Oxidation/Alkylation of Amino Acids with α-Bromo Carbonyls Catalyzed by Copper and Quick Access to HDAC Inhibitor.

A facile and efficient method was reported for Cu-catalyzed selective α-alkylation processes of amino acids/peptides and α-bromo esters/ketones through a radical-radical coupling pathway. The reaction displays an excellent functional group tolerance and broad substrate scope, allowing access to desired products in moderate to excellent yields. Notably, this method is distinguished by site-specificity and exhibits total selectivity for aryl glycine motifs over other amino acid units. Furthermore, the practicality of this strategy is certified by the efficient synthesis of the novel SAHA phenylalanine-containing analogue (SPACA).

Dandelion polysaccharide treatment protects against dextran sodium sulfate-induced colitis by suppressing NF-κB/NLRP3 inflammasome-mediated inflammation and activating Nrf2 in mouse colon.

The treatment of ulcerative colitis (UC) is still an intractable medical problem. Polysaccharides are promising candidates for the treatment of UC and have received widespread attention in recent years. The objective of this study was to explore the protective effect and underlying mechanism of dandelion polysaccharide (DP) on dextran sulfate sodium (DSS)-induced colitis in mice. Our results showed that oral administration of DP could dramatically alleviate colonic lesions, as evidenced by reduced DAI scores, shortening of colon length, and ameliorating pathologic abnormalities in colons. Additionally, the expressions of pro-inflammatory factors (TNF-α, IL-1ß, and IL-6) and the infiltration of inflammation-regulation cells, marked by myeloperoxidase and F4/80, were also inhibited after DP treatment. Moreover, DP treatment also markedly suppressed the nuclear translocation of NF-κB-p65 and the activation of the NLRP3 inflammasome. Furthermore, DP also activated the Nrf2/HO-1 pathway and reduced the oxidative stress induced by DSS. Overall, these results suggest that DP could be a promising novel therapeutic approach for the treatment of UC.

Design, Synthesis and Biological Evaluation of Histone Deacetylase Inhibitors Based on Pyrrolo[2,3-d]pyrimidine and Pyrrolo[2,3-b]pyridine Scaffolds.

Histone deacetylases (HDACs) are validated targets for the development of anticancer drugs in epigenetics. We have designed and synthesized a series of novel HDAC inhibitors based on pyrrolo[2,3-d]pyrimidine and pyrrolo[2,3-b]pyridine scaffolds. Compound B3 {(E)-3-(4-(((1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-yl)amino)methyl)phenyl)-N-hydroxyacrylamide} exhibits potent inhibitory activity against HDACs 1, 2, 3, 6, and 8 with IC50 values of 5.2, 6.0, 8.8, 4.4, and 173.0 nM, respectively. It exhibited potent antiproliferative effects against three tumour cell lines (IC50 values of 0.13, 0.37, and 1.11 µM, against MV-4-11, K562, and WSU-DLCL-2 cells, respectively) with two- to sixfold improvement relative to suberoylanilide hydroxamic acid (SAHA). Mechanistic studies on WSU-DLCL-2 cells revealed that B3 exhibits anticancer effects through the induction of G0 /G1 -phase arrest and promotion of apoptosis. The results of this study warrant further investigation of this compound series for the treatment of hematological malignancy.

Design, synthesis and biological evaluation of novel histone deacetylase (HDAC) inhibitors derived from ß-elemene scaffold.

ß-Elemene is the major active ingredient of TCM anticancer drug elemene extracts. To further improve its antitumor activity and poor solubility, a polar HDACi pharmacophore was incorporated its scaffold. Systematic SAR studies led to the discovery of compounds 27f and 39f, which exhibited potent inhibitory activity against HDACs (HDAC1: IC50 = 22 and 9 nM; HDAC6: 8 and 14 nM, respectively). In cellular levels, 27f and 39f significantly inhibited cell proliferation of five tumour cell lines (IC50: 0.79 - 4.42 µM). Preliminary mechanistic studies indicated that 27f and 39f efficiently induced cell apoptosis. Unexpectedly, compound 39f could also stimulate cell cycle arrest in G1 phase. Further in vivo study in WSU-DLCL-2 xenografted mouse model validated the antitumor activities of 27f, without significant toxicity. The results suggest the therapeutic potential of these HDACs inhibitors in lymphoma and provide valuable insight and understanding for further structural optimisation around ß-elemene scaffold.

