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Electrospinning technology enables the fabrication of electrospun nanofibers with exceptional properties, which are highly influenced by their diameter. This work focuses on the electrospinning of polyacrylonitrile (PAN) to obtain PAN nanofibers under different processing conditions. The morphology and size of the resulting PAN nanofibers were characterized using scanning electron microscopy (SEM), and the corresponding diameter data were measured using Nano Measure 1.2 software. The processing conditions and corresponding nanofiber diameter data were then inputted into an artificial neural network (ANN) to establish the relationship between the electrospinning process parameters (polymer concentration, applied voltage, collecting distance, and solution flow rate), and the diameter of PAN nanofibers. The results indicate that the polymer concentration has the greatest influence on the diameter of PAN nanofibers. The developed neural network prediction model provides guidance for the preparation of PAN nanofibers with specific dimensions. [ABSTRACT FROM AUTHOR]

[Display omitted] Boron-containing compounds which possess unique and attractive properties have recently received increasing attention in organic, material and medicinal chemistry. Specifically, they have displayed interesting and useful biological activities, which promoted a great deal of interest in their synthetic approaches. This digest covers the recent developments of synthetic methods towards bioactive boron-containing compounds, with selected examples including peptidyl boronates/boronic acids, benzoxaboroles, benzoxaborines, benzodiazaborines, amine cyanoboranes and amine carboxyboranes. [ABSTRACT FROM AUTHOR]

Synthetic hemoprotein model compounds are of great interest due to the vital roles and complexities of hemoproteins. This study reports a novel, self-assembled hemoprotein model, hemodextrin. The synthesis and characterization of py-PPCD (2A-monopyridylmethyl-perPEGylated-β-cyclodextrin) (2) is described. The molecular design is based on a pegylated cyclodextrin scaffold that bears both a heme-binding pocket and an axial ligand that binds an iron porphyrin. The binding constant for Fe(III)TPPS [iron(III) meso-tetra(4-sulphonatophenyl)porphyrin] by py-PPCD (2) was determined to be 2×106 M-1 at pH 6.0 by observing characteristic changes in the UV–Vis spectrum of the porphyrin. The pyridyl nitrogen of py-PPCD (2) was shown to ligate to the iron center by observing signal changes in the Fe(II)-porphyrin 1H-NMR spectrum. This hemodextrin ensemble was shown to bind dioxygen reversibly and to form a stable ferryl species. [Copyright &y& Elsevier]

Cdc42 is a member of the Rho family of small GTPases that are at the crossroads of major oncogenic signaling pathways involved in both lung and prostate cancers. However, the therapeutic potential of Cdc42 regulation is still unclear due to the lack of pharmacological tools. Herein, we report that ZCL367 is a bona fide Cdc42 inhibitor that suppressed cancer development and ZCL278 can act as a partial Cdc42 agonist. In lung cancer cell lines with varying EGFR and Ras mutations as well as both androgen-independent and androgen-dependent prostate cancer cell lines, ZCL367 impeded cell cycle progression, reduced proliferation, and suppressed migration. ZCL367 decreased Cdc42–intersectin interactions and reduced Cdc42-mediated filopodia formation. ZCL367 showed increased potency and selectivity for Cdc42 when compared to Rac1 and RhoA. ZCL367 reduced A549 tumorigenesis in a xenograft mouse model. Altogether, ZCL367 is a selective Cdc42 inhibitor and an excellent candidate for lead compound optimization for further anticancer studies. [ABSTRACT FROM AUTHOR]

Ubiquitylation and deubiquitylation are reversible protein post-translational modification (PTM) processes involving the regulation of protein degradation under physiological conditions. Loss of balance in this regulatory system can lead to a wide range of diseases, such as cancer and inflammation. As the main members of the deubiquitinases (DUBs) family, ubiquitin-specific peptidases (USPs) are closely related to biological processes through a variety of molecular signaling pathways, including DNA damage repair, p53 and transforming growth factor-β (TGF-β) pathways. Over the past decade, increasing attention has been drawn to USPs as potential targets for the development of therapeutics across diverse therapeutic areas. In this review, we summarize the crucial roles of USPs in different signaling pathways and focus on advances in the development of USP inhibitors, as well as the methods of screening and identifying USP inhibitors. [ABSTRACT FROM AUTHOR]

