Exocyclic Olefinic Maleimides: Synthesis and Application for Stable and Thiol‐Selective Bioconjugation

Michael addition reactions between biological thiols and endocyclic olefinic maleimides are extensively used for site‐specific bioconjugation. The resulting thio‐succinimidyl linkages, however, lack stability because of their susceptibility to thiol exchange. Reported herein is that in contrast to their endocyclic counterparts, exocyclic olefinic maleimides form highly stable thio‐Michael adducts which resist thiol exchange at physiological conditions. A high‐yielding approach for synthesizing a variety of exocyclic olefinic maleimides, by 4‐nitrophenol‐catalyzed solvent‐free Wittig reactions, is reported. Mechanistic studies reveal that the catalyst facilitates the formation of the Wittig ylide intermediate through sequential proton donation and abstraction. Overall, this report details an improved thiol bioconjugation approach, a facile method for synthesizing exocyclic olefinic maleimides, and demonstrates that phenolic compounds can catalyze ylide formation.     

Crystallinity and stability of covalent organic frameworks

Covalent organic frameworks(COFs) are a class of organic porous polymers with high crystallinity, and their structures can be precisely tailored via topology design. Owing to the characteristics of permanent pores, periodic structures and rich building blocks, COFs have triggered tremendous attention in the past fifteen years and are extensively investigated in various fields.Crystallinity and stability are two crucial features for practical applications. In general, these two features are contradictory for COFs formed via dynamic covalent chemistry(DCC). High thermodynamic reversibility is usually required to attain exceptional crystallinity of COFs, often resulting in limited stability. The first two reported COFs are based on the boroxine and boronate ester linkages, which are unstable in water and even in humid conditions. Therefore, many researchers doubt the stability of COFs for real applications. Actually, in these years, various novel linkages have been developed for the construction of COFs,and numerous newly synthesized COFs are robust towards strong acid/base and even some of them can resist the attack of strong oxidizing and reducing agents. In this review, we focus on the linkage chemistry of the COFs in terms of crystallinity and stability, further extending it to the investigation in the mechanisms of the crystal growth and the overall regulation of the contradiction between stability and crystallinity. The strategies for improving the crystallinity, including selecting building units,introducing non-covalent interactions and slowing nucleation and growth rate, are described in the third section, while the methodologies for increasing the stability from the viewpoints of chemical modification and non-covalent interactions are summarized in the fourth section. Finally, the challenges and perspectives are presented.     

Covalent Adaptable Networks with Tunable Exchange Rates Based on Reversible Thiol–yne Cross-Linking

The design of covalent adaptable networks (CANs) relies on the ability to trigger the rearrangement of bonds within a polymer network. Simple activated alkynes are now used as versatile reversible cross-linkers for thiols. The click-like thiol–yne cross-linking reaction readily enables network synthesis from polythiols through a double Michael addition with a reversible and tunable second addition step. The resulting thioacetal cross-linking moieties are robust but dynamic linkages. A series of different activated alkynes have been synthesized and systematically probed for their ability to produce dynamic thioacetal linkages, both in kinetic studies of small molecule models, as well as in stress relaxation and creep measurements on thiol–yne-based CANs. The results are further rationalized by DFT calculations, showing that the bond exchange rates can be significantly influenced by the choice of the activated alkyne cross-linker.     

Covalent Adaptable Networks with Tunable Exchange Rates Based on Reversible Thiol–yne Cross‐Linking

The design of covalent adaptable networks (CANs) relies on the ability to trigger the rearrangement of bonds within a polymer network. Simple activated alkynes are now used as versatile reversible cross‐linkers for thiols. The click‐like thiol–yne cross‐linking reaction readily enables network synthesis from polythiols through a double Michael addition with a reversible and tunable second addition step. The resulting thioacetal cross‐linking moieties are robust but dynamic linkages. A series of different activated alkynes have been synthesized and systematically probed for their ability to produce dynamic thioacetal linkages, both in kinetic studies of small molecule models, as well as in stress relaxation and creep measurements on thiol–yne‐based CANs. The results are further rationalized by DFT calculations, showing that the bond exchange rates can be significantly influenced by the choice of the activated alkyne cross‐linker.     