Dysregulation of PD-L1 by UFMylation imparts tumor immune evasion and identified as a potential therapeutic target.

Immunotherapy of PD-L1/PD-1 blockage elicited impressive clinical benefits for cancer treatment. However, the relative low response and therapy resistance highlight the need to better understand the molecular regulation of PD-L1 in tumors. Here, we report that PD-L1 is a target of UFMylation. UFMylation of PD-L1 destabilizes PD-L1 by synergizing its ubiquitination. Inhibition of PD-L1 UFMylation via silencing of UFL1 or Ubiquitin-fold modifier 1 (UFM1), or the defective UFMylation of PD-L1, stabilizes the PD-L1 in multiple human and murine cancer cells, and undermines antitumor immunity in vitro and mice, respectively. Clinically, UFL1 expression was decreased in multiple cancers and lower expression of UFL1 negatively correlated with the response of anti-PD1 therapy in melanoma patients. Moreover, we identified a covalent inhibitor of UFSP2 that promoted the UFMylation activity and contributed to the combination therapy with PD-1 blockade. Our findings identified a previously unrecognized regulator of PD-L1 and highlighted UFMylation as a potential therapeutic target.

Recent advances of novel fourth generation EGFR inhibitors in overcoming C797S mutation of lung cancer therapy.

Lung cancer is the second place among the global cancer population in term of the morbidity and mortality, while non-small cell lung cancer (NSCLC) accounts for the largest proportion of all lung cancer patient. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are commonly used in the treatment of NSCLC. Despite of the success in coping with EGFR kinase resistance lung cancer using the first three generations of EGFR-TK inhibitors (EGFR-TKIs), the new problem of resistance to Osimertinib occurred due to the newly developed EGFRC797S mutation. In recent years, scientists have proposed several pharmacochemical strategies for the treatment of Osimertinib-resistant NSCLC patients. This paper intends to collect the references in this field since 2021 and to summarize the pharmacochemical processes and strategies in discovery of novel EGFR-TKIs for overcoming C797S mutation in lung cancer patients. It could serve as quick information provider for further structural modifications and drug discovery.

Design, synthesis and antitumor efficacy evaluation of a series of novel ß-elemene-based macrocycles.

ß-Elemene is the major constituent of the antitumor drugs elemene extract approved in China. By incorporating macrocyclization strategy into the ß-elemene skeleton, we designed a series of novel macrocycles retaining three key carbon-carbon double bonds. Four different methods have been successfully developed for these challenging ring systems. A total of twenty-eight 14- to 24-membered macrocycles were synthesized. Most of these macrocycles exhibited good antitumor activity against several cancer cell lines (PC-3, A549, U87MG, U251 and HCT116), with up to 40 folds improvement of activity comparing to ß-elemene. Additionally, X-ray single crystal structures of compounds Ic, Ip, and IIh were successfully solved as the proof of macrocycle formation. The results warrant the further investigation of this novel class macrocycles in pharmacokinetic and pharmacodynamics studies, which will be reported in due course.

Discovery of small-molecule compounds and natural products against Parkinson's disease: Pathological mechanism and structural modification.

Parkinson's disease (PD) is the second common neurodegenerative disease characterized by movement disorder. The symptoms of PD harm both the physical and mental health of patients. However, the current treatment strategies for PD only alleviate the symptoms but cannot recover the degenerative process of dopaminergic neurons. Therefore, it is necessary to develop novel and safe drugs for the treatment of PD. In this review, we comprehensively summarized the detailed pathological mechanisms and potential drugable targets of PD. The approved anti-PD drugs in clinical use and the drug candidates under clinical trials were also listed. More importantly, the compounds in the drug discovery phase with in vivo anti-PD activities in the recent two decades (2000-2020) were summarized. The structure-activity relationships (SARs) were also analyzed. Additionally, we predicted all the reviewed compounds' blood-brain barrier (BBB) permeability and statistically analyzed their pharmacological targets and in vivo anti-PD testing models. It is hoped that this review can provide practical information for researchers in the field of anti-PD drug discovery and promote their research work.

