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Scientific Reports Feb 2018Ants use pheromones to coordinate their communal activity. Volatile pyrazines, for instance, mediate food resource gathering and alarm behaviors in different ant...
Ants use pheromones to coordinate their communal activity. Volatile pyrazines, for instance, mediate food resource gathering and alarm behaviors in different ant species. Here we report that leaf-cutter ant-associated bacteria produce a family of pyrazines that includes members previously identified as ant trail and alarm pheromones. We found that L-threonine induces the bacterial production of the trail pheromone pyrazines, which are common for the host leaf-cutter ants. Isotope feeding experiments revealed that L-threonine along with sodium acetate were the biosynthetic precursors of these natural products and a biosynthetic pathway was proposed.
Topics: Animals; Ants; Ecosystem; Gas Chromatography-Mass Spectrometry; Pheromones; Pyrazines; Serratia marcescens; Sodium Acetate; Threonine
PubMed: 29416082
DOI: 10.1038/s41598-018-20953-6 -
Scientific Reports Jun 2020The first catalyst-free post-Ugi cascade methodology was developed for expeditious access to structurally diverse and complex pyrazole-pyrazines in one-pot. This novel...
The first catalyst-free post-Ugi cascade methodology was developed for expeditious access to structurally diverse and complex pyrazole-pyrazines in one-pot. This novel cascade reaction features an intramolecular N2-arylation of pyrazoles with allenes at the C-β position of triple bond. Screening in the colorectal cancer cell lines HCT116 and SW620 validated the feasibility of the methodology for generating bioactive compounds. The lead compound 7h which is active against HCT116 and SW620 with IC of 1.3 and 1.8 µM, respectively, can be synthesized and purified in a gram process synthetic scale in 7 hours. The mechanical studies indicated that compound 7h can induce cell cycle arrest in the G2/M phase and inhibit proliferation and viability in human colon cancer cells. Overall, compound 7h is represented as a promising starting point for the development of new anti-colorectal cancer drugs.
Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Cell Survival; Colorectal Neoplasms; Dose-Response Relationship, Drug; Drug Discovery; Drug Screening Assays, Antitumor; G2 Phase Cell Cycle Checkpoints; HCT116 Cells; Humans; Pyrazines; Pyrazoles; Structure-Activity Relationship
PubMed: 32518332
DOI: 10.1038/s41598-020-66137-z -
Molecules (Basel, Switzerland) Nov 2023Infectious diseases pose a major challenge to human health, and there is an urgent need to develop new antimicrobial agents with excellent antibacterial activity. A...
Infectious diseases pose a major challenge to human health, and there is an urgent need to develop new antimicrobial agents with excellent antibacterial activity. A series of novel triazolo[4,3-]pyrazine derivatives were synthesized and their structures were characterized using various techniques, such as melting point, H and C nuclear magnetic resonance spectroscopy, mass spectrometry, and elemental analysis. All the synthesized compounds were evaluated for in vitro antibacterial activity using the microbroth dilution method. Among all the tested compounds, some showed moderate to good antibacterial activities against both Gram-positive and Gram-negative strains. In particular, compound exhibited superior antibacterial activities (MICs: 32 μg/mL against and 16 μg/mL against ), which was comparable to the first-line antibacterial agent ampicillin. In addition, the structure-activity relationship of the triazolo[4,3-]pyrazine derivatives was preliminarily investigated.
Topics: Humans; Pyrazines; Anti-Bacterial Agents; Anti-Infective Agents; Escherichia coli; Structure-Activity Relationship; Staphylococcal Infections; Microbial Sensitivity Tests; Molecular Structure
PubMed: 38067606
DOI: 10.3390/molecules28237876 -
Drug Design, Development and Therapy 2016Pulmonary arterial hypertension is characterized by abnormalities in the small pulmonary arteries including increased vasoconstriction, vascular remodeling,... (Review)
Review
Pulmonary arterial hypertension is characterized by abnormalities in the small pulmonary arteries including increased vasoconstriction, vascular remodeling, proliferation of smooth muscle cells, and in situ thrombosis. Selexipag, a novel, oral prostacyclin receptor agonist, has been shown to improve hemodynamics in a phase II clinical trial and reduce clinical worsening in a large phase III clinical trial involving patients with pulmonary arterial hypertension. In this paper, we describe the prostacyclin signaling pathway, currently available oral prostanoid medications, and the development and clinical use of selexipag.
