Mixed small cell neuroendocrine carcinoma and squamous cell carcinoma covered by tubulovillous adenoma in the rectum: a case report and detailed molecular analyses.

BACKGROUND: Previously, only six cases of mixed neuroendocrine-non-neuroendocrine neoplasm (MiNENs) with squamous cell carcinoma (SCC) component have been described in the colorectum, and the molecular landscape of MiNENs is also poorly understood. Herein, we present a unique case in which the SCC developed as a component of a MiNEN in the rectum. CASE PRESENTATION: The patient was firstly diagnosed as rectal small cell neuroendocrine carcinoma (SCNEC) covered by tubulovillous adenoma, and then mixed SCNEC and SCC in the same site 6 months later. Representative samples from the three histologic subtypes were then sent for next-generation sequencing (NGS) separately. Multiple liver metastases occurred in the following month after the last surgery. The patient died of ketoacidosis 1 year after initial diagnosis of the tumor. CONCLUSION: This is the first report of this exceedingly rare tumor type to include NGS of the 3 separate morphological entities. Our findings may expedite the understanding of combined tumors in the colorectum.

Anti-influenza virus activity of the REV-ERBα agonist SR9009 and related analogues.

REV-ERBα is a member of the nuclear receptor superfamily of transcription factors that aids in the regulation of many diseases. However, the prospect of using REV-ERBα for anti-influenza virus treatment remains poorly described, and there is an urgent need to develop effective anti-influenza agents due to the emergence of drug-resistant influenza viruses. In this study, eight SR9009 analogues were designed, synthesized, and evaluated for their biological activities against multiple influenza virus strains (H1N1, H3N2, adamantane- and oseltamivir-resistant H1N1 and influenza B virus), using ribavirin as the positive control. SR9009 and its analogues showed low micromolar or submicromolar EC50 values and exhibited modestly improved antiviral potency compared to that of ribavirin. In particular, compound 5a possessed the most potent inhibitory activity (EC50 = 0.471, 0.644, 1.644, 0.712 and 0.661 µM for A/PR/8/34, A/WSN/33, A/Wisconsin/67/2005, B/Yamagata/16/88 and Hebei/SWL1/2006, respectively). Cotransfection assays showed that all synthesized derivatives efficaciously suppressed transcription driven by the Bmal1 promoter. Mechanistic study results indicated that 5a efficiently inhibited IAV replication and interfered with the ealry stage of influenza virus life cycle. In addition, we found that 5a upregulated the key antiviral interferon-stimulated genes MxA, OAS2 and CH25H. Further in-depth transcriptome analysis revealed a series of upregulated genes that may contribute to the antiviral activities of 5a. These findings may provide an important direction for the development of new host-targeted broad-spectrum antiviral agents.

Copper-Promoted One-Pot Sandmeyer-Type Reaction for the Synthesis of N-Aryltriazoles.

Herein, we report the copper-catalyzed one-pot Sandmeyer-type reaction of aromatic amines with triazoles to afford N-aryl-1,2,3-triazoles. Diazonium salts, formed from aromatic amines and tert-butyl nitrite in the presence of fluoroboric acid, reacted with triazoles in a copper-catalyzed Sandmeyer-type reaction. The reaction proceeded under mild conditions to afford N-aryltriazoles in moderate to good yields. This method is amenable to a wide range of aromatic amines and triazoles and shows diverse functional group tolerance. Inhibition of the reaction upon the addition of free radical scavengers suggested a radical pathway, in which the aryl radical, copper, and triazole formed a complex that underwent reductive elimination to give aryltriazole compounds; this is consistent with the mechanism underlying the Sandmeyer reaction. Thus, we demonstrate a new effective strategy for the construction of C-N bonds via Sandmeyer-type reactions and a valuable alternative approach for the synthesis of aryltriazole derivatives.

Small-molecule probes for fluorescent detection of cellular hypoxia-related nitroreductase.

Nitroreductase is a reductase that catalyzes nitro aromatic compounds to aromatic amines. It effectively reduces nitro to hydroxylamine or amino when in the presence of nicotinamide adenine dinucleotide or nicotinamide adenine dinucleotide phosphate. In terms of tumor, nitroreductase is upregulated in hypoxic tumor cells, and its content is directly related to the degree of hypoxia. Therefore, effective detection of nitroreductase is important not only for the study of cellular hypoxia, but also for the diagnosis and treatment of tumors and related diseases. In this review, we summarized the latest advances in small-molecule fluorescent probes for nitroreductase detection based on different fluorescence mechanisms, with a focus on research conducted between May 2018 and December 2020. The development trends and application prospect in this rapidly developing field were also highlighted.