The dynamic modification of proteins with ubiquitin plays crucial roles in major celluar functions, and is associated with a number of pathological conditions. Ubiquitin-specific proteases (USPs) cleave ubiquitin from substrate proteins, and rescue them from proteasomal degradation. Among them, USP2 is overexpressed and plays important roles in various cancers including prostate cancer. Thus, it represents an attractive target for drug discovery. In order to develop potent and selective USP2 inhibitors, a highly reliable assay is needed for in-depth structure-activity relationship study. We report the cloning, expression, and purification of USP2 and UBA52, and the development of a highly reliable assay based on readily available SDS-PAGE-Coomassie systeme using UBA52 as the substrate protein. A number of effective USP2 inhibitors were also identified using this assay. [ABSTRACT FROM AUTHOR]

In this study, we report the synthesis of a series of chalcone–benzoxaborole hybrid molecules and the evaluation of their anticancer activity. Their anticancer potency and toxicity were tested on three human cancer cell lines and two normal cell lines. The 4-fluoro compound 15 was found to be the most potent compound with an IC 50 value of 1.4 μM on SKOV3 cells. The 4-iodo compound 18 and 3-methyloxy-4-amino compound 47 showed good potency on SKOV3 cells while exhibiting low toxicity on normal cells. This work extended the application of benzoxaboroles to the field of anticancer research. [ABSTRACT FROM AUTHOR]

The small ubiquitin-related modifier (SUMO)-specific proteases (SENPs) catalyze the deconjugation of SUMO from their substrate proteins. SENP1 which is the most studied isoform is closely related to many cancers such as prostate cancer and colon cancer, thus representing a potential therapeutic target for cancer treatment. In the present study, we identified eleven SENP1 inhibitors representing a variety of scaffolds through in silico screening. Based on these scaffolds, a series of new compounds were designed and synthesized in order to improve their SENP1 inhibitory potency. As a result, compounds with IC 50 as low as 3.5 μM (compound 13m ) were obtained and a preliminary structure-activity relationship was discussed. [ABSTRACT FROM AUTHOR]

SUMOylation, as a post-translational modification of proteins, plays essential regulatory roles in a variety of pathological conditions. In the dynamic process of SUMOylation and deSUMOylation, SENPs (SUMO-specific proteases), in charge of deconjugation of SUMO (small ubiquitin-related modifier) from substrate proteins, have recently been found to be potential therapeutic targets for cancer treatment. A reliable and practical assay is much needed to accelerate the discovery of SENPs inhibitors. We established a quantitative assay based on readily available SDS–PAGE-Coomassie system using RanGAP-SUMO as the substrate, thus avoiding the use of expensive fluorescent dyes or the error-prone fluorescent reporter. Its reproducibility and reliability were also evaluated in this report. [ABSTRACT FROM AUTHOR]

Abstract: Human African trypanosomiasis is a fatal parasitic infection caused by the protozoan Trypanosoma brucei. The development of novel antitrypanosomal agents is urgently needed. Here we report the synthesis and structure–activity relationship of a new class of benzoxaboroles as antitrypanosomal agents. These compounds showed antiparasitic IC50 values ranging from 4.02 to 0.03 μg/mL and satisfactory cytotoxicity profile. Three of the lead compounds were demonstrated to cure the parasitic infection in a murine acute infection model. The structure–activity relationship of the pyrrolobenzoxaboroles are also discussed. [Copyright &y& Elsevier]

