强大的cAMP信号传导主动体 (-) -alotaketal A 的总合成
Jinhua Huang1, Jessica R Yang, Jin Zhang
1Department of Chemistry, Texas A&M University, College Station, Texas 77843, USA.
Journal of the American Chemical Society
|May 9, 2012
概括
研究人员合成了 (-) - - 甲,一种强大的循环腺单酸盐 (cAMP) 信号传导激动剂. 这种新的合成利用了SmI(2) 介导的反应,并揭示了独特的螺旋环形成,有助于研究结构-活性关系.
科学领域:
- 有机合成 有机合成
- 药用化学 医学化学
- 化学生物学 化学生物学
背景情况:
- 循环腺单酸盐 (cAMP) 是一个关键的第二信使,调节各种细胞过程.
- (-) -alotaketal A是cAMP信号传递的强有力的激动剂,但其复杂的结构带来了合成挑战.
- 了解 (-) - 甲的结构-活性关系 (SAR) 是开发新治疗剂的关键.
研究的目的:
- 开发一种高效且融合的合成途径,以获得 (-) - 甲基甲酸.
- 研究合成中涉及的关键化学转化,包括螺旋体的形成.
- 通过使用生物探针评估cAMP信号对抗活性和 (-) - 基甲基的SAR.
主要方法:
- 收合成策略. 收合成策略.
- 两阶段的萨马 (II) 化物 (SmI) 介导的还原性合,用于多循环组件和碎片合.
- 通过(II) 乙酸盐 (Hg(OAc) ((2)) 介导的选择性烯氧化.
- 使用AKAR4和ICUE3探针进行生物活性评估.
主要成果:
- 成功开发了一种融合合成路径,用于 (-) - 甲基甲酸.
- 证明了SmI(2) 中介的还原性合在构建多环核中的实用性.
- 标志着前所未有的螺旋环系统的形成.
- 评估了cAMP信号的激活活性,并阐明了 (-) - 基甲酸的SAR.
结论:
- 开发的合成途径提供了对 (-) - - 甲的有效获取.
- 该研究强调了新的合成方法,包括SmI(2) 化学和螺旋形成.
- 生物评估提供了对这种强大的cAMP信号激动剂的SAR的见解,为未来的药物发现工作铺平了道路.
相关概念视频
01:25cAMP-dependent Protein Kinase Pathways
Cyclic Adenosine Monophosphate (cAMP) is an essential second messenger that activates protein kinase A (PKA) and regulates various biological processes. A single epinephrine molecule binds to GPCR and activates several heterotrimeric G proteins, each stimulating multiple adenylyl cyclase, amplifying the signal, and synthesizing large numbers of cAMP molecules. Small changes in cAMP concentration affect PKA activity. The binding of four cAMP molecules induces a conformational change in PKA,...
01:22Amplifying Signals via Enzymatic Cascade
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01:24Intracellular Signaling Cascades
Once a ligand binds to a receptor, the signal is transmitted through the membrane and into the cytoplasm. The continuation of a signal in this manner is called signal transduction. Signal transduction only occurs with cell-surface receptors, which cannot interact with most components of the cell, such as DNA. Only internal receptors can interact directly with DNA in the nucleus to initiate protein synthesis. When a ligand binds to its receptor, conformational changes occur that affect the...
01:19Interactions Between Signaling Pathways
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Convergence and divergence, and cross-talk between signaling pathways
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01:19Allosteric Proteins-ATCase
Binding sites linkages can regulate a protein's function. For example, enzyme activity is often regulated through a feedback mechanism where the end product of the biochemical process serves as an inhibitor.
Aspartate transcarbamoylase (ATCase) is a cytosolic enzyme that catalyzes the condensation of L-aspartate and carbamoyl phosphate to N-carbamoyl-L-aspartate. This reaction is the first step in pyrimidine biosynthesis. UTP and CTP, the end products of the pyrimidine synthesis pathway,...
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01:16Calmodulin-dependent Signaling
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The Ca2+-CaM complex does not have enzymatic activity by itself. Instead, the complex binds downstream target proteins, including membrane proteins or enzymes,...