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31.
Lydia Saidi Dr. Djenisa H. A. Rocha Dr. Oualid Talhi Dr. Yamina Bentarzi Prof. Dr. Bellara Nedjar-Kolli Dr. Khaldoun Bachari Dr. Filipe A. Almeida Paz Dr. Luisa A. Helguero Prof. Dr. Artur M. S. Silva 《ChemMedChem》2019,14(10):1041-1048
Breast and prostate cancers are frequently treated with chemotherapy. Several novel chemicals are being reported for this purpose, particularly synthetic and natural benzophenones. This work reports the synthesis of substituted 2-hydroxybenzophenones through 1,4-conjugate addition/intramolecular cycloaddition/dehydration of nitromethane on key intermediate chromones. Structures were extensively studied by means of 2D NMR spectroscopy and single-crystal XRD. Their cytotoxicity was evaluated in vitro in two breast cancer cell lines (MDA-MB-231 and T47-D) and one prostate cancer cell line (PC3). The most potent compound exhibited good cytotoxic effects against the three cancer cell lines (IC50 values ranging from 12.09 to 26.49 μm ) and induced cell-cycle retardation only on prostate cancer cells, which suggested that it might exert cell-type-specific effects. 相似文献
32.
Dr. Maria L. Di Paolo Dr. Michael S. Christodoulou Dr. Alessandra M. Calogero Dr. Luca Pinzi Prof. Giulio Rastelli Prof. Daniele Passarella Prof. Graziella Cappelletti Prof. Lisa Dalla Via 《ChemMedChem》2019,14(18):1641-1652
A series of 2-phenyloxazoles bearing an amide group at position 4 were designed and synthesized for evaluation as potential inhibitors of human recombinant monoamine oxidases (hrMAOs). Results of kinetics experiments demonstrated that all compounds behave as competitive MAO inhibitors, with good selectivity toward the MAO-B isoform. The most potent and selective derivatives are characterized by inhibition constant (Ki) values in the sub-micromolar range and a good selectivity index (Ki MAO-A/Ki MAO-B>50). Some derivatives were also found to be able to inhibit MAO activity in nerve growth factor (NGF)-differentiated PC12 cells, taken as a model of neuronal cells. In particular, 2-(2-hydroxyphenyl)-N-phenyloxazole-4-carboxamide (compound 4 a ) may be a promising new scaffold, exerting the highest selectivity and inhibitory effect toward MAOs in NGF-differentiated PC12 cell lysates, without compromising cell viability. Molecular docking analysis allowed a rationalization of the experimentally observed binding affinity and selectivity. 相似文献
33.
Shibo Lv Yuyang Miao Dr. Dapeng Liu Prof. Fengling Song 《Chembiochem : a European journal of chemical biology》2020,21(15):2098-2110
Photothermal therapy (PTT) has attracted great attention due to its noninvasive and effective use against cancer. Various photothermal agents (PTAs) including organic and inorganic PTAs have been developed in the last decades. Organic PTAs based on small-molecule dyes exhibit great potential for future clinical applications considering their good biocompatibility and easy chemical modification or functionalization. In this review, we discuss the recent progress of organic PTAs based on small-molecule dyes for enhanced PTT. We summarize the strategies to improve the light penetration of PTAs, methods to enhance their photothermal conversion efficiency, how to optimize PTAs’ delivery into deep tumors, and how to resist photobleaching under repeated laser irradiation. We hope that this review can rouse the interest of researchers in the field of PTAs based on small-molecule dyes and help them to fabricate next-generation PTAs for noninvasive cancer therapy. 相似文献
34.
Dr. Iain J. W. McKean Prof. Paul A. Hoskisson Prof. Glenn A. Burley 《Chembiochem : a European journal of chemical biology》2020,21(20):2890-2897
This Concept article describes the latest developments in the emerging area of late-stage biocatalytic alkylation. Central to these developments is the ability to efficiently prepare S-adenosyl methionine (SAM) cofactor analogues and couple this with enzymatic alkyl transfer. Recent developments in the enzymatic synthesis of SAM cofactor analogues are summarized first, followed by their application as alkyl transfer agents catalyzed by methyltransferases (MTases). Second, innovative methods to regenerate SAM cofactors by enzymatic cascades is reported. Finally, future opportunities towards establishing a generalized platform for late-stage alkylation are described. 相似文献
35.
Dr. Lina Liang Tong-You Wade Wei Pei-Yu Wu Wouter Herrebout Ming-Daw Tsai Prof. Stéphane P. Vincent 《Chembiochem : a European journal of chemical biology》2020,21(20):2982-2990
d -Glycero-d -manno-heptose-1β,7-bisphosphate (HBP) and d -glycero-d -manno-heptose-1β-phosphate (H1P) are bacterial metabolites that were recently shown to stimulate inflammatory responses in host cells through the activation of the TIFA-dependent NF-κB pathway. To better understand structure-based activity in relation to this process, a family of nonhydrolyzable phosphonate analogues of HBP and H1P was synthesized. The inflammation modulation by which these molecules induce the TIFA-NF-κB signal axis was evaluated in vivo at a low-nanomolar concentration (6 nM) and compared to that of the natural metabolites. Our data showed that three phosphonate analogues had similar stimulatory activity to HBP, whereas two phosphonates antagonized HBP-induced TIFA-NF-κB signaling. These results open new horizons for the design of pro-inflammatory and innate immune modulators that could be used as vaccine adjuvant. 相似文献
36.