Despite the rapid progress in the diagnosis and treatment, the prognosis of some types of non-Hodgkin's lymphoma (NHL), especially those with double-hit or double-expressor genotypes, remains poor. Novel targets and compounds are needed to improve the prognosis of NHL. We investigated the effect of ZCL-082, a novel boron-containing compound with anti-proliferating activity against ovarian cancer cells, on NHL cells and human peripheral blood mononuclear cells by CCK-8 assay, Annexin V/PI double staining assay, RH123/PI double staining, Western blot, and immunohistochemistry. NF-κB pathway activity was analyzed using luciferase reporter gene assay and RT-PCR. The location of p65 was detected by immunofluorescence and nuclear/cytoplasmic fractionation assay. Immunoprecipitation and chromatin immunoprecipitation assays were used to detect the binding between p65 and p300. CETSA and molecular docking assay were carried out to test the interaction between ZCL-082 and p90 ribosomal S6 kinase 1 (RSK1). Kinase reaction was conducted to examine the inhibition of RSK1 kinase activity by ZCL-082. We found that ZCL-082 can induce the apoptosis of various NHL cell lines in vitro and in vivo. ZCL-082 significantly inhibits TNFα- or LPS-induced NF-κB activation without disturbing TNFα-induced IκBα degradation or the nuclear translocation and DNA-binding ability of p65. However, ZCL-082 markedly suppresses the phosphorylation of p65 on Ser536 and the interaction between p65 and p300. The overexpression of the phosphomimetic mutant of p65 at Ser536 partially abrogates ZCL-082-induced cell death. We further found that ZCL-082 directly binds to and inhibits the activity of RSK1. RSK1 can phosphorylate RelA/p65 on Ser536 and its overexpression is associated with the poor prognosis of lymphoma. The overexpression of RSK1 partially rescues ZCL-082-induced cell death. Molecular docking studies show that ZCL-082 fits well with the N-terminal kinase domain of RSK1. Furthermore, the combination of ZCL-082 and BCL-2 inhibitor ABT-199 has a synergistic apoptosis-inducing effect against double-hit lymphoma cell line OCI-Ly10. We found that ZCL-082 is a highly promising anti-lymphoma compound that targets RSK1 and interferes with the RSK1/NF-κB signaling pathway. The combination of ZCL-082 with BCL-2 inhibitor may represent a novel strategy to improve the outcome of double-hit or double-expressor lymphoma. • Boron-containing compound ZCL-082 is a novel RSK1 inhibitor with anti-lymphoma activity in vitro and in vivo. • RSK1 is a novel target of lymphoma. • Combined ZCL-082 with BCl-2 inhibitor has a synergistic apoptosis-inducing effect against double-hit lymphoma. [ABSTRACT FROM AUTHOR]

Abstract: Among the regulation mechanisms of cellular function, allosteric regulation is the most direct, rapid and efficient. Due to the wider receptor selectivity and lower target-based toxicity, compared with orthosteric ligands, allosteric modulators are expected to play a larger role in pharmaceutical research and development. However, current difficulties, such as a low affinity and unknown structural features of potential allosteric small-molecules, usually obstruct the discovery of allosteric modulators. In this study, we compared known allosteric modulators with various compounds from different databases to unveil the structural and qualitative characteristics of allosteric modulators. The results show that allosteric modulators generally contain more hydrophobic scaffolds and have a higher structural rigidity, i.e., less rotatable bonds and more rings. Based on this analysis, an empirical rule was defined to determine the structural requirements for an allosteric modulator. It was found that a large proportion of allosteric modulators (80%) can be successfully retrieved by this “allosteric-like” filter, which shows good discriminatory power in identifying allosteric modulators. Therefore, the study provides deeper insight into the chemical properties of allosteric modulators and has a good potential for the design or optimization of allosteric compounds. [Copyright &y& Elsevier]

We report the novel chalcone–benzoxaborole hybrids and their structure–activity relationship against Trypanosoma brucei parasites. The 4-NH2 derivative 29 and 3-OMe derivative 43 were found to have excellent potency. The synergistic 4-NH2-3-OMe compound 49 showed an IC50 of 0.010 μg/mL and resulted in 100% survival and zero parasitemia in a murine infection model, which represents one of the most potent compounds discovered to date from the benzoxaborole class that inhibit T. brucei growth. [ABSTRACT FROM AUTHOR]

Abstract: Human African trypanosomiasis (HAT), caused by the protozoan parasite Trypanosoma brucei, is a neglected fatal disease. Leucyl-tRNA synthetase (LeuRS), which has been successfully applied in the development of antifungal agent, represents a potential antiprotozoal drug target. In this study, a 3D model of T. brucei LeuRS (TbLeuRS) synthetic active site was constructed and subjected to virtual screening using a combination of pharmacophore- and docking-based methods. A new 2-pyrrolinone scaffold was discovered and the structure–activity relationship (SAR) studies aided by the docking model and organic synthesis were carried out. Compounds with various substituents on R1, R2 and R3 were synthesized and their SAR was discussed. [Copyright &y& Elsevier]