马来酰亚胺类GSK-3β抑制剂的QSAR研究及分子设计

为了研究马来酰亚胺类化合物抑制活性与分子结构的定量构效关系,在分子理论的基础上计算了67个马来酰亚胺类化合物的电性距离矢量,通过最佳变量子集回归的方法,建立了抑制活性的五元线性回归模型,模型的传统相关系数(R2)和交叉验证相关系数(RCV2)分别为0.864和0.825.该模型经过Jackknife法检验、交叉验证、F检验及外部检验法证明具有良好的稳健性和预测能力.根据进入模型的5个变量分析,影响马来酰亚胺类GSK-3β抑制剂抑制活性的主要结构基团是-NH-,=O(或-OH),≡CH,Cl-及-O-(或-S-).同时基于QSAR模型设计了6个抑制活性显著提高的马来酰亚胺类分子,并预测了它们的抑制活性.     

Advanced Surfaces by Anchoring Thin Hydrogel Layers of Functional Polymers

Surface design and engineering is a critical tool to improve the interaction of materials with their surroundings. Immobilization of soft hydrogels is one of the attractive strategies to achieve surface modification. The goal of this review is to provide a comprehensive overview of the different strategies used for surface tethering of hydrogel layers via crosslinking immobilization of pre-fabricated functional polymers. In this strategy, crosslinkable polymers are first prepared via various polymerization techniques or post-functionalization of polymers. Afterwards, the crosslinkable polymers are attached or tethered on the surfaces of substrates using a variety of approaches including photo-crosslinking, click reactions, reversible linkages, etc. For each case, the principles of hydrogel tethering have been explained in detail with representative examples.Moreover, the potential applications of the as-modified substrates in specific cases have also been addressed and overviewed.     

A new mild radical route to 3-substituted maleimides using organoboroles

A new, mild, radical route for the synthesis of 3-substituted maleimides has been developed. This new method incorporates alkene hydroboration, conjugate addition-aminoxylation and TEMPO-H elimination in a one-pot procedure, using cheap, readily available starting materials. A variety of 3-substituted maleimides have been prepared in good to excellent yield.     

Research Progress in Covalent Organic Frameworks for Photoluminescent Materials

Covalent organic frameworks (COFs) are an emerging kind of crystalline porous polymers that present the precise integration of organic building blocks into extensible structures with regular pores and periodic skeletons. The diversity of organic units and covalent linkages makes COFs a rising materials platform for the design of structure and functionality. Herein, recent research progress in developing COFs for photoluminescent materials is summarised. Structural and functional design strategies are highlighted and fundamental problems that need to be solved are identified, in conjunction with potential applications from perspectives of photoluminescent materials.     

Recent advances in stimuli-responsive degradable block copolymer micelles: synthesis and controlled drug delivery applications

(Bio)degradation in response to external stimuli (stimuli-responsive degradation, SRD) is a desired property in constructing novel nanostructured materials. For polymer-based multifunctional drug delivery applications, the degradation enables fast and controlled release of encapsulated therapeutic drugs from delivery vehicles in targeted cells. It also ensures the clearance of the empty device after drugs are delivered to the body. This review summarizes recent development of various strategies to the design and synthesis of self-assembled micellar aggregates based on novel amphiphilic block copolymers having different numbers of stimuli-responsive cleavable elements at various locations. These cleavable linkages including disulfide, acid-labile, and photo-cleavable linkages are incorporated into micelles, and then are cleaved in response to cellular triggers such as reductive reaction, light, and low acid. The well-designed SRD micelles have been explored as controlled/enhanced delivery vehicles of drugs and genes. For future design and development of effective stimuli-responsive degradable micelles toward tumor-targeting delivery applications in vivo, a high degree of control over degradation for tunable release of encapsulated anticancer drugs as well as bioconjugation for active tumor-targeting is required.     

Synthesis on N-Alkylated Maleimides

A two step synthesis of N-alkylated maleimides is presented. This method allows for the use of widely available starting materials and produces maleimides in high purity and yields. The maleimide precursors are of interest for potential thermo- and photo-setting polymerization processes.     

