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Current Topics in Medicinal Chemistry 2020Cancer is a devastating disease that has plagued humans from ancient times to this day. After decades of slow research progress, promising drug development, and the... (Review)
Review
Cancer is a devastating disease that has plagued humans from ancient times to this day. After decades of slow research progress, promising drug development, and the identification of new targets, the war on cancer was launched, in 1972. The P13K/Akt pathway is a growth-regulating cellular signaling pathway, which in many human cancers is over-activated. Studies have demonstrated that a decrease in Akt activity by Akt inhibitors is associated with a reduction in tumor cell proliferation. There have been several promising drug candidates that have been studied, including but not limited to ipatasertib (RG7440), 1; afuresertib (GSK2110183), 2; uprosertib (GSK2141795), 3; capivasertib (AZD5363), 4; which reportedly bind to the ATP active site and inhibit Akt activity, thus exerting cytotoxic and antiproliferative activities against human cancer cells. For most of the compounds discussed in this review, data from preclinical studies in various cancers suggest a mechanistic basis involving hyperactivated Akt signaling. Allosteric inhibitors are also known to alter the activity of kinases. Perifosine (KRX- 0401), 5, an alkylphospholipid, is known as the first allosteric Akt inhibitor to enter clinical development and is mechanistically characterized as a PH-domain dependent inhibitor, non-competitive with ATP. This results in a reduction in Akt enzymatic and cellular activities. Other small molecule (MK- 2206, 6, PHT-427, Akti-1/2) inhibitors with a similar mechanism of action, alter Akt activity through the suppression of cell growth mediated by the inhibition of Akt membrane localization and subsequent activation. The natural product solenopsin has been identified as an inhibitor of Akt. A few promising solenopsin derivatives have emerged through pharmacophore modeling, energy-based calculations, and property predictions.
Topics: Antineoplastic Agents; Benzylamines; Cell Line, Tumor; Diamines; Drug Design; Heterocyclic Compounds, 3-Ring; Humans; Molecular Docking Simulation; Phosphatidylinositol 3-Kinases; Phospholipids; Piperazines; Protein Conformation; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Pyrazoles; Pyrimidines; Pyrroles; Quinoxalines; Signal Transduction; Structure-Activity Relationship; Sulfonamides; Thiadiazoles; Thiophenes
PubMed: 32091335
DOI: 10.2174/1568026620666200224101808 -
Methods in Enzymology 2020Siderophores have important functions for bacteria in iron acquisition and as virulence factors. In this chapter we will discuss the engineering of cyclic hydroxamate...
Siderophores have important functions for bacteria in iron acquisition and as virulence factors. In this chapter we will discuss the engineering of cyclic hydroxamate siderophores by various biochemical approaches based on the example of Shewanella algae. The marine gamma-proteobacterium S. algae produces three different cyclic hydroxamate siderophores as metabolites via a single biosynthetic gene cluster and one of them is an important key player in interspecies competition blocking swarming of Vibrio alginolyticus. AvbD is the key metabolic enzyme assembling the precursors into three different core structures and hence an interesting target for metabolic and biochemical engineering. Synthetic natural and unnatural precursors can be converted in vitro with purified AvbD to generate siderophores with various ring sizes ranging from analytical to milligram scale. These engineered siderophores can be applied, for example, as swarming inhibitors against V. alginolyticus. Here, we describe the synthesis of the natural and unnatural siderophore precursors HS[X]A and provide our detailed protocols for protein expression of AvbD, conversion of HS[X]A with the enzyme to produce ring-size engineered siderophores and secondly for a biosynthetic feeding strategy that allows to extract engineered siderophores in the milligram scale.
Topics: Antibiosis; Bacterial Proteins; Diamines; Escherichia coli; Hydroxamic Acids; Metabolic Engineering; Movement; Peptides, Cyclic; Putrescine; Recombinant Proteins; Shewanella; Siderophores; Succinates; Vibrio alginolyticus
PubMed: 32046852
DOI: 10.1016/bs.mie.2019.10.030 -
Autophagy Feb 2023Impaired mitophagy is a primary pathogenic event underlying diverse aging-associated diseases such as Alzheimer and Parkinson diseases and sarcopenia. Therefore,...