Drug discovery of histone lysine demethylases (KDMs) inhibitors (progress from 2018 to present).

Post-translational modifications (PTMs) of histone by histone demethylases (KDMs) play an important role in the regulation of gene expression, which implicates the development of various human cancers and other diseases. Discovering and developing inhibitors targeting KDMs have become an active and fast-growing research area over the past decades. In this review, the latest emerging small-molecule inhibitors of KDMs were surveyed with the emphasis on the literature since 2018, including lysine specific demethylases (LSD or KDM1) inhibitors and JmjC family N-methyl lysine demethylases (JmjC KDMs, i.e. KDM2-7) inhibitors. The drug design strategy, the structure-activity relationships (SARs), the analysis and insight of co-crystal structures, and the mechanisms of action (MOA) were also discussed.

Medicinal chemistry updates of novel HDACs inhibitors (2020 to present).

Epigentic enzymes histone deacetylases (HDACs) catalyze the removal of acetyl groups from the ε-N-acetylated lysine residues of various protein substrates including both histone and non-histone proteins. Different HDACs have distinct biological functions and are recruited to specific regions of the genome. Due to their important biological functions, HDACs have been validated in clinics for anticancer therapy, and are being explored for potential treatment of several other diseases such as Alzheimer disease (AD), metabolic disease, viral infection, and multiple sclerosis, etc. Besides five approved drugs, there are more than thirty HDACs inhibitors currently being investigated in clinical trials. Centering on the advances of drug discovery programs in this field since 2020, this review discusses HDACs inhibitors from the aspects of the structure-based rational design, isoform selectivity, pharmacology, and toxicology of the compounds of interest. The hope is to provide the medicinal chemistry community with up-to-date information and to accelerate the drug discovery programs in this area.

Two phenanthroimidazole turn-on probes for the rapid detection of selenocysteine and its application in living cells imaging.

Detection of selenocysteine (Sec) content in cells by fluorescence probe is of great significance for the identification of human related diseases. To achieve fast and sensitive detection of Sec, two isomers A4 and B4 as turn-on fluorescent probes to detect Sec were designed and synthesized. Both A4 and B4 display fast turn-on response, high selectivity and sensitivity toward Sec, which can be applied for fluorescence imaging of Sec in living cells. Compared with B4, A4 has a larger Stokes shift (125 nm), wider pH range (5-10) and lower detection limit (65.4 nM) due to its ESIPT (excited state intramolecular proton transfer) effect. In view of the detection performance of these two probes, they can be used as effective tools for detecting Sec in biological systems.

ß-Elemene derivatives produced from SeO2-mediated oxidation reaction.

Herein, we report the first access of ß-elemene derivatives through the SeO2-mediated oxidation reaction. Several new compounds were isolated through such a one-step reaction, and their structures were elucidated using various 2D-NMR techniques. This method provides easy access to multiple oxidative ß-elemene derivatives in one single step and represents the first modifications on cyclohexyl ring of ß-elemene. It is expected to open up the opportunity for future derivatization on cyclohexyl ring of ß-elemene. The new compounds obtained above showed better anti-proliferation activities than ß-elemene itself on several cancer cell lines. Among them, compound 17 shows the best activity in antiproliferation assays of A549 and U-87MG cell lines.

4-Hydroxy-3-methylbenzofuran-2-carbohydrazones as novel LSD1 inhibitors.

Histone lysine specific demethylase 1 (LSD1 or KDM1A) is a potential therapeutic target in oncology due to its overexpression in various human tumors. We report herein a new class of benzofuran acylhydrazones as potent LSD1 inhibitors. Among the 31 compounds prepared, 14 compounds exhibited excellent LSD1 inhibitory activity with IC50 values ranging from 7.2 to 68.8 nM. In cellular assays, several compounds inhibited the proliferations of various cancer cell lines, including PC-3, MCG-803, U87 MG, PANC-1, HT-29 and MCF-7. This opens up the opportunity for further optimization and investigation of this class compounds for potential cancer treatment.

