（SAR）研究和先导化合物鉴定的多种illudalogs;以及（3）创建 PTPRD酶学和细胞生物学的功能探针。预期成果包括创新 化学合成，提供PTPRD抑制剂和探针的转化途径。这些结果 将支持开发PTPRD作为抗成瘾药物靶点的治疗潜力。

PROJECT SUMMARY The objective of this undergraduate-centered project is to develop innovations in chemical synthesis that produce novel therapeutic lead compounds for stimulant use disorder. Stimulant use disorder affects millions of Americans. Overdose deaths involving stimulants have increased significantly in recent years, and they surged during the COVID-19 pandemic, especially in conjunction with opioid abuse. There are no FDA-approved medications for stimulant use disorder, but the protein tyrosine phosphatase receptor-type D (PTPRD) has been identified as an important therapeutic target. Genetic studies link higher PTPRD expression levels with greater propensity for substance abuse and addiction, and reducing PTPRD activity reduces cocaine-seeking behavior in mice. PTPRD inhibitors thus provide potential new avenues for developing treatments for stimulant use disorder. The natural product illudalic acid is a potent PTPRD inhibitor. Chemical synthesis of illudalic acid has been prohibitively difficult, so a simplified analog known as 7-BIA emerged as a lead compound for targeting PTPRD. 7-BIA was more synthetically accessible than illudalic acid but is less potent. Illudalic acid (and 7-BIA) is postulated to bind reversibly in the PTPRD catalytic domain, unmask a reactive dialdehyde, and then ligate covalently to a key cysteine residue, irreversibly blocking PTPRD activity. Synthesis of illudalic acid analogs is proposed. Preliminary results establish a convergent 5-step synthesis (longest linear sequence, LLS) of illudalic acid, whereas prior approaches require 16-20 linear steps. The key step here is a [4+2] benzannulation to assemble the fully substituted arene core and carbon framework. Undergraduate students will develop the approach and related methodology for the synthesis and late-stage functionalization of illudalic acid analogs, called “illudalogs”. Compounds will be evaluated for PTPRD inhibitory activity and selectivity, alongside illudalic acid and 7-BIA as positive controls. The rationale for this work is that illudalic acid-based PTPRD inhibitors can lead to pharmacotherapies for stimulant use disorder. Three complementary aims focus on: (1) developing the synthetic chemistry of the illudalogs, including late- stage functionalization and a new benzannulation; (2) building and maintaining a synthetic compound library of diverse illudalogs for structure-activity relationship (SAR) studies and lead identification; and (3) creating functional probes for PTPRD enzymology and cell biology. Expected outcomes include innovations in chemical synthesis that provide transformative access to PTPRD inhibitors and probes. These outcomes will support development of the therapeutic potential of PTPRD as a target for antiaddiction medication.