Impaired mitophagy is a primary pathogenic event underlying diverse aging-associated diseases such as Alzheimer and Parkinson diseases and sarcopenia. Therefore, augmentation of mitophagy, the process by which defective mitochondria are removed, then replaced by new ones, is an emerging strategy for preventing the evolvement of multiple morbidities in the elderly population. Based on the scaffold of spermidine (Spd), a known mitophagy-promoting agent, we designed and tested a family of structurally related compounds. A prototypic member, 1,8-diaminooctane (VL-004), exceeds Spd in its ability to induce mitophagy and protect against oxidative stress. VL-004 activity is mediated by canonical aging genes and promotes lifespan and healthspan in . Moreover, it enhances mitophagy and protects against oxidative injury in rodent and human cells. Initial structural characterization suggests simple rules for the design of compounds with improved bioactivity, opening the way for a new generation of agents with a potential to promote healthy aging.
Topics: Aged; Animals; Humans; Caenorhabditis elegans; Mitophagy; Diamines; Autophagy; Oxidative Stress
PubMed: 35579620
DOI: 10.1080/15548627.2022.2078069 -
Journal of Inorganic Biochemistry Jun 2022With the interest in radiometal-containing diagnostic and therapeutic pharmaceuticals increasing rapidly, appropriate ligands to coordinate completely and stably said...
With the interest in radiometal-containing diagnostic and therapeutic pharmaceuticals increasing rapidly, appropriate ligands to coordinate completely and stably said radiometals is essential. Reported here are two novel, bis(amido)bis(oxinate)diamine ligands, Hamidohox (2,2'-(ethane-1,2-diylbis(((8-hydroxyquinolin-2-yl)methyl)azanediyl))diacetamide) and HamidoC3hox (2,2'-(propane-1,3-diylbis(((8-hydroxyquinolin-2-yl)methyl)azanediyl))diacetamide), that combine two 8-hydroxyquinoline and amide donor groups and differ by one carbon in their 1,2-ethylenediamine vs. 1,3-diaminopropane backbones, respectively. Both ligands have been thoroughly studied via metal complexation, solution thermodynamics and radiolabeling with three radiometal ions: [Cu]Cu, [In]In, and [Pb]Pb. X-ray crystallography determined the structures of the hexacoordinated Cu-ligand complexes, indicating a better fit of Cu to the Hamidohox binding pocket. Concentration dependent radiolabeling with [Cu]Cu was successfully quantitative as low as 1 μM with Hamidohox and 10 μM with HamidoC3hox within 5 min at room temperature. However, [Cu][Cu(amidohox)] maintained higher kinetic inertness against a superoxide dismutase enzyme-challenge assay and ligand challenges compared to the [Cu][Cu(amidoC3hox)] counterpart. Similarly, Hamidohox had significantly higher radiochemical conversion with both [In]In (97% at 1 μM) and [Pb]Pb (97% at 100 μM) under mild conditions compared to HamidoC3hox (76% with [In]In at 1 μM and 0% with [Pb]Pb). By studying non-radioactive and radioactive complexation with both ligands, a comprehensive understanding of the coordination differences between two- and three‑carbon diamine backbones is discussed. Overall, the ethylenediamine backbone of Hamidohox proves to be superior in rapid, mild radiolabeling and kinetic inertness towards competing ligands and proteins.