Abstract: A series of new boron-containing benzoxaborole compounds was designed and synthesized for a continuing structure–activity relationship (SAR) investigation to assess the antimalarial activity changes derived from side-chain structural variation, substituent modification on the benzene ring and removal of boron from five-membered oxaborole ring. This SAR study demonstrated that boron is required for the antimalarial activity, and discovered that three fluoro-substituted 7-(2-carboxyethyl)-1,3-dihydro-1-hydroxy-2,1-benzoxaboroles (9, 14 and 20) have excellent potencies (IC50 0.026–0.209μM) against Plasmodium falciparum. [Copyright &y& Elsevier]

Abstract: As the best-characterized ubiquitin-like protein (UBL), small ubiquitin-related modifier (SUMO) was found to conjugate with a number of proteins to regulate cellular functions including transcription, signal transduction, and cell cycle. While E1, E2 and E3 ligases are responsible for the forward SUMOylation reaction, SUMO-specific proteases (SENPs) reversibly remove SUMO from the SUMOylated proteins. Recently, SENP1 was found to be a potential therapeutic target for the treatment of prostate cancers, but the design and synthesis of its inhibitors have not been reported. We designed and synthesized a series of benzodiazepine-based SENP1 inhibitors, and they showed inhibitory activity as good as IC50 =9.2μM (compound 38). The structure–activity relationship was also discussed. [Copyright &y& Elsevier]

Abstract: Despite of the medicinal significance of benzoxaboroles, with the newly discovered clinical compound AN2690 as an example, the synthetic method for rapid diversification of this novel scaffold is lacking. To this end, a versatile and scalable synthesis of formyl-substituted benzoxaboroles is described here. A key step is the mono-oxidation of the two hydroxyls in compound 4 by taking advantage of the stable oxaborole ring in non-coordinating solvents, which was devised based on the study of the intramolecular coordination and exchange properties. [Copyright &y& Elsevier]

Abstract: A series of phenoxy benzoxaboroles were synthesized and screened for their inhibitory activity against PDE4 and cytokine release. 5-(4-Cyanophenoxy)-2,3-dihydro-1-hydroxy-2,1-benzoxaborole (AN2728) showed potent activity both in vitro and in vivo. This compound is now in clinical development for the topical treatment of psoriasis and being pursued for the topical treatment of atopic dermatitis. [Copyright &y& Elsevier]

The protozoan parasite Trypanosoma brucei (T. brucei) causes human African trypanosomiasis (HAT), which is a fatal and neglected disease in the tropic areas, and new treatments are urgently needed. Leucyl-tRNA synthetase (LeuRS) is an attractive target for the development of antimicrobial agents. In this work, starting from the hit compound thiourea ZCL539, we designed and synthesized a series of amides as effective T. brucei LeuRS (Tb LeuRS) synthetic site inhibitors. The most potent compounds 74 and 91 showed IC 50 of 0.24 and 0.25 μM, which were about 700-fold more potent than the starting hit compound. The structure-activity relationship was also discussed. These compounds provided a new scaffold and lead compounds for further development of antitrypanosomal agents. [Display omitted] • A new scaffold as Trypanosome brucei LeuRS inhibitor was discovered. • A series of new Tb LeuRS inhibitors was synthesized and structure activity relationship was discussed. • The best compounds afforded about 700-fold improvement from the initial hit compound. [ABSTRACT FROM AUTHOR]

