Harnessing the versatility of hydrazones through electrosynthetic oxidative transformations.

Hydrazones are important structural motifs in organic synthesis, providing a useful molecular platform for the construction of valuable compounds. Electrooxidative transformations of hydrazones constitute an attractive opportunity to take advantage of the versatility of these reagents. By directly harnessing the electrical current to perform the oxidative process, a large panel of organic molecules can be accessed from readily available hydrazones under mild, safe and oxidant-free reaction conditions. This review presents a comprehensive overview of oxidative electrosynthetic transformations of hydrazones. It includes the construction of azacycles, the C(sp2)-H functionalization of aldehyde-derived hydrazones and the access to diazo compounds as either synthetic intermediates or products. A special attention is paid to the reaction mechanism with the aim to encourage further development in this field.

Spatial Distribution of Nitrogen Binding Sites in Metal-Organic Frameworks for Selective Ethane Adsorption and One-Step Ethylene Purification.

The one-step purification of ethylene (C2 H4 ) from mixtures containing ethane (C2 H6 ) and acetylene (C2 H2 ) is an industrially important yet challenging process. In this work, we present a site-engineering strategy aimed at manipulating the spatial distribution of binding sites within a confined pore space. We realized successfully by incorporating nitrogen-containing heterocycles, such as indole-5-carboxylic acid (Ind), benzimidazole-5-carboxylic acid (Bzz), and indazole-5-carboxylic acid (Izo), into the robust MOF-808 platform via post-synthetic modification. The resulting functionalized materials, namely MOF-808-Ind, MOF-808-Bzz, and MOF-808-Izo, demonstrated significantly improved selectivity for C2 H2 and C2 H6 over C2 H4 . MOF-808-Bzz with two uniformly distributed nitrogen binding sites gave the optimal geometry for selective ethane trapping through multiple strong C-H⋅⋅⋅N hydrogen bonds, leading to the highest C2 H2 /C2 H4 and C2 H6 /C2 H4 combined selectivities among known MOFs. Column breakthrough experiments validated its ability to purify C2 H4 from ternary C2 H2 /C2 H4 /C2 H6 mixtures in a single step.

The Development of HDAC and Tubulin Dual-Targeting Inhibitors for Cancer Therapy.

Histone deacetylases (HDACs) are a class of enzymes that are responsible for the removal of acetyl groups from the ε-N-acetyl lysine of histones, allowing histones to wrap DNA more tightly. HDACs play an essential role in many biological processes, such as gene regulation, transcription, cell proliferation, angiogenesis, migration, differentiation and metastasis, which make it an excellent target for anticancer drug discovery. The search for histone deacetylase inhibitors (HDACis) has been intensified, with numerous HDACis being discovered, and five of them have reached the market. However, currently available HDAC always suffers from several shortcomings, such as limited efficacy, drug resistance, and toxicity. Accordingly, dual-targeting HDACis have attracted much attention from academia to industry, and great advances have been achieved in this area. In this review, we summarize the progress on inhibitors with the capacity to concurrently inhibit tubulin polymerization and HDAC activity and their application in cancer treatment.

N-Amidation of Nitrogen-Containing Heterocyclic Compounds: Can We Apply Enzymatic Tools?

Amide bond is often seen in value-added nitrogen-containing heterocyclic compounds, which can present promising chemical, biological, and pharmaceutical significance. However, current synthesis methods in the preparation of amide-containing N-heterocyclic compounds have low specificity (large amount of by-products) and efficiency. In this study, we focused on reviewing the feasible enzymes (nitrogen acetyltransferase, carboxylic acid reductase, lipase, and cutinase) for the amidation of N-heterocyclic compounds; summarizing their advantages and weakness in the specific applications; and further predicting candidate enzymes through in silico structure-functional analysis. For future prospects, current enzymes demand further engineering and improving for practical industrial applications and more enzymatic tools need to be explored and developed for a broader range of N-heterocyclic substrates.

Design, synthesis, and tumor drug resistance reversal activity of novel hederagenin derivatives modified by nitrogen-containing heterocycles.