Novel Selective Histone Deacetylase 6 (HDAC6) Inhibitors: A Patent Review (2016-2019).

BACKGROUND: Many human diseases are associated with dysregulation of HDACs. HDAC6 exhibits deacetylase activity not only to histone protein but also to non-histone proteins such as α- tubulin, HSP90, cortactin, and peroxiredoxin. These unique functions of HDAC6 have gained significant attention in the medicinal chemistry community in recent years. Thus a great deal of effort has devoted to developing selective HDAC6 inhibitors for therapy with the hope to minimize the side effects caused by pan-HDAC inhibition. OBJECTIVE: The review intends to analyze the structural feature of the scaffolds, to provide useful information for those who are interested in this field, as well as to spark the future design of the new inhibitors. METHODS: The primary tool used for patent searching is SciFinder. All patents are retrieved from the following websites: the World Intellectual Property Organization (WIPO®), the United States Patent Trademark Office (USPTO®), Espacenet®, and Google Patents. The years of patents covered in this review are between 2016 and 2019. RESULTS: Thirty-six patents from seventeen companies/academic institutes were classified into three categories based on the structure of ZBG: hydroxamic acid, 1,3,4-oxadiazole, and 1,2,4-oxadiazole. ZBG connects to the cap group through a linker. The cap group can tolerate different functional groups, including amide, urea, sulfonamide, sulfamide, etc. The cap group appears to modulate the selectivity of HDAC6 over other HDAC subtypes. CONCLUSION: Selectively targeting HDAC6 over other subtypes represents two fold advantages: it maximizes the pharmacological effects and minimizes the side effects seen in pan-HDAC inhibitors. Many small molecule selective HDAC6 inhibitors have advanced to clinical studies in recent years. We anticipate the approval of selective HDAC6 inhibitors as therapeutic agents in the near future.

Identification and characterization of the first cytokinin glycosyltransferase from rice.

BACKGROUND: Cytokinins are one of the five major hormones families in plants and are important for their normal growth and environmental adaptability. In plants, cytokinins are mostly present as glycosides in plants, and their glycosylation modifications are catalyzed by family 1 glycosyltransferases. Current research on cytokinin glycosylation has focused on the biochemical identification of enzymes and the analysis of metabolites in Arabidopsis. There are few studies that examine how cytokinin glycosylation affects its synthesis and accumulation in plants. It is particularly important to understand these processes in food crops such as rice (Oryza sativa); however, to date, cytokinin glycosyltransferase genes in rice have not been reported. RESULTS: In this study, we identified eight rice genes that were functionally homologous to an Arabidopsis cytokinin glycosyltransferase gene. These genes were cloned and expressed in a prokaryotic system to obtain their purified proteins. Through enzymatic analysis and liquid chromatography-mass spectrometry, a single rice glycosyltransferase, Os6, was identified that glycosylated cytokinin in vitro. Os6 was overexpressed in Arabidopsis, and the extraction of cytokinin glycosides showed that Os6 is functionally active in planta. CONCLUSIONS: The identification and characterization of the first cytokinin glycosyltransferase from rice is important for future studies on the cytokinin metabolic pathway in rice. An improved understanding of rice cytokinin glycosyltransferases may facilitate genetic improvements in rice quality.

Selective Tyk2 inhibitors as potential therapeutic agents: a patent review (2015-2018).