• C28 can inhibit the proliferation and reduce cell viability of FGSCs in vitro by autophagy. • The changes of histone H3K27 acetylation involves in C28 induced FGSCs autophagy. • C28 induced autophagy of FGSCs by possibly activating endoplasmic reticulum stress. There are a few studies indicating that small molecular compounds affect the proliferation, differentiation, apoptosis, and autophagy of female germline stem cells (FGSCs). However, whether small molecular compound 28 (C28) affect development of FGSCs remains unknown. In this study, we found that C28 reduced the viability and proliferation of FGSCs, respectively. Additionally, western blotting showed that the expression of autophagy marker light chain 3 beta II (LC3B-II) was significantly increased and expression of sequestosome-1 (SQSTM1) was significantly reduced in C28-treated groups. Immunofluorescence showed that, in C28-treated groups, the number of LC3B-II-positive puncta was increased significantly. These results indicated that C28 induced autophagy of FGSCs in vitro. Furthermore, data from Chromatin Immunoprecipitation Sequencing for H3K27ac showed that autophagy-related biological processes such as regulation of mitochondrial membrane potential, Golgi vesicle transport, and cellular response to reactive oxygen species were different after C28-treated. In addition, RNA-Seq showed that the expression of genes (Trib3 , DDIT3 , and ATF4) related to endoplasmic reticulum (ER) stress was enhanced by C28. These results suggest that the changes of H3K27ac and ER stress might be associated with C28-induced FGSC autophagy. [ABSTRACT FROM AUTHOR]

• Starting from initial hit compound 1 , a series of benzhydrol-oxaborole hybrid compounds were designed and synthesized as inhibitors of S. pneumoniae LeuRS. • Structure-based optimization led to the discovery of compound 46 and 54 , which showed improved potency (IC 50 = 0.368 and 0.950 μM) when compared with parent compound 1. • The co-crystal of compound 54 in the editing domain pocket of Sp LeuRS was obtained and revealed the binding mode of compound 54. Pneumonia caused by bacterium S. pneumoniae is a severe acute respiratory infectious disease with high morbidity and mortality, especially for children and immunity-compromised patients. The emergence of multidrug-resistant S. pneumoniae also presents a challenge to human health. Leucyl-tRNA synthetase (LeuRS) catalyzes the attachment of l -leucine to tRNALeu, which plays an essential role in protein translation and is considered an attractive antimicrobial drug target. In the present work, benzhydrol-oxaborole hybrid compounds were designed and synthesized as inhibitors of S. pneumoniae LeuRS. Exploration of the phenyl ring near Lysine 389 eventually yielded compounds 46 and 54 with submicromolar inhibitory potency. The co-crystal of compound 54 in the editing domain pocket of Sp LeuRS was obtained and confirmed the formation of an additional hydrogen bond between the carbonyl of 54 and Lysine 389. It also showed anti-pneumococcal activity in vitro. The structure–activity relationship was discussed. This work will provide an essential foundation for the further development of anti-pneumococcal agents by targeting LeuRS. [ABSTRACT FROM AUTHOR]

The SUMO (small ubiquitin-related modifier)-specific proteases (SENPs) are responsible for the cleavage of SUMO from its target proteins, thus play important roles in the dynamic SUMOylation and deSUMOylation processes. SENPs are related to a variety of human diseases including cancer and represent a new class of potential therapeutic targets with mechanism of action that is likely to be different from that of current clinically used drugs. However, potent inhibitors that are selective within the SENPs family members still remain a challenge due to their high homology. In order to demonstrate the feasibility of developing selective inhibitors within the SENPs family, we chose SENP1/2/5 as representatives, aiming to identify inhibitors with selectivity among the members. Starting from a hit compound ZCL951 from virtual screening, a series of benzothiophene-2-carboxamide inhibitors were designed based on the protein structures of SENP1, 2, and 5. First, an unoccupied hydrophobic pocket was first identified which led to IC 50 as low as 0.56 μM. Furthermore, the ethylacetate 77 gave both submicromolar inhibitory activity and 33-fold selectivity for SENP2 versus SENP5. They are the most potent and selective nonpeptidic inhibitor reported so far for the SENPs family, as far as we are aware. Their structure-activity relationship was also discussed. Image 1 • Starting from ZCL951 , a series of benzothiophene-2-carboxamide SENPs inhibitors were designed. • An unoccupied hydrophobic pocket was first identified which led to IC 50 as low as 0.56 μM. • Compound 77 gave a 33-fold selectivity of SENP2 vs. SENP5. • These compounds represent the most potent and selective nonpeptidic inhibitors reported so far for the SENPs family. [ABSTRACT FROM AUTHOR]

Abstract: The synthesis and characterization of highly challenging 2,3,6-trideoxy sugar nucleotides were described for the first time. The study of their hydrolysis kinetics in aqueous buffers provided insight into their application as glycosyl donors. [Copyright &y& Elsevier]