The emergence of multidrug resistance (MDR) in tumors leads to reduced chemotherapeutic efficacy, and P-glycoprotein (P-gp) overexpression is one of the main causes of MDR. In previous reports, we demonstrated that a variety of hederagenin (HD) derivatives could reverse MDR in tumors in vivo and in vitro. To further enrich the structure types, enhance the activity, and improve the structure-activity relationships (SARs), three series of HD derivatives were designed and synthesized in this study via A-ring fusion and innovative utilization of the structural advantages of nitrogen-containing heterocycles and benzyl group substitution. We evaluated the MDR reversal activity of 21 HD derivatives in KBV (multidrug-resistant oral epidermoid carcinoma) cells and refined their SARs. The results of cell experiments illustrated that more than half of the compounds had MDR reversal activity. Among them, compound 16 displayed relatively stronger MDR reversal ability, as it improved the sensitivity of KBV cells to paclitaxel, vincristine, mitoxantrone and cisplatin with IC50 values of 3.19, 0.65, 125.30, and 4.54 nM, respectively. The results of mechanistic analysis demonstrated that compound 16 inhibited the efflux function of P-gp by activating P-gp ATPase and increased the accumulation of rhodamine 123 in KBV cells. Importantly, the efficacy of paclitaxel against KBV cancer cell-derived xenograft tumors in nude mice was enhanced by compound 16 based on the growth suppression rate of 56.24%. These results indicated that introducing nitrogen-containing heterocycles could effectively improve the MDR reversal activity of HD derivatives, which appear to be promising lead compounds for tumor MDR reversal agent development.

Synthesis and biological evaluation of heterocyclic ring-fused dammarane-type ginsenoside derivatives as potential anti-tumor agents.

Twenty-one AD-1 derivatives were designed and synthesized by introducing various nitrogen-containing heterocycles into C-2 and C-3 positions. Their anti-proliferative activities were evaluated on two human cancer cell lines (HCT-116 and RM-1 cells) and one normal human gastric mucosal epithelial cell GES-1. Most of derivatives exhibited increased inhibitory potency, compared with lead compound AD-1. The most potent compound 6d had an IC50 value of 6.03 µM against HCT-116 cells, while it did not exhibit obvious cytotoxicity on GES-1 cells. The primary mechanistic study indicated that 6d induced G2/M-phase arrest by regulating the expression levels of p53, p21, Cyclin B1 and CDK1. Furthermore, 6d also induced apoptosis in HCT-116 cells. Moreover, western blot analysis indicated that 6d blocked the activation of MEK/ERK signaling pathway by inhibiting the phosphorylation of MEK and ERK, and remarkably up-regulated the expression of Cyt-c and Cl-caspase-3/9/PARP. The results suggested that 6d caused apoptosis through regulating MEK/ERK signaling pathway and mitochondrial pathway.

One-Pot NBS-Promoted Synthesis of Imidazoles and Thiazoles from Ethylarenes in Water.

A facile and eco-friendly method has been developed for the synthesis of imidazoles and thiazoles from ethylarenes in water. The reaction proceeds via in situ formation of α-bromoketone using NBS as a bromine source as well as an oxidant, followed by trapping with suitable nucleophiles to provide the corresponding products in good yields under metal-free conditions.

Recent advances in the development of polycyclic skeletons via Ugi reaction cascades.

Isocyanide-based multicomponent reactions are among the most powerful synthetic tools available. Particularly, the isocyanide-based Ugi reaction can allow rapid preparation of [Formula: see text]-aminoacyl amide derivatives and polyazaheterocycles with extensive pharmaceutical applications. Moreover, bridged polyazaheterocycles, including one or more quaternary carbon centers, can be constructed via the Ugi cascade reaction in a few steps. This review will emphasize synthesis and bioactivities of bridged compounds with quaternary centers constructed through Ugi cascade reactions.

Two seven-membered heterocycles with 1,2-diaza ring N atoms: 3,5,7-triphenyl-1,2-diazacyclohepta-1(7),2-diene and 3,7-bis(2-hydroxyphenyl)-5-phenyl-1,2-diazacyclohepta-1(7),2-diene.

The title compounds, 3,5,7-triphenyl-1,2-diazacyclohepta-1(7),2-diene, C23H20N2, (I), and 3,7-bis(2-hydroxyphenyl)-5-phenyl-1,2-diazacyclohepta-1(7),2-diene, C23H20N2O2, (II), constitute the first structurally characterized examples of seven-membered heterocycles with 1,2-diaza ring N atoms. Compound (I) crystallizes in the space group P1, with two independent molecules in the asymmetric unit that differ in the conformation of one of the phenyl rings, while (II) crystallizes in the space group C2/c. The C5N2 ring in each of (I) and (II) adopts a twist-boat conformation. Compound (I) exhibits neither C-H···π interactions nor π-π stacking interactions, whereas (II) shows both intramolecular O-H···N hydrogen bonds and a C-H···π interaction that joins the molecules into an infinite chain in the [010] direction.