Pharmacophore Directed Retrosynthesis Toward the Anti-Inflammatory Agent Rameswaralide and Anti-Cancer Agent Ineleganolide

药效团定向逆合成抗炎药 Rameswaralide 和抗癌药 Inelegananolide

• 批准号: 9761153
• 负责人: Nathanyal J Truax
• 金额: $ 4.19万
• 依托单位: BAYLOR UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9761153
• 关键词: AlamarBlue; Alder plant; Anti-Inflammatory Agents; Anti-inflammatory; Antineoplastic Agents; Biological; Biological Assay; Cancer cell line; Cell physiology; Cells; Chlorides; Collaborations; Collection; Complex; Cyclohexanones; Data; Fermentation; Glean; Kinetics; Laboratories; Lead; Luciferases; Malignant Neoplasms; Measurement; Methodology; Methylene Chloride; Mind; Modeling; NF-kappa B; Natural Products; Nature; Pharmaceutical Preparations; Production; Reporter; Research; Resolution; Route; Solvents; Source; Structure; Structure-Activity Relationship; System; Testing; Therapeutic; Therapeutic Intervention; Universities; Variant; analog; anti-cancer; anticancer activity; bioactive natural products; cellular targeting; counterscreen; cytotoxicity; drug development; drug discovery; human disease; innovation; macrophage; new therapeutic target; novel; pharmacophore; small molecule therapeutics; tetrahydrofuran

Project Summary. The study of natural products has impacted drug discovery dramatically from the standpoint of identifying novel therapeutic targets and drug leads. Herein, we propose to apply our group’s ‘Pharmacophore- Directed Retrosynthesis (PDR) concept to the synthesis and biological studies of two structurally, and biologically intriguing natural products, rameswaralide and ineleganolide, having anti-inflammatory and anticancer activity, respectively. Due to the complex structure of many natural products, their use as therapeutics can be limited if an adequate supply is not available through, for example, fermentation or from a renewable source. With this in mind, we will pursue a total synthesis of these natural products guided by PDR to enable the identification of simplified equipotent lead molecules in route to the natural products. The pharmacophore of these natural products is hypothesized to be the common 5,5,7 tricyclic core. The core will be accessed in a concise manner through an organocatalyzed, Diels-Alder-Lactonization (DAL) cascade involving a kinetic resolution developed in our laboratory followed by a ring expansion. We propose that the disparate biological activity of these natural products is derived from the structural variations beyond the common 5,5,7-tricyclic core. Systematic annulation onto this tricyclic core of (i) a substituted cyclohexanone in the case of rameswaralide and (ii) both a substituted cyclohexanone and tetrahydrofuran through intramolecular oxa-Michael addition in the case of ineleganolide, will provide extensive SAR data. Over the course of our synthetic endeavors, Prof. Jun Liu’s group (Johns Hopkins) will assay synthetic intermediates leading up to rameswaralide and ineleganolide for anti-inflammatory and anti-cancer activity, respectively. These data will further refine the synthesis of proposed alkynylated cellular probes for subsequent cellular target identification in collaboration with Prof. Jun Liu’s Laboratory (Johns Hopkins University). The proposed research seeks to identify an equipotent, simplified derivative of these natural products as potential anti-inflammatory and anticancer drug leads while also potentially revealing novel cellular targets for therapeutic intervention of human disease. A caveat to our hypothesis is that the fully or almost fully functionalized natural product may be required for the observed bioactivity; however, application of a PDR approach has the potential to identify simpler derivatives prior to completion of a total synthesis. Hypothesis. We hypothesize that the common 5,5,7 core tricycle of rameswaralide and ineleganolide is the pharmacophore of these bioactive natural products. We further hypothesize that the selectivity and disparate bioactivity, namely anti-inflammatory and anticancer activity, observed for these structurally related natural products arises from a substituted cyclohexanone in the case of rameswaralide and both a substituted cyclohexanone and a tetrahydrofuran derived from intramolecular oxa-Michael addition in the case of ineleganolide.

项目摘要。从药物发现的角度来看，天然产物的研究对药物发现产生了巨大的影响 发现新的治疗靶点和药物先导物。在此，我们建议应用我们小组的“药效团- 直接逆合成（PDR）概念的合成和生物学研究的两个结构，和生物学 具有抗炎和抗癌活性的有趣的天然产物，雷美瓦拉内酯和艾菊内酯， 分别由于许多天然产品的复杂结构，如果出现以下情况，它们作为治疗方法的用途可能会受到限制 不能通过例如发酵或从可再生来源获得足够的供应。出于这种 考虑到这一点，我们将在PDR的指导下对这些天然产物进行全合成，以识别 简化的等价先导分子的天然产物的途径。这些天然药物的药效团 产物被假设为常见的5，5，7三环核心。核心将以简洁的方式访问 通过有机催化的Diels-Alder-Lactonization（DAL）级联反应， 在我们的实验室里，然后是环膨胀。我们认为，这些天然产物的不同生物活性 产物是从普通的5，5，7-三环核心之外的结构变异衍生的。系统性成环 在（i）在雷美瓦拉利特的情况下为取代的环己酮和（ii）在雷美瓦拉利特的情况下为取代的环己酮和（iii）在雷美瓦拉利特的情况下为取代的环己酮的三环核上， 环己酮和四氢呋喃通过分子内氧杂-迈克尔加成反应在不优雅的情况下， 将提供广泛的SAR数据。在我们的合成努力过程中，刘军教授的小组（约翰 霍普金斯）将分析合成中间体的雷美瓦拉利和伊力甘肽的抗炎作用 和抗癌活性。这些数据将进一步完善所提出的炔基化细胞的合成。 与Jun Liu教授的实验室（约翰霍普金斯）合作， 大学）。拟议的研究旨在确定这些天然产物的等效简化衍生物 作为潜在的抗炎和抗癌药物，同时也可能揭示新的细胞靶点， 人类疾病的治疗干预。我们假设的一个警告是， 观察到的生物活性可能需要功能化的天然产物;然而，PDR的应用 该方法具有在完成全合成之前识别更简单的衍生物的潜力。 假说.我们假设rameswaralide和ineleganalide共同的5，5，7核心三轮车是 这些生物活性天然产物的药效团。我们进一步假设，选择性和不同的 这些结构上相关的天然药物具有生物活性，即抗炎和抗癌活性， 在雷美瓦拉利特的情况下，产物由取代的环己酮产生， 环己酮和衍生自分子内氧杂-迈克尔加成的四氢呋喃， 不优雅的。