Activity-directed synthesis (ADS) is a structure-blind, functional-driven molecular discovery approach. In this Concept, four case studies highlight the general applicability of ADS and showcase its flexibility to support different medicinal chemistry strategies. ADS deliberately harnesses reactions with multiple possible outcomes, and allows many chemotypes to be evaluated in parallel. Resources are focused on bioactive molecules, which emerge in tandem with associated synthetic routes. Some of the future challenges for ADS are highlighted, including the realisation of an autonomous molecular discovery platform. The prospects for ADS to become a mainstream lead generation approach are discussed. 相似文献
37.
A Synthetic Transcriptional Activator of Genes Associated with the Retina in Human Dermal Fibroblasts
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38.
Dr. Blijke S. Kroezen Gabriele Conti Benedetta Girardi Dr. Jonathan Cramer Dr. Xiaohua Jiang Dr. Said Rabbani Jennifer Müller Maja Kokot Enrico Luisoni Prof. Daniel Ricklin Dr. Oliver Schwardt Prof. Beat Ernst 《ChemMedChem》2020,15(18):1706-1719
Siglecs are members of the immunoglobulin gene family containing sialic acid binding N-terminal domains. Among them, Siglec-8 is expressed on various cell types of the immune system such as eosinophils, mast cells and weakly on basophils. Cross-linking of Siglec-8 with monoclonal antibodies triggers apoptosis in eosinophils and inhibits degranulation of mast cells, making Siglec-8 a promising target for the treatment of eosinophil- and mast cell-associated diseases such as asthma. The tetrasaccharide 6’-sulfo-sialyl Lewisx has been identified as a specific Siglec-8 ligand in glycan array screening. Here, we describe an extended study enlightening the pharmacophores of 6’-sulfo-sialyl Lewisx and the successful development of a high-affinity mimetic. Retaining the neuraminic acid core, the introduction of a carbocyclic mimetic of the Gal moiety and a sulfonamide substituent in the 9-position gave a 20-fold improved binding affinity. Finally, the residence time, which usually is the Achilles tendon of carbohydrate/lectin interactions, could be improved. 相似文献
39.
Nidhi Nandu Mustafa Salih Hizir Neil M. Roberston Dr. Birol Ozturk Prof. Dr. Mehmet V. Yigit 《Chembiochem : a European journal of chemical biology》2019,20(14):1861-1867
Two-dimensional MoS2 nanoparticles (2D-nps) exhibit artificial enzyme properties that can be regulated at bio-nanointerfaces. We discovered that protein lipase is able to tune the peroxidase-like activity of MoS2 2D-nps, offering low-nanomolar, label-free detection and identification in samples with unknown identity. The inhibition of the peroxidase-like activity of the MoS2 2D-nps was demonstrated to be concentration dependent, and as low as 5 nm lipase was detected with this approach. The results were compared with those obtained with several other proteins that did not display any significant interference with the nanozyme behavior of the MoS2 2D-nps. This unique response of lipase was characterized and exploited for the successful identification of lipase in six unknown samples by using qualitative visual inspection and a quantitative statistical analysis method. The developed methodology in this approach is noteworthy for many aspects; MoS2 2D-nps are neither labeled with a signaling moiety nor modified with any ligands for signal readout. Only the intrinsic nanozyme activity of the MoS2 2D-nps is exploited for this detection approach. No analytical equipment is necessary for the visual detection of lipase. The synthesis of the water-soluble MoS2 2D-nps is low costing and can be performed in bulk scale. Exploring the properties of 2D-nps and their interactions with biological materials reveals highly interesting yet instrumental features that offer the development of novel bioanalytical approaches. 相似文献
40.
Dr. Emilianne M. Limbrick Audrey E. Yñigez-Gutierrez Callie C. Dulin Dagmara K. Derewacz Dr. Jeffrey M. Spraggins Dr. Kathryn M. McCulloch Prof. T. M. Iverson Prof. Brian O. Bachmann 《Chembiochem : a European journal of chemical biology》2020,21(23):3349-3358
Everninomicins are orthoester oligosaccharide antibiotics with potent activity against multidrug-resistant bacterial pathogens. Everninomicins act by disrupting ribosomal assembly in a distinct region in comparison to clinically prescribed drugs. We employed microporous intergeneric conjugation with Escherichia coli to manipulate Micromonospora for targeted gene-replacement studies of multiple putative methyltransferases across the octasaccharide scaffold of everninomicin effecting the A1, C, F, and H rings. Analyses of gene-replacement and genetic complementation mutants established the mutability of the everninomicin scaffold through the generation of 12 previously unreported analogues and, together with previous results, permitted assignment of the ten methyltransferases required for everninomicin biosynthesis. The in vitro activity of A1- and H-ring-modifying methyltransferases demonstrated the ability to catalyze late-stage modification of the scaffold on an A1-ring phenol and H-ring C-4’ hydroxy moiety. Together these results establish the potential of the everninomicin scaffold for modification through mutagenesis and in vitro modification of advanced biosynthetic intermediates. 相似文献