Topics: Carbon; Copper; Crystallography, X-Ray; Diamines; Lead; Ligands; Theranostic Nanomedicine
PubMed: 35305407
DOI: 10.1016/j.jinorgbio.2022.111789 -
Applied and Environmental Microbiology Nov 2020Diamines are important monomers for polyamide plastics; they include 1,3-diaminopropane, 1,4-diaminobutane, 1,5-diaminopentane, and 1,6-diaminohexane, among others. With... (Review)
Review
Diamines are important monomers for polyamide plastics; they include 1,3-diaminopropane, 1,4-diaminobutane, 1,5-diaminopentane, and 1,6-diaminohexane, among others. With increasing attention on environmental problems and green sustainable development, utilizing renewable raw materials for the synthesis of diamines is crucial for the establishment of a sustainable plastics industry. Recently, high-performance microbial factories, such as and , have been widely used in the production of diamines. In particular, several synthetic pathways of 1,6-diaminohexane have been proposed based on glutamate or adipic acid. Here, we reviewed approaches for the biosynthesis of diamines, including metabolic engineering and biocatalysis, and the application of bio-based diamines in nylon materials. The related challenges and opportunities in the development of renewable bio-based diamines and nylon materials are also discussed.
Topics: Bacteria; Biocatalysis; Biosynthetic Pathways; Diamines; Metabolic Engineering; Nylons
PubMed: 32978133
DOI: 10.1128/AEM.01972-20 -
Cold Spring Harbor Protocols Feb 2020This introduction describes the features and uses of ethidium bromide, methylene blue, and SYBR dyes for staining nucleic acids.
This introduction describes the features and uses of ethidium bromide, methylene blue, and SYBR dyes for staining nucleic acids.
Topics: Benzothiazoles; DNA; Diamines; Ethidium; Fluorescent Dyes; Methylene Blue; Nucleic Acids; Organic Chemicals; Quinolines; Reproducibility of Results; Staining and Labeling
PubMed: 32015006
DOI: 10.1101/pdb.top098228 -
European Journal of Medicinal Chemistry Mar 2018A set of 18 amide derivatives of oleanolic or maslinic acid has been semi-synthesised. Twelve were diamine conjugates at C-28 of these triterpenic acids and the other...
A set of 18 amide derivatives of oleanolic or maslinic acid has been semi-synthesised. Twelve were diamine conjugates at C-28 of these triterpenic acids and the other six were PEGylated-diamine derivatives. The cytotoxic effects of these 18 triterpenic derivatives in three cancer-cell lines (B16-F10, HT29, and Hep G2) have been assayed, and have been compared to three non-tumour cell lines of the same or a similar tissue (HPF, IEC-18, and WRL68). The cell viability percentages for the non-tumour HPF line for almost all diamine conjugates of the tested triterpenic acids ranged from 81% to 94%. The best cytotoxic results were achieved with the diamine conjugates of oleanolic or maslinic acid with the shortest and the longest diamine chain (IC values from 0.76 μM to 1.76 μM), on the B16-F10 cell line, being between 140- and 20-fold more effective than their corresponding precursors. Four diamine conjugates of these triterpenic acids showed apoptotic effects on treated cells of the B16-F10 line, with total apoptosis rates, relative to control, of between 73% and 90%. The DNA-histogram analysis revealed that all compounds tested produced cell-cycle arrest in B16-F10 cells, increasing the number of these cells in the S phase. All the compounds analysed, except one, did not cause changes in mitochondrial-membrane potential during apoptosis of the B16-F10 cancer cells, suggesting an activation of the extrinsic apoptotic pathway for these compounds.
Topics: Antineoplastic Agents; Apoptosis; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Survival; Diamines; Humans; Membrane Potential, Mitochondrial; Oleanolic Acid; Triterpenes
PubMed: 29471121
DOI: 10.1016/j.ejmech.2018.02.044 -
ACS Infectious Diseases Dec 2021Leishmaniasis is one of the world's most neglected diseases with a worldwide prevalence of 12 million people. There are no effective human vaccines for its prevention,...