Topics: Acetamides; Administration, Oral; Antihypertensive Agents; Clinical Trials as Topic; Epoprostenol; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; Pyrazines; Tachyphylaxis
PubMed: 27895464
DOI: 10.2147/DDDT.S103534 -
British Journal of Haematology Sep 2021The addition of molecularly targeted therapies to current chemotherapy regimens may improve acute lymphoblastic leukemia (ALL) outcomes and reduce acute and late...
The addition of molecularly targeted therapies to current chemotherapy regimens may improve acute lymphoblastic leukemia (ALL) outcomes and reduce acute and late toxicities. Checkpoint kinase 1 (CHK1) orchestrates cell cycle checkpoint control in the setting of DNA damage. CHK1 is expressed in both T- and B-ALL and represents a promising therapeutic target. Herein, we show that prexasertib, a targeted CHK1 inhibitor, exhibits significant single-agent efficacy using ALL patient-derived xenograft (PDX) models and synergizes with a nucleoside analog. These results support further clinical testing of prexasertib in ALL.
Topics: Animals; Cell Line, Tumor; Cell Proliferation; Checkpoint Kinase 1; Deoxycytidine; Drug Synergism; Humans; Mice; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Protein Kinase Inhibitors; Pyrazines; Pyrazoles; Gemcitabine
PubMed: 34096630
DOI: 10.1111/bjh.17610 -
Bioorganic & Medicinal Chemistry Letters Oct 2022We report new mitochondrial uncouplers derived from the conversion of [1,2,5]oxadiazolo[3,4-b]pyrazines to 1H-imidazo[4,5-b]pyrazines. The in situ Fe-mediated reduction...
We report new mitochondrial uncouplers derived from the conversion of [1,2,5]oxadiazolo[3,4-b]pyrazines to 1H-imidazo[4,5-b]pyrazines. The in situ Fe-mediated reduction of the oxadiazole fragment followed by cyclization gave access to imidazopyrazines in moderate to good yields. A selection of orthoesters also allowed functionalization on the 2-position of the imidazole ring. This method afforded a variety of imidazopyrazine derivatives with varying substitution on the 2, 5 and 6 positions. Our studies suggest that both a 2-trifluoromethyl group and N-methylation are crucial for mitochondrial uncoupling capacity.
Topics: Cyclization; Mitochondria; Oxadiazoles; Pyrazines
PubMed: 35907607
DOI: 10.1016/j.bmcl.2022.128912 -
Journal of Managed Care & Specialty... Oct 2021Patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) and confirmed feline McDonough sarcoma (FMS)-like tyrosine kinase 3 gene mutations () have a...
Patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) and confirmed feline McDonough sarcoma (FMS)-like tyrosine kinase 3 gene mutations () have a poor prognosis and limited effective treatment options. Gilteritinib is the first targeted therapy approved in the United States and Europe for R/R AML with significantly improved efficacy compared with existing treatments. To evaluate gilteritinib against salvage chemotherapy (SC) and best supportive care (BSC) over a lifetime horizon among adult patients with R/R AML from a US third-party payer's perspective. The model structure of this cost-effectiveness analysis included a decision tree to stratify patients based on their hematopoietic stem cell transplantation (HSCT) status, followed by 2 separate 3-state partitioned survival models to predict the long-term health status conditional on HSCT status. The ADMIRAL trial data and literature were used to predict probabilities of patients being in different health states until a conservative cure point at year 3. Afterwards, living patients followed the survival outcomes of long-term survivors with AML. Model inputs for utilities, medical resource use, and costs were based on the ADMIRAL trial, published literature, and public sources. All costs were inflated to 2019 US dollars (USD). Total incremental costs (in 2019 USD), life-years (LYs), quality-adjusted LYs (QALYs), and incremental cost-effectiveness ratios (ICERs) were calculated. Deterministic sensitivity analyses and probabilistic sensitivity analyses were performed. Over a lifetime horizon with a 3.0% annual discount rate, the base-case model estimated that gilteritinib led to an increase of 1.29 discounted QALYs at an additional cost of $148,106 vs SC, corresponding to an ICER of $115,192 per QALY; for BSC, results were an increase of 2.32 discounted QALYs, $249,674, and $107,435, respectively. The base-case findings were robust in sensitivity analyses. The estimated probabilities of gilteritinib being cost-effective vs SC and BSC were 90.5% and 99.8%, respectively, in the probabilistic sensitivity analyses, based on a willingness-to-pay threshold of $150,000 per QALY. Gilteritinib is a cost-effective novel treatment for patients with R/R AML in the United States. This work was supported by Astellas Pharma, Inc., which was involved in all stages of the research and manuscript development. Garnham, Pandya, and Shah are employees of Astellas and hold stock/stock options. Zeidan consulted and received personal fees/honoraria and research funding from Astellas. Zeidan also has received research funding from Celgene/BMS, Abbvie, Astex, Pfizer, Medimmune/AstraZeneca, Boehringer-Ingelheim, Trovagene/Cardiff Oncology, Incyte, Takeda, Novartis, Amgen, Aprea, and ADC Therapeutics; has participated in advisory boards; has consulted with and/or received honoraria from AbbVie, Otsuka, Pfizer, Celgene/BMS, Jazz, Incyte, Agios, Boehringer-Ingelheim, Novartis, Acceleron, Daiichi Sankyo, Taiho, Seattle Genetics, BeyondSpring, Cardiff Oncology, Takeda, Ionis, Amgen, Janssen, Syndax, Gilead, Kura, Aprea, Lox Oncology, Genentech, Servier, Jasper, Tyme, and Epizyme; has served on clinical trial committees for Novartis, Abbvie, Geron, Gilead, Kura, Lox Oncology, BioCryst, and Celgene/BMS; and has received travel support for meetings from Pfizer, Novartis, and Cardiff Oncology. Qi and Yang are employees of Analysis Group, Inc., which received consulting fees from Astellas for work on this study. Part of this material was presented at the American Society of Hematology (ASH) Annual Meeting; December 7-10, 2019; Orlando, FL.
Topics: Aniline Compounds; Cost-Benefit Analysis; Humans; Leukemia, Myeloid, Acute; Pyrazines; Quality-Adjusted Life Years; Recurrence; Survival Analysis; fms-Like Tyrosine Kinase 3
PubMed: 34595955
DOI: 10.18553/jmcp.2021.27.10.1469 -
Sensors (Basel, Switzerland) Dec 2018Developing a controlled method for obtaining hybrid enzymatic-based interfaces for sensing application require the use of a multiuse, reusable sensor. By controlling the...