Intermediates of radiation-induced polymerisation of maleimides studied by ESR

Radicals produced by radiolysis and photolysis of maleimides (maleimide, N-methylmaleimide, N-ethylmaleimide, N-phenyl-maleimide) in bulk have been identified by ESR spectroscopy. γ-Irradiation of maleimides yields up to five different radicals depending on the type of maleimide. Because of the great linewidth of powder ESR spectra, the hyperfine splittings are determined by means of computer simulation. For N-alkyl maleimides the starting species of polymerisation are formed by abstraction of a H-atom from the alkyl group in radiolysis as well as in photolysis. The structure of the propagating radical shows that polymerisation proceeds via the ethylenic double bond. The detection of maleimide ions makes participation of these ions in polymerisation conceivable. Radiolysis of maleimide and N-phenylmaleimide yields the same type of radicals whereas only ions could be detected after u.v.-irradiation.     

Asymmetric Organocatalytic Addition Reactions of Maleimides: A Promising Approach Towards the Synthesis of Chiral Succinimide Derivatives

Recent progress in asymmetric organocatalysis has led to the development of several asymmetric transformations that employ various substrates. Among these substrates, maleimides have emerged as excellent Michael acceptors, dienophiles, and dipolarophiles. In this Focus Review we highlight the advances in the asymmetric synthesis of succinimide derivatives through asymmetric organocatalytic addition reactions of maleimides.     

Peptide-Catalyzed Stereoselective Conjugate Addition Reaction of Aldehydes to C-Substituted Maleimides

Catalytic stereoselective additions with maleimides are useful one-step reactions to yield chiral succinimides, molecules that are widespread among therapeutically active compounds but challenging to prepare when the maleimide is C-substituted. We present the tripeptide H-Pro-Pro-Asp-NHC₁₂H₂₅ as a catalyst for conjugate addition reactions between aldehydes and C-substituted maleimides to form succinimides with three contiguous stereogenic centers in high yields and stereoselectivities. The peptidic catalyst is so chemoselective that no protecting group is needed at the imide nitrogen of the maleimides. Derivatization of the succinimides was straightforward and provided access to chiral pyrrolidines, lactones, and lactams. Kinetic studies, including a Hammett plot, provided detailed insight into the reaction mechanism.     

Development of a library of N-substituted maleimides for the local functionalization of linear polymer chains

A novel kinetic process was investigated for functionalizing "on-demand" local regions of well-defined linear polystyrene chains. This concept relies on the atom transfer radical copolymerization (ATRP) of functional N-substituted maleimides with styrene. This copolymerization is a controlled radical process, which combines two unique kinetic features: i) all the polymers chains are growing simultaneously and ii) the cross-propagation of the comonomers is highly-favored as compared to homopolymerization. Thus, discrete amounts of N-substituted maleimides (e.g., 1 equiv as compared to initiator) are consumed extremely fast in the copolymerization process and are therefore locally incorporated in narrow regions of the growing polystyrene chains. MALDI-TOF analysis of model copolymers indicated that this kinetic concept is efficient. Although a sequence distribution is observed, well-defined polymer chains having only one or two functional maleimide units per chain were found to be the most abundant species. Furthermore, the position of the functional groups in the polystyrene chains can be kinetically-controlled by adding the N-substituted maleimides at desired times during the course of the polymerization. This method is very versatile and can be applied to a wide variety of N-substituted maleimides. Herein, a library of 20 different maleimides bearing various functional groups (e.g., aromatic moieties, fluorinated groups, hydroxy functions, protected esters, protected amines, light-responsive moieties, fluorophores and biorelevant functions such as short poly(ethylene glycol) segments or biotin moieties) was investigated. In most cases, the functional N-substituted maleimides could be efficiently incorporated in the polystyrene chains.     

Strategies for Improving the Catalytic Performance of 2D Covalent Organic Frameworks for Hydrogen Evolution and Oxygen Evolution Reactions

Hydrogen evolution reaction (HER) and oxygen evolution reaction (OER) have been deemed as clean and sustainable strategies to solve the energy crisis and environmental problems. Various catalysts have been developed to promote the process of HER and OER. Among them, two-dimensional covalent organic frameworks (2D COFs) have received great attention due to their diverse and designable structure. In this minireview, we mainly summarize the diverse linkages of 2D COFs and strategies for enhancing the catalytic performance of 2D COFs for HER and OER, such as introducing active building blocks, metal ions and tailored linkages. Furthermore, a brief outlook for the development directions of COFs in the field of HER and OER is provided, expecting to stimulate new opportunities in future research.     