Leishmaniasis is one of the world's most neglected diseases with a worldwide prevalence of 12 million people. There are no effective human vaccines for its prevention, and outdated drugs hamper treatment. Therefore, research aimed at developing new therapeutic tools to fight leishmaniasis remains a crucial goal today. With this purpose in mind, here, we present 10 new compounds made up by linking alkylated ethylenediamine units to pyridine or quinoline heterocycles with promising in vitro and in vivo efficacy against promastigote and amastigote forms of , , and species. Three compounds (, , and ) showed a selectivity index much higher in the amastigote form than the reference drug glucantime. These three derivatives affected the parasite infectivity rates; the result was lower parasite infectivity rates than glucantime tested at an IC dose. In addition, these derivatives were substantially more active against the three species tested than glucantime. The mechanism of action of these compounds has been studied, showing alterations in glucose catabolism and leading to greater levels of iron superoxide dismutase inhibition. These molecules could be potential candidates for leishmaniasis chemotherapy due to their effectiveness and their ready synthesis.
Topics: Antiprotozoal Agents; Diamines; Humans; Leishmania braziliensis; Leishmania infantum; Leishmaniasis
PubMed: 34734686
DOI: 10.1021/acsinfecdis.1c00215 -
Oral Health & Preventive Dentistry Nov 2022To determine the salivary flow rate and subsequent dilution of toothpaste and assess the pH of oral fluids during toothbrushing with toothpastes of various pHs. (Clinical Trial)
Clinical Trial
PURPOSE
To determine the salivary flow rate and subsequent dilution of toothpaste and assess the pH of oral fluids during toothbrushing with toothpastes of various pHs.
MATERIALS AND METHODS
The study was conducted as an in-vivo trial involving 30 healthy volunteers. The participants took part in a series of trials distributed over four appointments. After a screening check, in which the participants' stimulated and unstimulated salivary flow rate and buffering capacities were determined, four test series involving toothbrushing were conducted. Participants brushed their teeth using a manual toothbrush for 2 min: once without toothpaste and three times using toothpastes of varying pHs. The salivary flow rate and subsequent dilution of the toothpaste was determined. Additionally, the pH of the collected oral fluid was analysed.
RESULTS
Brushing teeth with toothpaste caused a statistically significant increase in salivary flow rate (median/IQR in ml/min) (Elmex Kariesschutz 3.29/1.36, Colgate Total Original 3.23/1.08, Elmex Sensitive Professional 3.18/1.39) when compared to brushing teeth using a manual toothbrush without toothpaste (1.85/0.78) (p < 0.05). The variation in pH of the oral fluid samples was dictated primarily by the pH of the toothpaste used.
CONCLUSION
The salivary flow rate when brushing using toothpaste was similar across all tested toothpastes, independent of pH, and had an average median of 3.23 ml/min. The dilution of 1 g of toothpaste during a standard toothbrushing procedure of 2 min is therefore approximately at a ratio of one part toothpaste to 6.5 parts saliva.
Topics: Humans; Diamines; Fluorides; Toothbrushing; Toothpastes
PubMed: 36416604
DOI: 10.3290/j.ohpd.b3601691 -
Nature Communications Aug 2022Molecular conformations induced by the rotation about single bonds play a crucial role in chemical transformations. Revealing the relationship between the conformations...
Molecular conformations induced by the rotation about single bonds play a crucial role in chemical transformations. Revealing the relationship between the conformations of chiral catalysts and the enantiodiscrimination is a formidable challenge due to the great difficulty in isolating the conformers. Herein, we report a chiral catalytic system composed of an achiral catalytically active unit and an axially chiral 1,1'-bi-2-naphthol (BINOL) unit which are connected via a C-O single bond. The two conformers of the catalyst induced by the rotation about the C-O bond, are determined via single-crystal X-ray diffraction and found to respectively lead to the formation of highly important axially chiral 1,1'-binaphthyl-2,2'-diamine (BINAM) and 2-amino-2'-hydroxy-1,1'-binaphthyl (NOBIN) derivatives in high yields (up to 98%), with excellent enantioselectivities (up to 98:2 e.r.) and opposite absolute configurations. The results highlight the importance of conformational dynamics of chiral catalysts in asymmetric catalysis.
Topics: Catalysis; Crystallography, X-Ray; Diamines; Molecular Conformation
PubMed: 35961985
DOI: 10.1038/s41467-022-32432-8