Developing a controlled method for obtaining hybrid enzymatic-based interfaces for sensing application require the use of a multiuse, reusable sensor. By controlling the interface characteristics in terms of the surface chemistry, thickness, and roughness, a tailored response toward various toxic compounds can be obtained, regarding both materials used as active surfaces and fabrication methods. Herein, we report a preliminary study on using a laser-based method (i.e., matrix-assisted pulsed laser evaporation, or MAPLE) for obtaining active polymeric⁻enzymatic interfaces as hybrid or layered coatings for detecting toxic vapors. The MAPLE fabrication consisted of the simultaneous alternating evaporation of layers of polyethylenimine (PEI) and acetylcholinesterase (AchE) in order to obtain active surfaces as both hybrid PEI-AchE and a PEI/AchE layered coating, respectively. The deposition processes of the polymer and enzyme were carried out using a double-target system and a Nd:YAG pulsed laser, operating at 0.45 J/cm² fluences with a wavelength of 266 nm and a repetition rate of 10 Hz. Fourier transform infrared spectroscopy revealed no significant changes in the functional groups of both hybrid and layered coatings compared with the initial material. The thickness and roughness, as well as the morphologies of the coatings revealed by atomic force microscopy and scanning electron microscopy showed coatings thicker than two μm that had smooth surfaces and average roughness values below six nm. The sensors were tested with simulants for nerve gases and pesticides containing phosphonate ester groups, namely dimethyl methylphosphonate (DMMP) and diisopropyl methylphosphonate (DIMP), and a different sensitivity was shown to the selected chemical agents for each of the sensors. The best sensitivities for DMMP and DIMP obtained by using a PEI-AchE coated sensor are 65 kHz and 200 kHz, respectively, whereas the best sensitivity when using multilayered interfaces is 30 kHz and 10 KHz for DIMP and DMMP, respectively.
Topics: Acetylcholinesterase; Biosensing Techniques; Gases; Organophosphorus Compounds; Polyethyleneimine; Pyrazines
PubMed: 30518102
DOI: 10.3390/s18124265 -
Scientific Reports Apr 2017Spectral overlaps among the multiple optical readouts commonly cause optical contamination in fluorescence and bioluminescence. To tackle this issue, we created...
Spectral overlaps among the multiple optical readouts commonly cause optical contamination in fluorescence and bioluminescence. To tackle this issue, we created five-different lineages of coelenterazine (CTZ) analogues designed to selectively illuminate a specific luciferase with unique luciferase selectivity. In the attempt, we found that CTZ analogues with ethynyl or styryl groups display dramatically biased bioluminescence to specific luciferases and pHs by modifying the functional groups at the C-2 and C-6 positions of the imidazopyradinone backbone of CTZ. The optical contamination-free feature was exemplified with the luciferase-specific CTZ analogues, which illuminated anti-estrogenic and rapamycin activities in a mixture of optical probes. This unique bioluminescence platform has great potential for specific and high throughput imaging of multiple optical readouts in bioassays without optical contamination.
Topics: Bias; Imidazoles; Luciferases; Luminescent Agents; Luminescent Measurements; Molecular Structure; Pyrazines
PubMed: 28424463
DOI: 10.1038/s41598-017-00955-6 -
Proceedings of the Japan Academy.... 2017Favipiravir (T-705; 6-fluoro-3-hydroxy-2-pyrazinecarboxamide) is an anti-viral agent that selectively and potently inhibits the RNA-dependent RNA polymerase (RdRp) of... (Review)
Review
Favipiravir (T-705; 6-fluoro-3-hydroxy-2-pyrazinecarboxamide) is an anti-viral agent that selectively and potently inhibits the RNA-dependent RNA polymerase (RdRp) of RNA viruses. Favipiravir was discovered through screening chemical library for anti-viral activity against the influenza virus by Toyama Chemical Co., Ltd. Favipiravir undergoes an intracellular phosphoribosylation to be an active form, favipiravir-RTP (favipiravir ribofuranosyl-5'-triphosphate), which is recognized as a substrate by RdRp, and inhibits the RNA polymerase activity. Since the catalytic domain of RdRp is conserved among various types of RNA viruses, this mechanism of action underpins a broader spectrum of anti-viral activities of favipiravir. Favipiravir is effective against a wide range of types and subtypes of influenza viruses, including strains resistant to existing anti-influenza drugs. Of note is that favipiravir shows anti-viral activities against other RNA viruses such as arenaviruses, bunyaviruses and filoviruses, all of which are known to cause fatal hemorrhagic fever. These unique anti-viral profiles will make favipiravir a potentially promising drug for specifically untreatable RNA viral infections.
Topics: Amides; Animals; Antiviral Agents; DNA-Directed RNA Polymerases; Enzyme Inhibitors; Humans; Pyrazines; Viruses
PubMed: 28769016
DOI: 10.2183/pjab.93.027