A chemical genetics approach for specific differentiation of stem cells to somatic cells: a new promising therapeutical approach

Cell replacement therapy of severe degenerative diseases such as diabetes, myocardial infarction and Parkinson's disease through transplantation of somatic cells generated from embryonic stem (ES) cells is currently receiving considerable attention for the therapeutic applications. ES cells harvested from the inner cell mass (ICM) of the early embryo, can proliferate indefinitely in vitro while retaining the ability to differentiate into all somatic cells thereby providing an unlimited renewable source of somatic cells. In this context, identifying soluble factors, in particular chemically synthesized small molecules, and signal cascades involved in specific differentiation processes toward a defined tissue specific cell type are crucial for optimizing the generation of somatic cells in vitro for therapeutic approaches. However, experimental models are required allowing rapid and "easy-to-handle" parallel screening of chemical libraries to achieve this goal. Recently, the forward chemical genetic screening strategy has been postulated to screen small molecules in cellular systems for a specific desired phenotypic effect. The current review is focused on the progress of ES cell research in the context of the chemical genetics to identify small molecules promoting specific differentiation of ES cells to desired cell phenotype. Chemical genetics in the context of the cell ES-based cell replacement therapy remains a challenge for the near future for several scientific fields including chemistry, molecular biology, medicinal physics and robotic technologies.     

从生物有机化学到化学生物学

生物体系中的发现一直是与小分子连系在一起的.生物有机化学是生物学和有机化学相互交叉发展起来的新领域,特别是小分子与蛋白结合后引起蛋白功能变化的研究如抑制作用和活化.化学生物学和结构多样性有机合成使系统研究生物学成为可能,人工转录因子可以用作探针来发现生命过程中新的奥秘.     

Recognition of Nucleic Acid Junctions Using Triptycene‐Based Molecules

The modulation of nucleic acids by small molecules is an essential process across the kingdoms of life. Targeting nucleic acids with small molecules represents a significant challenge at the forefront of chemical biology. Nucleic acid junctions are ubiquitous structural motifs in nature and in designed materials. Herein, we describe a new class of structure‐specific nucleic acid junction stabilizers based on a triptycene scaffold. Triptycenes provide significant stabilization of DNA and RNA three‐way junctions, providing a new scaffold for the development of nucleic acid junction binders with enhanced recognition properties. Additionally, we report cytotoxicity and cell uptake data in two human ovarian carcinoma cell lines.     

An inexpensive fluorescent labeling protocol for bioactive natural products utilizing Cu(I)-catalyzed Huisgen reaction

Labeling of bioactive small molecules with organic dyes for various applications in cell biology has been emerging as an attractive research field. Using an easily prepared and inexpensive fluorescein derivative 1 and a Cu(I)-catalyzed Huisgen reaction, an efficient fluorescent labeling strategy is developed generally for bioactive natural products. Essentials of a successful labeling include the personalized introduction of an azido functionality to specific targets by a selective and efficient manner, and the strategic adjustment of reaction sequence to avoid possible side reactions under the ‘click’ reaction conditions. Such a protocol has been successfully applied to the fluorescent labeling of four bioactive small molecules in different chemical categories in this study. Advantages of this labeling protocol include the use of inexpensive reagents, ease of operation, free-of-protections at the ‘click’ step, and suiting a wide range of bioactive molecules bearing the reactive functionalities.     

Chemical technologies for probing embryonic development

Embryogenesis is a remarkable program of cell proliferation, migration, and differentiation that transforms a single fertilized egg into a complex multicellular organism. Understanding this process at the molecular and systems levels will require an interdisciplinary approach, including the concepts and technologies of chemical biology. This tutorial review provides an overview of chemical tools that have been used in developmental biology research, focusing on methods that enable spatiotemporal control of gene function and the visualization of embryonic patterning. Limitations of current approaches and future challenges are also discussed.     

γ-Resorcyclic Acid-Based AIEgens for Illuminating Endoplasmic Reticulum**

Endoplasmic reticulum (ER) has emerged as one of the interesting sub-cellular organelles due to its role in myriads of biological phenomena. Subsequently, visualization of the structure-function and dynamics of ER remained a major challenge to understand its involvement in different diseased states including cancer. To illuminate the ER, herein we have designed and synthesized γ-resorcyclic acid-based small molecules, which showed remarkable aggregation-induced emission (AIE) property in water. This AIE property was originated from the dual intramolecular H-bonding leading to the self-assembled 2D aggregation confirmed by pH- and temperature-dependent fluorescence quenching studies as well as scanning electron microscopy. These small molecules illuminated the sub-cellular ER in HeLa cervical cancer cells as well as non-cancerous RPE-1 human retinal epithelial cells within 1 h. These novel small molecules have the potential to light up ER chemical biology in diseased states.     

Spectral assignments for 1H, 13C and 15N solution and solid-state NMR spectra of s-tetrazine and dihydro-s-tetrazine derivatives

Tetrazine-based organic species are interesting intermediates for organic synthesis and represent a source of new materials bearing specific properties with potential applications in biology and material science. 1H, 13C, 15N NMR measurements carried out in solution and in the solid-state have been used to characterize a series of 3,6-disubstituted 1,2,4,5-tetrazine/dihydrotetrazine new derivatives. Experimental results presented here provide data for the assignment of 15N chemical shifts including new organic small molecules; two polymers having the tetrazine ring in the main chain and several previously published compounds. We report apparently for the first time 15N experimental chemical shift data for tetrazine systems in the solid state.     

Pathway development and pilot library realization in diversity-oriented synthesis: exploring Ferrier and Pauson-Khand reactions on a glycal template

Through a correlation of the ability of small molecules to bind biological macromolecules and their ability to modulate cellular and organismal processes, chemistry can inform biology and vice versa. Diversity-oriented organic synthesis (DOS), which aims to provide structurally complex and diverse small molecules efficiently, can play a key role in such chemical genetic studies. Here we illustrate the trial-and-error experimentation that can refine an initial pathway-planning exercise and result eventually in an effective diversity pathway. By exploring Ferrier and Pauson-Khand reactions on a glycal template, we have developed efficient and stereoselective syntheses of tricyclic compounds. In this pathway, diversity results from the substituents and their spatial relationships about the tricyclic rings. A pilot split-pool library synthesis of 2500 tricyclic compounds highlights the use of planning considerations in DOS and a "one-bead, one-stock solution" technology platform. Additionally, it illustrates a promising synthetic pathway for future chemical genetic studies.