Synthesis, Structure, and Mechanism of Biorelevant Molecules and Reactions

生物相关分子和反应的合成、结构和机制

• 批准号: 9888376
• 负责人: THOMAS R. HOYE
• 金额: $ 38.05万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9888376
• 关键词: Abate; Acute; Address; Alder plant; Anabolism; Antibody-drug conjugates; Area; Automobile Driving; Biological; Catalysis; Chemicals; Chemistry; Clinical; Complex; Cytotoxin; Diels Alder reaction; Discipline; Event; Family; Flowers; Formulation; Funding; Future; Grant; Hydrocarbons; Ice; Knowledge; Lead; Methodology; NMR Spectroscopy; National Institute of General Medical Sciences; Natural Products; Natural Products Chemistry; Nuclear Magnetic Resonance; Oncology; Organic Chemistry; Organic Synthesis; Organism; Pharmaceutical Preparations; Pharmacologic Substance; Property; Publishing; Reaction; Research; Research Support; Skeleton; Structure; Therapeutic; United States National Institutes of Health; Work; cancer stem cell; chemical synthesis; chemotherapeutic agent; clinically relevant; cytotoxicity; drug discovery; improved; innovation; insight; interest; nanoparticle; novel; ottelione A; programs; small molecule; tumor

PROJECT SUMMARY/ABSTRACT Synthesis, Structure, and Mechanism of Biorelevant Molecules and Reactions Our NIH-supported research program encompasses synthetic, mechanistic, and structural organic chemis- try. We address unresolved contemporary problems through studies that lead to i) new ways to make mole- cules, ii) new molecules with promise of valuable biological properties, iii) new insights about how chemical re- actions, including spontaneous biosynthetic transformations, proceed, and iv) new ways of deducing the struc- tures of novel chemical entities, often through innovative use of nuclear magnetic resonance (NMR) methodol- ogies. We plan to capitalize on recent accomplishments in two topical areas, I. and II. I. Natural Products Chemistry Three subtopics are pursued. A. We frequently engage in natural product structure determination studies. These challenges have often required that we develop new NMR strategies for interrogating complex structures. These studies have had im- pact extending far beyond the specific question being addressed. Our track record is strong. Our most notable recent example teaches methodology for calculation of chemical shifts to the experimentalist who may be a nov- ice computationalist. Earlier contributions include first-order multiplet analysis and “No-D” NMR spectroscopy. B. We plan to capitalize on our previous work in the synthesis of extremely potent cytotoxins. If their acute cytotoxicity could be properly harnessed, these agents have the potential to be quite useful as chemo- therapeutic agents in oncology. We have the opportunity to do just that through collaborative studies using: (i) nanoparticle formulations targeted for portions of tumors called cancer stem cells or (ii) novel antibody-drug conjugates that also have the potential to improve the therapeutic window of these powerful agents. C. We remain interested in unraveling key steps in the biosynthesis of natural products that proceed in the absence of enzymatic catalysis—that is, spontaneously. Specific hypotheses driving future work involve (i) an unprecedented Cope rearrangement to fashion the unique skeleton of ottelione A from an achiral diarylhep- tanoid and (ii) an isomerization of a highly unsaturated linear precursor (a tetrayne) to the bicyclic hydrocarbon core skeleton of the 9-membered enediyne family of natural products; a cyclase for this event remains elusive. II. HDDA*-Benzyne Chemistry (*hexadehydro-Diels-Alder). Our discovery of the broad scope of the hexadehydro-Diels–Alder (HDDA) reaction is both exciting and en- abling. This work blossomed tremendously during the current funding period of our NIGMS grant. Many of the reaction classes that we have A. Recently Published or that are the subject of B. Ongoing/Future Research are revolutionary. In a number of instances, these thermally induced, uncatalyzed transformations are not just remarkable, but were, literally, inconceivable prior to this work. The opportunities in this program show no sign of abating. To the contrary, it seems that every week or so a coworker arrives at my doorstep with yet another new result that elicits from me something to the effect of “Wow, they'll also do that!” (30 lines)

项目总结/摘要 生物相关分子的合成、结构、作用机理及反应 我们的NIH支持的研究计划包括合成，机械和结构有机化学， 试试我们通过研究解决未解决的当代问题，这些研究导致i）新的方法来制造摩尔- cules，ii）具有有价值的生物学特性的新分子，iii）关于化学如何重新组合的新见解， 行动，包括自发的生物合成转化，进行，和iv）推导结构的新方法， 新的化学实体的结构，通常通过创新使用核磁共振（NMR）方法， 妖怪我们计划利用最近在两个专题领域取得的成就，和二. I.天然产物化学三个子课题进行。 A.我们经常从事天然产物结构测定研究。这些挑战往往 要求我们开发新的核磁共振策略来询问复杂的结构。这些研究已经在- 它远远超出了所处理的具体问题。我们的业绩记录很好。我们最著名的 最近的例子向实验者教导了计算化学位移的方法， 冰计算专家早期的贡献包括一阶多重峰分析和“No-D”NMR光谱。 B。我们计划利用我们以前的工作在合成极其有效的细胞毒素。如果他们的 急性细胞毒性可以适当利用，这些药物有潜力作为化疗药物， 肿瘤治疗剂。我们有机会通过合作研究做到这一点，使用：（一） 靶向称为癌症干细胞的肿瘤部分的纳米颗粒制剂，或（ii）新型抗体药物 这些缀合物也具有改善这些强效药剂的治疗窗的潜力。 C.我们仍然对解开天然产物生物合成的关键步骤感兴趣， 不存在酶催化，也就是说，自发地。推动未来工作的具体假设包括：（一） 一个前所未有的科普重排，从一个非手性的二芳基庚- 类烷和（ii）高度不饱和的线性前体（四炔）异构化为双环烃 天然产物的9元烯二炔家族的核心骨架;该事件的环化酶仍然难以捉摸。 二. HDDA*-苄化学（* 六氢-狄尔斯-桤木）。 我们发现的六氢-狄尔斯-桤木（HDDA）反应的广泛范围既令人兴奋，又令人兴奋。 abling.在我们的NIGMS赠款的当前资助期间，这项工作取得了巨大的进展。许多 我们有A的反应类。最近发表的或B的主题。正在进行/未来的研究 是革命性的。在许多情况下，这些热诱导的、未催化的转化不仅仅是 但在这项工作之前，这是不可想象的。这个项目的机会没有任何迹象表明 减少。相反，似乎每周左右都会有一位同事带着另一位同事来到我家门口。 新的结果让我想起了“哇，他们也会这么做！” (30线）