RUI: Exploring Shape-selective Binding of the DNA Major Groove by Haiprin bis(diarylmethylene)Hydrazides

RUI：探索 Haiprin 双（二芳基亚甲基）酰肼对 DNA 主沟的形状选择性结合

• 批准号: 2003261
• 负责人: Thomas Minehan
• 金额: $ 33.07万
• 依托单位: The University Corporation, Northridge
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2003261&HistoricalAwards=false
• 关键词: RUI; Exploring; Shape; selective; Binding

With this award, the Chemistry of Life Processes Program of the Chemistry Division is funding Dr. Thomas Minehan from California State University-Northridge to investigate how tightly a set of hairpin bis(diarylmethylene)-hydrazide compounds bind to the DNA major groove and thereby potentially provide new tools to control when and at what levels genes are expressed. Nature's transcription factors are proteins that control when genes are turned on in cells by recognizing and binding DNA sequences in the major groove of the double-helix. Compounds that compete against transcription factor binding can thus be used to control genes that may be out of control. The molecules being constructed herein are to recognize regions in the DNA that are widened, mimicking the shape of the double-helix when proteins bind. Efforts to develop molecules that recognize DNA shape-selectively represent important new exploratory directions in chemistry and chemical biology. Success here could lead to a new class of tailored synthetic agents that modulate gene expression. The research provides valuable training at the interface of organic and biological chemistry to both undergraduate and graduate students. In addition, a new course and teaching resources are being developed to increase the appreciation of chemistry-related fields by non-science students.There is great need to develop new chemical scaffolds for sequence-specific major-groove binders. Peptide-tethered bis(diarylmethylene)-hydrazides are sterically bulky small molecules with defined distances between positively charged dimethylamino groups. Varying the tether length and aromatic surface area of these molecules allows the design of ligands with well defined distances between the projected positive charges so as to contact the negatively charged phosphate groups on opposite sides of expanded DNA major groove. Four hydrazide ligands possessing varying N-N spans will be synthesized and their DNA binding affinity and sequence selectivity evaluated using fluorescent intercalator displacement assays and isothermal titration calorimetry. These studies, together with X-ray crystallographic data on select DNA-ligand complexes, will be used to achieve optimal ligand structures for sequence-selective binding. Finally, an electrophoretic mobility shift assay is to be utilized to assess the ability of the ligands to selectively inhibit the binding of transcription factors to their target nucleic acid sequences, thus shedding light on the therapeutic and biotechnological promise of this class of compounds.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

有了这个奖项，化学部的生命过程化学计划正在资助加州州立大学北岭分校的托马斯米恩汉博士研究一组发夹双（二芳基亚甲基）酰肼化合物与DNA大沟结合的紧密程度，从而可能提供新的工具来控制基因表达的时间和水平。自然界的转录因子是一种蛋白质，它通过识别和结合双螺旋大沟中的DNA序列来控制细胞中基因的启动。因此，与转录因子结合竞争的化合物可用于控制可能失控的基因。本文构建的分子将识别DNA中加宽的区域，模拟蛋白质结合时双螺旋的形状。开发识别DNA形状选择性的分子的努力代表了化学和化学生物学中重要的新探索方向。 这方面的成功可能会导致一类新的调节基因表达的定制合成试剂。这项研究为本科生和研究生提供了有机化学和生物化学界面的宝贵培训。此外，正在开发新的课程和教学资源，以增加非理科学生对化学相关领域的欣赏。肽系连的双（二芳基亚甲基）酰肼是在带正电荷的二甲基氨基之间具有限定距离的空间体积小分子。改变这些分子的系链长度和芳香族表面积允许设计具有投射的正电荷之间的明确限定的距离的配体，以便接触扩展的DNA大沟的相对侧上的带负电荷的磷酸基团。四个具有不同的N-N跨度的酰肼配体将被合成和它们的DNA结合亲和力和序列选择性使用荧光嵌入剂置换分析和等温滴定量热法进行评估。这些研究，连同X-射线晶体学数据选择DNA-配体复合物，将用于实现最佳的配体结构的序列选择性结合。最后，利用电泳迁移率变动分析来评估配体选择性抑制转录因子与其靶核酸序列结合的能力，这一奖项反映了NSF的法定使命，并通过利用基金会的知识价值和更广泛的影响进行评估，被认为值得支持审查标准。

项目成果

[3,3]-Sigmatropic rearrangements of propargyl alkynyl ethers. Synthesis of complex dienoates and unsaturated lactones

• DOI: 10.1039/d2ob02121h
• 发表时间: 2023-01-06
• 期刊: ORGANIC & BIOMOLECULAR CHEMISTRY
• 影响因子: 3.2
• 作者: Sosa，Juan R.;Tudjarian，Armen A.;Minehan，Thomas G.
• 通讯作者: Minehan，Thomas G.

Total Syntheses and Absolute Configuration Assignment of (+)-Sootepdienone, (−)-Jambolanin C, (−)-Jambolanin I, and (−) - Gibberodione

( )-Sootepdienone、(-)-Jambolanin C、(-)-Jambolanin I 和 (-)-Gibberodione 的全合成和绝对构型分配

• DOI: 10.1021/acs.joc.0c02747
• 发表时间: 2021
• 期刊: The Journal of Organic Chemistry
• 作者: Ng, Kevin;Khoury, Michael;Minehan, Thomas Gerard
• 通讯作者: Minehan, Thomas Gerard

DNA major versus minor groove occupancy of monomeric and dimeric crystal violet derivatives. Toward structural correlations

• DOI: 10.1016/j.bmc.2023.117438
• 发表时间: 2023-09-25
• 期刊: BIOORGANIC & MEDICINAL CHEMISTRY
• 影响因子: 3.5
• 作者: Mirzakhanian，Aren;Khoury，Michael;Minehan，Thomas
• 通讯作者: Minehan，Thomas