Synthesis of vinyl-1,2,3-triazole derivatives under transition metal-free conditions.

Herein, we describe a novel and green route for the direct synthesis of vinyl triazole derivatives with alkynes and triazoles promoted by an inorganic base under transition metal-free conditions. The base shows great catalytic activity for the anti-Markovnikov stereoselective hydroamination of alkynes. Moreover, good yields with excellent functional group tolerance are successfully achieved for a range of substrates, including aryl and heteroaryl groups, terminal alkynes and internal alkynes, and various triazole derivatives. This work presents an advanced concept for the synthesis of alkenyl triazole with a versatile and cost-efficient approach.

Synthesis of novel tryptanthrin derivatives as dual inhibitors of indoleamine 2,3-dioxygenase 1 and tryptophan 2,3-dioxygenase.

Indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO) are promising drug development targets due to their implications in pathologies such as cancer and neurodegenerative diseases. The search for IDO1 inhibitor has been intensely pursued but there is a paucity of potent TDO and IDO1/TDO dual inhibitors. Natural product tryptanthrin has been confirmed to bear IDO1 and/or TDO inhibitory activities. Herein, twelve novel tryptanthrin derivatives were synthesized and evaluated for the IDO1 and TDO inhibitory potency. All of the compounds were found to be IDO1/TDO dual inhibitors, in particular, compound 9a and 9b bore IDO1 inhibitory activity similar to that of INCB024360, and compound 5a and 9b had remarkable TDO inhibitory activity superior to that of the well-known TDO inhibitor LM10. This work enriches the collection of IDO1/TDO dual inhibitors and provides chemical molecules for potential development into drugs.

Regulation of aggregation behavior and neurotoxicity of prion neuropeptides by platinum complexes.

Prion diseases belong to a group of infectious, fatal neurodegenerative disorders. The conformational conversion of a cellular prion protein (PrP(C)) into an abnormal misfolded isoform (PrP(Sc)) is the key event in prion disease pathology. PrP106-126 resembles PrP(Sc) in some physicochemical and biological characteristics, such as apoptosis induction in neurons, fibrillar formation, and mediation of the conversion of native cellular PrP(C) to PrP(Sc). Numerous studies have been conducted to explore the inhibiting methods on the aggregation and neurotoxicity of prion neuropeptide PrP106-126. We showed that PrP106-126 aggregation, as assessed by fluorescence assay and atomic force microscopy, is inhibited by platinum complexes cisplatin, carboplatin, and Pt(bpy)Cl2. ESI-MS and NMR assessments of PrP106-126 and its mutant peptides demonstrate that platinum complexes bind to the peptides in coordination and nonbonded interactions, which rely on the ligand properties and the peptide sequence. In peptides, methionine residue is preferred as a potent binding site over histidine residue for the studied platinum complexes, implying a typical thiophile characteristic of platinum. The neurotoxicity induced by PrP106-126 is better inhibited by Pt(bpy)Cl2 and cisplatin. Furthermore, the ligand configuration contributes to both the binding affinity and the inhibition of peptide aggregation. The pursuit of novel platinum candidates that selectively target prion neuropeptide is noteworthy for medicinal inorganic chemistry and chemical biology.

Inhibition of human prion neuropeptide PrP106-126 aggregation by hexacoordinated ruthenium complexes.

Prion disease is a neurodegenerative disorder that can occur among humans and other animals. The aberrant isoform of prion protein PrP(Sc) has been identified as the infectious agent. The neuropeptide PrP106-126 has been widely used as a suitable model to study the biological and physiochemical properties of PrP(Sc). PrP106-126 shares several physicochemical and biological properties with PrP(Sc), including cellular toxicity, fibrillogenesis, and membrane-binding affinity. Ruthenium complexes are commonly employed in anti-cancer studies due to their low cellular toxicity. In this study, six hexacoordinated ruthenium complexes with different molecular configurations were used to investigate their effects on PrP106-126 aggregation inhibition. Results revealed that the interaction between the complexes and the peptide included metal coordination and hydrophobic interaction mainly. Those complexes with aromatic structure displayed better inhibitory effects, although they only had a common binding affinity to PrP106-126. This study provided better understanding on the interaction of metal complexes with PrP106-126 and paved the way for potential Ru-based metallodrugs against prion diseases.