Human African trypanosomiasis (HAT), caused by the parasitic protozoa Trypanosoma brucei , is one of the fatal diseases in tropical areas and current medicines are insufficient. Thus, development of new drugs for HAT is urgently needed. Leucyl-tRNA synthetase (LeuRS), a recently clinically validated antimicrobial target, is an attractive target for development of antitrypanosomal drugs. In this work, we report a series of α-phenoxy- N -sulfonylphenyl acetamides as T. brucei LeuRS inhibitors. The most potent compound 28g showed an IC 50 of 0.70 μM which was 250-fold more potent than the starting hit compound 1. The structure-activity relationship was also discussed. These acetamides provided a new scaffold and lead compounds for the further development of clinically useful antitrypanosomal agents. Image 1 • An α-phenoxy- N -sulfonylphenyl acetamide scaffold discovered to inhibit Tb LeuRS with good potency. • A series of new Tb LeuRS inhibitors synthesized and a structure-activity relationship discussed. • Compound 28g showed an IC 50 as low as 0.70 μM. [ABSTRACT FROM AUTHOR]

Postnatal female germline stem cells (FGSCs) are a type of germline stem cell with self-renewal ability and the capacity of differentiation toward oocyte. The proliferation, differentiation, and apoptosis of FGSCs have been researched in recent years, but autophagy in FGSCs has not been explored. This study investigated the effects of the small-molecule compound 89 (C89) on FGSCs and the underlying molecular mechanism in vitro. Cytometry, Cell Counting Kit-8 (CCK8), and 5-ethynyl-2'-deoxyuridine (EdU) assay showed that the number, viability, and proliferation of FGSCs were significantly reduced in C89-treated groups (0.5, 1, and 2 µM) compared with controls. C89 had no impact on FGSC apoptosis or differentiation. However, C89 treatment induced the expression of light chain 3 beta II (LC3BII) and reduced the expression of sequestosome-1 (SQSTM1) in FGSCs, indicating that C89 induced FGSC autophagy. To investigate the mechanism of C89-induced FGSC autophagy, RNA-seq technology was used to compare the transcriptome differences between C89-treated FGSCs and controls. Bioinformatics analysis of the sequencing data indicated a potential involvement of the phosphatidylinositol 3 kinase and kinase Akt (PI3K-Akt) pathway in the effects of C89′s induction of autophagy in FGSCs. Western blot confirmed that levels of p-PI3K and p-Akt were significantly reduced in the C89- or LY294002 (PI3K inhibitor)-treated groups compared with controls. Moreover, we found cooperative functions of C89 and LY294002 in inducing FGSC autophagy through suppressing the PI3K-Akt pathway. Taken together, this research demonstrates that C89 can reduce the number, viability, and proliferation of FGSCs by inducing autophagy. Furthermore, C89 induced FGSC autophagy by inhibiting the activity of PI3K and Akt. The PI3K-Akt pathway may be a target to regulate FGSC proliferation and death. [ABSTRACT FROM AUTHOR]

A wide variety of prokaryotes possess DNA modifications consisting of sequence-specific phosphorothioates (PT) inserted by members of a five-gene cluster. Recent genome mapping studies revealed two unusual features of PT modifications: short consensus sequences and partial modification of a specific genomic site in a population of bacteria. To better understand the mechanism of target selection of PT modifications that underlies these features, we characterized the substrate recognition of the PT-modifying enzymes termed DptC, D and E in a cell extract system from Salmonella. The results revealed that double-stranded oligodeoxynucleotides underwent de novo PT modification in vitro, with the same modification pattern as in vivo, i. e., GpsAAC/GpsTTC motif. Unexpectedly, in these in vitro analyses we observed no significant effect on PT modification by sequences flanking GAAC/GTTC motif, while PT also occurred in the GAAC/GTTC motif that could not be modified in vivo. Hemi-PT DNA also served as substrate of the PT-modifying enzymes, but not single-stranded DNA. The PT-modifying enzymes were then found to function as a large protein complex, with all of three subunits in tetrameric conformations. This study provided the first demonstration of in vitro DNA PT modification by PT-modifying enzymes that function as a large protein complex. [ABSTRACT FROM AUTHOR]