INTRODUCTION: Tyrosine kinase 2 (Tyk2) is a non-receptor tyrosine-protein kinase, an enzyme that in humans is encoded by the TYK2 gene. Tyk2, together with three other family subtypes, namely, Jak1, Jak2, and Jak3, belong to the JAK family. Before 2014, far more publications and patents appeared in public domain attributing to the development of selective Jak2 and Jak3 inhibitors than those for selective Tyk2 and Jak1 inhibitors. AREAS COVERED: This review sought to give an overview of patents related to small molecule selective Tyk2 inhibitors published from 2015 to 2018. The article also covers clinical activities of small molecule selective Tyk2 inhibitors in recent years. EXPERT OPINION: As a key component of the JAK-STAT signaling pathway, Tyk2 regulates INFα, IL12, and IL23. Selective inhibition of Tyk2 can provide pharmacological benefits in the treatment of many diseases such as psoriasis, systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), rheumatoid arthritis (RA), cancer, and diabetes. The selectivity against other Jak family subtypes (such as Jak2) is crucial in order to minimize the potential side effects and to maximize the desired pharmacological effects. In this context, this review of recent selective Tyk2 inhibitor patents may prove valid, interesting, and promising within the therapeutic paradigm.

Diversity-Oriented Synthesis of Natural-Product-like Libraries Containing a 3-Methylbenzofuran Moiety for the Discovery of New Chemical Elicitors.

Natural products are a major source of biological molecules. The 3-methylfuran scaffold is found in a variety of plant secondary metabolite chemical elicitors that confer host-plant resistance against insect pests. Herein, the diversity-oriented synthesis of a natural-product-like library is reported, in which the 3-methylfuran core is fused in an angular attachment to six common natural product scaffolds-coumarin, chalcone, flavone, flavonol, isoflavone and isoquinolinone. The structural diversity of this library is assessed computationally using cheminformatic analysis. Phenotypic high-throughput screening of ß-glucuronidase activity uncovers several hits. Further in vivo screening confirms that these hits can induce resistance in rice to nymphs of the brown planthopper Nilaparvata lugens. This work validates the combination of diversity-oriented synthesis and high-throughput screening of ß-glucuronidase activity as a strategy for discovering new chemical elicitors.

Finding new elicitors that induce resistance in rice to the white-backed planthopper Sogatella furcifera.

Herein we report a new way to identify chemical elicitors that induce resistance in rice to herbivores. Using this method, by quantifying the induction of chemicals for GUS activity in a specific screening system that we established previously, 5 candidate elicitors were selected from the 29 designed and synthesized phenoxyalkanoic acid derivatives. Bioassays confirmed that these candidate elicitors could induce plant defense and then repel feeding of white-backed planthopper Sogatella furcifera.

3-(2,5-Di-methyl-phen-yl)-8-meth-oxy-2-oxo-1-aza-spiro-[4.5]dec-3-en-4-yl 3-(2-bromo-4-fluoro-phen-yl)acrylate.

In the title compound, C27H27BrFNO4, which is an inhibitor of acetyl-CoA carboxyl-ase, the cyclo-hexane ring displays a chair comformation with the spiro-C and meth-oxy-bearing C atoms deviating by 0.681 (7) and -0.655 (1) Å, resppectively, from the mean plane formed by the other four C atoms of the spiro-C6 ring. The mean planes of the cyclo-hexane and 2-bromo-4-fluoro-phenyl rings are nearly perpendicular to that of the pyrrolidine ring, making dihedral angles 89.75 (6) and 87.60 (9)°, respectively. In the crystal, mol-ecules are linked via pairs of N-H⋯O hydrogen bonds, forming inversion dimers.

(1'S,4'S)-5-(2,5-Dimethyl-phen-yl)-4'-meth-oxy-6-oxa-3-aza-spiro-[bicyclo-[3.1.0]hexane-2,1'-cyclo-hexa-n]-4-one.

In the title compound, C18H23NO3, the cyclo-hexane ring has a chair conformation. The oxirane plane (OCC) makes a dihedral angle of 76.15 (13)° with that of the pyrrolidine ring to which it is fused. The mean plane of the cyclo-hexane ring and the benzene ring are almost normal to the pyrrolidine ring, with dihedral angles of 88.47 (8) and 77.85 (8)°, respectively. In the crystal, mol-ecules are linked via pairs of N-H⋯O hydrogen bonds, forming inversion dimers. These dimers are linked via pairs of C-H⋯O hydrogen bonds, forming chains along the a-axis direction.