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: 10624523
• 负责人: THOMAS R. HOYE
• 金额: $ 40.46万
• 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 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10624523
• 关键词: Abate; Address; Anabolism; Basic Science; Biological; Catalysis; Chemicals; Chemistry; Clinical; Communication; Communities; Cyclic Peptides; Development; Diels Alder reaction; Discipline; Funding; Future; Genome Mappings; HRK gene; Knowledge; Methodology; Methods; Natural Products; Natural Products Chemistry; Organic Chemistry; Organic Synthesis; Organism; Outcome; Peptides; Pharmaceutical Preparations; Pharmacologic Substance; Property; Reaction; Research; Research Personnel; Research Support; Skeleton; Structure; Teaching Method; Therapeutic Research; Work; chemical reaction; clinically relevant; coping; drug candidate; drug discovery; effectiveness evaluation; improved; innovation; insight; interest; novel; novel strategies; ottelione A; programs; secondary metabolite; small molecule

PROJECT SUMMARY/ABSTRACT Synthesis, Structure, and Mechanism of Biorelevant Molecules and Reactions Our MIRA-supported research program encompasses synthetic, mechanistic, and structural organic chem- istry. We address unresolved contemporary problems through studies that lead to i) new ways of deducing the structures of novel chemical entities, often through innovative use of NMR methodologies, ii) new insights about how chemical reactions, including spontaneous biosynthetic transformations, proceed, and iii) new ways to make molecules that have structural features of interest to researchers pursuing targets with promising bio- logical properties. We will capitalize on recent accomplishments and launch new efforts as follows. I. Natural Products Chemistry A. We remain interested in unraveling key steps in the biosynthesis of natural products that proceed in the absence of enzymatic catalysis—that is, spontaneously. Two specific hypotheses related to the origin of the unique skeleton of ottelione A drive current work: i) an unprecedented, low-barrier Cope rearrangement fashions the strange, dearomatized 4-methylenecyclohexenone present in this secondary metabolite and ii) a simple, achiral diarylheptanoid is oxidatively transformed into the strained and preorganized Cope substrate. The engagement of an outstanding collaborator to use genome mapping approaches will be of great benefit. B. We frequently engage in natural product structure determination studies and the development of methodologies of value to those who do the same. These studies have had impact extending well beyond the specific questions that we address. Our record in doing this is strong. One notable example teaches methodol- ogy for calculation of chemical shifts to the experimentalist who may be a novice computationalist. Our ap- proach was the same as that used in the newest developments of probabilistic methods for comparison of computed vs. experimental NMR chemical shifts to validate structure assignments (DP4, DP4+, DP4-AI, DP5). We find a gap in that some communities have yet to embrace these approaches. We propose to evaluate the effectiveness (and limitations) of these methods for structural assessment of various cyclic peptides and then to communicate, advertise if you will, these outcomes to benefit future structural studies by peptide chemists. II. HDDA-Benzyne Chemistry Our discovery of the broad scope of the hexadehydro-Diels–Alder (HDDA) reaction is both exciting and en- abling. This work has advanced significantly since the onset of our MIRA funding four years ago. The opportu- nities in this arena show no sign of abating. To the contrary, it seems that every month or so a coworker arrives at my doorstep with yet another new result that elicits from me something to the effect of “Wow, HDDA- benzynes will also do that!” Myriad new directions are presented in pages 4–6 of the Research Strategy. Many will lead to products containing a greater preponderance of heteroatoms, thereby demonstrating new ap- proaches for consideration and use by researchers engaged in drug discovery activities. (30 lines)

项目摘要/摘要 生物含量分子和反应的合成，结构和机制 我们的MIRA支持的研究计划包括合成，机械和结构有机化学 伊斯特里。我们通过导致I）推论的新方法来解决未解决的当代问题 新型化学实体的结构，通常是通过创新的NMR方法，ii）新见解 关于化学反应如何，包括自发生物合成转化，进行和iii）新方法 为了使追求目标的研究人员提供有望生物的目标的分子 逻辑属性。我们将利用最近的成就，并如下发动新的努力。 I.天然产品化学 答：我们对揭开天然产品生物合成的关键步骤仍然感兴趣 缺乏酶促催化 - 也就是说。与起源有关的两个具体假设 Ottelione A的独特骨骼驱动器当前工作：i）前所未有的低障碍应对重排 时尚奇异的，亲爱的4-甲基苯基己烯酮存在于此次级代谢物中，ii）a） 简单的，精神的二女型植物类动物被氧化转化为紧张的和预组织的COPE底物。 杰出合作者使用基因组映射方法的参与将带来很大的好处。 B.我们经常从事自然产品结构确定研究和发展 对那些这样做的人的价值方法。这些研究的影响远远超出了 我们解决的具体问题。我们这样做的记录很强。一个值得注意的例子教方法 - OGY用于计算可能是新计算家的实验家的化学转移。我们的ap- ProACH与概率方法的最新发展中所用的相同 计算的与实验性NMR化学位移以验证结构分配（DP4，DP4+，DP4-AI，DP5）。 我们发现差距是一些社区尚未接受这些方法。我们建议评估 这些方法的有效性（和局限性）用于对各种环状肽进行结构评估，然后 为了沟通，如果您愿意的话，这些结果会受益于辣椒化学家将来的结构研究。 ii。 HDDA-Benzyne化学 我们发现六卫二二烷 - 阿尔德（HDDA）反应的广泛范围既令人兴奋又令人兴奋 阿布。自从四年前我们的Mira资金发作以来，这项工作已取得了长足的进步。机会 - 这个舞台上的城市没有减弱的迹象。相比之下，似乎每个月左右的同事都到来 在我家门口，还有另一个新的结果，这些结果引起了我的影响，“哇，hdda-- Benzynes也将做到这一点！ 将导致含有更大优势的杂原子的产品，从而证明了新的AP- 旨在考虑和使用从事药物发现活动的研究人员。 （30行）