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: 10378524
• 负责人: Nathanyal J Truax
• 金额: $ 4.36万
• 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/10378524
• 关键词: AlamarBlue; Alder plant; Anti-Inflammatory Agents; 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。从这个角度来看，对天然产物的研究极大地影响了药物的发现。 确定新的治疗靶点和药物线索。在此，我们建议应用我们小组的药效团- 定向逆合成(PDR)概念用于两个化合物的合成和生物学研究，从结构上和生物学上 具有抗炎和抗癌活性的耐人寻味的天然产物雷米斯瓦里德和伊莱甘内酯， 分别进行了分析。由于许多天然产品的复杂结构，它们在以下情况下的治疗用途可能会受到限制 例如，不能通过发酵或可再生来源获得足够的供应。有了这一点 记住，我们将在PDR的指导下对这些天然产物进行全合成，以使能够识别 简化的等效铅分子通向天然产物的路线。这些天然药物的药效团 产物被假定为常见的5，5，7三环核心。将以简明的方式访问核心 通过有机催化的Diels-Alder-Lacton化(DAL)级联反应，实现了动力学拆分 在我们的实验室里，随后进行了环状扩张。我们认为，这些天然生物的不同生物活性 产物来源于常见的5，5，7-三环核心以外的结构变化。系统环切术 在这个三环核心上，(I)在Rameswaralide的情况下是取代的环己酮和(Ii)都是取代的 在ineleganolide的情况下通过分子内氧-迈克尔加成反应得到环己酮和四氢呋喃， 将提供大量的合成孔径雷达数据。在我们的合成努力过程中，刘军教授的团队(Johns 霍普金斯大学)将测试导致雷米斯瓦里德和伊莱甘内酯的合成中间体的抗炎作用 和抗癌活性。这些数据将进一步完善拟议的炔化细胞的合成。 与刘军教授的实验室(约翰·霍普金斯大学)合作探索后续的细胞目标识别 大学)。拟议的研究试图确定这些天然产品的等价性、简化的衍生品。 作为潜在的抗炎和抗癌药物先导，同时也可能揭示新的细胞靶点 人类疾病的治疗性干预。对我们的假设的一个警告是，完全或几乎完全 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 该方法有可能在完成全合成之前确定更简单的衍生物。 假设。我们假设共同的5，5，7核心三轮车的雷姆斯瓦拉利和伊尼格内酯是 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 生物活性，即抗炎和抗癌活性，观察到的这些结构相关的天然 在Rameswaralide的情况下，产物来自取代的环己酮，两者都来自取代的环己酮 环己酮和四氢呋喃在分子内氧-迈克尔加成的情况下 依兰内酯。