An overview on covalent organic frameworks: synthetic reactions and miscellaneous applications

Covalent organic frameworks (COFs) are an emerging class of porous crystalline materials which are completely constructed from organic building blocks through robust covalent bonds. High surface areas, compositional and structural tunability, low density, and superior stability have rendered COF candidates in a variety of applications, such as adsorption and separation, catalysis, electronics, chemical sensing, optics, and so forth. To better understand the structures and properties of COFs as well as the design principles, it is of great significance to learn about the linkages formed during synthetic reactions that contribute to the high crystallinity and stability of COFs. In this review, we will first discuss various linkages that have been utilized for COF construction up to date, followed by an outline of their miscellaneous applications, providing a comprehensive and detailed overview in this file.     

Maleimides As a Building Block for the Synthesis of High Performance Polymers

Maleimides are gaining a great deal of attention in both scientific and industrial communities since they can be used in high performance macromolecular systems: thermosets with high temperature stability, self-healing systems, or in click chemistry reactions. After an introduction, this review reports in the first part the different routes to synthesize maleimides. In the second part, this review focuses on the use of maleimides in polymer synthesis, first through nucleophilic reactions, second via cycloaddition to yield remendable systems, and then via radical polymerization. Finally, the industrial availability of maleimides is discussed.     

One pot synthesis of maleimide and hydantoin by Fe(CO)5 catalyzed [2 + 2 + 1] co-cyclization of acetylene, isocyanate and CO

In the presence of a catalytic amount of Fe(CO)(5), terminal acetylenes, isocyanates and CO undergo [2 + 2 + 1] cyclization to form substituted maleimides and hydantoins; when internal alkynes are used, exclusive maleimide formation is observed. While the maleimides can be obtained as the major products, in up to 90% yield, when the reaction is carried out in CO atmosphere, in absence of CO, the hydantoins are formed in up to 87% yield. Formation of maleimides has been shown to occur via the formation of a ferrole intermediate, whereas the hydantoins are proposed to form through successive insertion of isocyanate into the iron-acetylide bond. All compounds were characterized by spectroscopic methods and molecular structures of some compounds were established by single crystal X-ray diffraction method.     

Thermal degradation of vinylidene chloride/vinyl chloride copolymers in the presence of N-substituted maleimides

As a consequence of their excellent barrier properties vinyl chloride/vinylidene chloride copolymers have long been prominent in the flexible packaging market. While these polymers possess a number of superior characteristics, they tend to undergo thermally- induced degradative dehydrochlorination at process temperatures. This degradation must be controlled to permit processing of the polymers. Three series of N-substituted maleimides (N-alkyl-, N-aralkyl, and N-aryl) have been synthesized, characterized spectroscopically, and evaluated as potential stabilizers for a standard vinyl chloride/vinylidene chloride (85 mass%) copolymer. As surface blends with the polymer, these compounds are ineffective as stabilizers. However, significant stabilization may be achieved by pretreatment of the polymer with N-substituted maleimides. The most effective stabilization of the polymer is afforded by N-aralkyl- or N-arylmaleimides, most notably, N-benzylmaleimide and N-p-methoxyphenylmaleimide.     

Designing electrostatic interactions in biological systems via charge optimization or combinatorial approaches: insights and challenges with a continuum electrostatic framework

Electrostatic interactions between biological molecules are crucially influenced by their aqueous environment, with efficient and accurate models of solvent effects required for robust molecular design strategies. Continuum electrostatic models provide a reasonable balance between computational efficiency and accurate system representation. In this article, I review two specific molecular design strategies, charge optimization and combinatorial design, paying particular attention to how the continuum framework (also briefly described herein) successfully enables both theoretical insights and molecular designs and presents a challenge in design applications due to what I call “the isostericity constraint.” Efforts to work around the isostericity constraint and other challenges are discussed. Additionally, particular emphasis is placed on using such models in the rational design of particularly tight, specific, or promiscuous interactions, in keeping with the increased sophistication of current molecular design applications.