RUI: Functionalized bis(morindone-C,O-glycosides) for the molecular recognition of DNA in the major groove

RUI：功能化双（吗啉酮-C,O-糖苷）用于大沟 DNA 的分子识别

• 批准号: 1508070
• 负责人: Thomas Minehan
• 金额: $ 28.67万
• 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: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1508070&HistoricalAwards=false
• 关键词: RUI; Functionalized; bis; morindone; glycosides

Investigators in the field of molecular recognition study the non-covalent interactions between two (or more) molecules with the aim of understanding the driving forces behind these associations. With this information in hand, it is possible to develop a set of rules for the design of molecules (ligands) capable of specific binding interactions with other target molecules (receptors). DNA has long been viewed as an important macromolecular target for the binding of small molecule ligands, and indeed there are numerous examples of natural and designed molecules that associate with the minor groove of DNA. However, no general paradigm currently exists for the design of major groove-binding small molecules. Since most of the DNA-binding proteins that regulate cellular processes associate with the major groove of DNA, a great need exists for the development of major groove ligands that may directly influence DNA binding-initiated cellular events. Using the tools of fluorescence spectroscopy and isothermal titration calorimetry, this study helps uncover a set of design principles for crafting such ligands from simple carbohydrate and aromatic starting materials. The project also provides hands-on training in organic synthesis, molecular spectroscopy and microcalorimetry for undergraduate and graduate students, including those from groups traditionally underrepresented in science. Furthermore, it is anticipated that the project may lead to new procedures and protocols that can be adapted for use in the undergraduate chemistry laboratory curriculum at Northridge, which is expected to increase student interest in interface sciences such as chemical biology, bioorganic chemistry and medicinal chemistry.Bicyclic aryl C,O-glycosides are naturally occurring molecular wedges that may be used as rigid intercalating scaffolds to position functional groups in proximity to the discriminatory edges of the A/T and G/C base pairs in the major groove of DNA. The unique architecture of this ligand allows an examination of the utility of base-complementary functional groups at C.2 and C.4 of the carbohydrate unit for sequence specific DNA binding. The research project involves: (1) the synthesis of a series of bis(morindone-C,O-glycosides) containing patterns of carbonate, carbamate, guanidine and carbamimidate recognition elements complementary to the 4 base-pair sequences 5'-CGCG-3', 5'-CATG-3', 5'-CGGC-3', 5'-CAAC-3', and 5'-CGTG-3', respectively, (2) the assessment of both the DNA binding affinity and sequence selectivity of the ligands for diverse nucleic acid polymers and DNA hairpins using fluorescent intercalator displacement assays, (3) the measurement of the thermodynamic parameters (deltaH and deltaS) for the tightest ligand-DNA combinations using isothermal titration calorimetry in order to optimize the structure of the ligands, and (4) the evaluation of the ability of these ligands to inhibit the binding of the transcription factor AP-1 to its consensus site by EMSA assay, which may shed light on the potential usefulness of this class of compounds for regulating cellular processes.

分子识别领域的研究人员研究两个（或多个）分子之间的非共价相互作用，目的是了解这些关联背后的驱动力。有了这些信息，就有可能开发出一套规则，用于设计能够与其他靶分子（受体）特异性结合相互作用的分子（配体）。长期以来，DNA一直被认为是小分子配体结合的重要大分子靶点，实际上，有许多天然和设计的分子与DNA小沟相关。然而，目前还没有通用的范式存在的主要沟结合小分子的设计。由于大多数调节细胞过程的DNA结合蛋白与DNA的大沟相关，因此非常需要开发可以直接影响DNA结合启动的细胞事件的大沟配体。使用荧光光谱和等温滴定量热法的工具，这项研究有助于揭示一套设计原则，从简单的碳水化合物和芳香族起始材料制作这样的配体。该项目还为本科生和研究生提供有机合成，分子光谱学和微量热法的实践培训，包括那些传统上在科学中代表性不足的群体。此外，预计该项目可能导致新的程序和协议，可适用于北岭大学本科化学实验室课程，预计将增加学生对化学生物学，生物有机化学和药物化学等界面科学的兴趣。O-糖苷是天然存在的分子楔形物，其可用作刚性嵌入支架以将官能团定位在A/T和G/T的区别性边缘附近。DNA大沟中的C碱基对。这种配体的独特结构允许检查在C. 2和C. 4的碳水化合物单元的序列特异性DNA结合的碱基互补官能团的效用。研究项目包括：（1）合成了一系列双（桑茚酮-C，O-糖苷），其含有分别与4个碱基对序列5’-CGCG-3’、5’-CATG-3’、5’-CGGC-3’、5’-CAAC-3’和5’-CGTG-3’互补的碳酸酯、氨基甲酸酯、胍和氨基甲酸酯识别元件的模式，（2）使用荧光嵌入剂置换测定评估配体对不同核酸聚合物和DNA发夹的DNA结合亲和力和序列选择性，（3）热力学参数的测定为了优化配体的结构，使用等温滴定量热法计算最紧密配体-DNA组合的Δ H和Δ S，和（4）通过EMSA分析评价这些配体抑制转录因子AP-1与其共有位点结合的能力，这可能揭示了这类化合物用于调节细胞过程的潜在有用性。

项目成果

A Single-Flask Synthesis of Morita–Baylis–Hillman Adducts from Ethoxyacetylene and Carbonyl Compounds: Synthesis of Subamolides D and E

由乙氧基乙炔和羰基化合物单瓶合成 Morita-Baylis-Hillman 加合物：Subamolides D 和 E 的合成

• DOI: 10.1021/acs.orglett.6b01772
• 发表时间: 2016
• 期刊: Organic Letters
• 影响因子: 5.2
• 作者: Ng, Kevin;Minehan, Thomas G.
• 通讯作者: Minehan, Thomas G.

Ring Expansion, Ring Contraction, and Annulation Reactions of Allylic Phosphonates under Oxidative Cleavage Conditions

氧化裂解条件下烯丙基膦酸酯的扩环、缩环和成环反应

• DOI: 10.1021/acs.orglett.8b00791
• 发表时间: 2018
• 期刊: Organic Letters
• 影响因子: 5.2
• 作者: Orr, Dupre;Yousefi, Nikolas;Minehan, Thomas G.
• 通讯作者: Minehan, Thomas G.