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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 -
Clinical Cancer Research : An Official... Aug 2021Lower grade gliomas (LGGs) are malignant brain tumors. Current therapy is associated with short- and long-term toxicity. Progression to higher tumor grade is associated...
PURPOSE
Lower grade gliomas (LGGs) are malignant brain tumors. Current therapy is associated with short- and long-term toxicity. Progression to higher tumor grade is associated with contrast enhancement on MRI. The majority of LGGs harbor mutations in the genes encoding isocitrate dehydrogenase 1 or 2 (). Vorasidenib (AG-881) is a first-in-class, brain-penetrant, dual inhibitor of the mutant IDH1 and mutant IDH2 enzymes.
PATIENTS AND METHODS
We conducted a multicenter, open-label, phase I, dose-escalation study of vorasidenib in 93 patients with mutant (m) solid tumors, including 52 patients with glioma that had recurred or progressed following standard therapy. Vorasidenib was administered orally, once daily, in 28-day cycles until progression or unacceptable toxicity. Enrollment is complete; this trial is registered with ClinicalTrials.gov, NCT02481154.
RESULTS
Vorasidenib showed a favorable safety profile in the glioma cohort. Dose-limiting toxicities of elevated transaminases occurred at doses ≥100 mg and were reversible. The protocol-defined objective response rate per Response Assessment in Neuro-Oncology criteria for LGG in patients with nonenhancing glioma was 18% (one partial response, three minor responses). The median progression-free survival was 36.8 months [95% confidence interval (CI), 11.2-40.8] for patients with nonenhancing glioma and 3.6 months (95% CI, 1.8-6.5) for patients with enhancing glioma. Exploratory evaluation of tumor volumes in patients with nonenhancing glioma showed sustained tumor shrinkage in multiple patients.
CONCLUSIONS
Vorasidenib was well tolerated and showed preliminary antitumor activity in patients with recurrent or progressive nonenhancing m LGG.
Topics: Adolescent; Adult; Aged; Brain Neoplasms; Diamines; Disease Progression; Female; Glioma; Humans; Isocitrate Dehydrogenase; Male; Middle Aged; Mutation; Neoplasm Recurrence, Local; Pyridines; Young Adult
PubMed: 34078652
DOI: 10.1158/1078-0432.CCR-21-0611 -
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 -
Toxicology and Industrial Health Apr 2023The WEEL for triethylenetetramine (TETA; CAS No. 112-24-3) was originally established in 1991 and updated in 1998 and 2009. Recent literature searches to identify new...
The WEEL for triethylenetetramine (TETA; CAS No. 112-24-3) was originally established in 1991 and updated in 1998 and 2009. Recent literature searches to identify new toxicity information were performed in 2016 and January 2021. No new studies or data relevant to the WEEL were identified. TETA is used in manufacturing; the hydrochloride salt of TETA is used as a copper-chelating drug in the treatment of Wilson's disease. TETA is severely irritating to the skin and eyes and produces skin sensitization; however, it is of low to moderate acute toxicity via the oral and dermal routes of exposure. In subchronic studies, signs of toxicity included multi-organ effects (lung, liver, and spleen) in mice, but not rats. TETA was genotoxic/mutagenic in short-term in vitro assays but not in in vivo assays. No data on reproductive toxicity were available. Embryo/fetal toxicity occurred at maternally toxic doses and was associated with copper deficiency. In humans, the use of TETA·2HCl for treatment of Wilson's disease during pregnancy resulted in no miscarriages or fetal abnormalities. No evidence of carcinogenicity was noted in a lifetime dermal study in mice. Based on a subchronic drinking water study in mice, 600 ppm (95 mg/kg-day) was determined to be the no-observed-adverse-effect level (NOAEL) and the point of departure (POD). This NOAEL was converted to an equivalent inhalation concentration by adjusting for respiratory rate, interindividual variability, and uncertainty. The resulting 8-h time-weighted average WEEL value of 1 ppm is expected to provide a significant margin of safety against any potential adverse health effects in workers exposed to airborne TETA.
Topics: Humans; Animals; Mice; Trientine; Copper; Hepatolenticular Degeneration; No-Observed-Adverse-Effect Level
PubMed: 36941775
DOI: 10.1177/07482337231161152 -
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 -
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 -
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