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International Journal of Molecular... Jul 2022Chemi- and bioluminescence are remarkable light-emitting phenomena, in which thermal energy is converted into excitation energy due to a (bio)chemical reaction. Among a...
Chemi- and bioluminescence are remarkable light-emitting phenomena, in which thermal energy is converted into excitation energy due to a (bio)chemical reaction. Among a wide variety of chemi-/bioluminescent systems, one of the most well-known and studied systems is that of marine imidazopyrazinones, such as Coelenterazine and luciferin. Due to the increasing usefulness of their chemi-/bioluminescent reactions in terms of imaging and sensing applications, among others, significant effort has been made over the years by researchers to develop new derivatives with enhanced properties. Herein, we report the synthesis and chemiluminescent characterization of a novel dibrominated Coelenterazine analog. This novel compound consistently showed superior luminescence, in terms of total light output and emission lifetime, to natural imidazopyrazinones and commercially available analogs in aprotic media, while being capable of yellow light emission. Finally, this new compound showed enhanced chemiluminescence in an aqueous solution when triggered by superoxide anion, showing potential to be used as a basis for optimized probes for reactive oxygen species. In conclusion, bromination of the imidazopyrazinone scaffold appears to be a suitable strategy for obtaining Coelenterazines with enhanced properties.
Topics: Imidazoles; Luminescence; Luminescent Measurements; Pyrazines; Superoxides
PubMed: 35955625
DOI: 10.3390/ijms23158490 -
ACS Chemical Biology Dec 2021Nonribosomal peptide synthetases (NRPSs) are typically multimodular enzymes that assemble amino acids or carboxylic acids into complex natural products. Here, we...
Nonribosomal peptide synthetases (NRPSs) are typically multimodular enzymes that assemble amino acids or carboxylic acids into complex natural products. Here, we characterize a monomodular NRPS, PvfC, encoded by the () gene cluster that is essential for virulence and signaling in different bacterial species. PvfC exhibits a unique adenylation-thiolation-reductase (ATR) domain architecture that is understudied in bacteria. We show that the activity of PvfC is essential in the production of seven leucine-derived heterocyclic natural products, including two pyrazines, a pyrazinone, and a rare disubstituted imidazole, as well as three pyrazine -oxides that require an additional oxygenation step. Mechanistic studies reveal that PvfC, without a canonical peptide-forming domain, makes a dipeptide aldehyde intermediate en route to both the pyrazinone and imidazole. Our work identifies a novel biosynthetic route for the production of pyrazinones, an emerging class of signaling molecules and virulence factors. Our discovery also showcases the ability of monomodular NRPSs to generate amino acid- and dipeptide-aldehydes that lead to diverse natural products. The diversity-prone biosynthesis by the -encoded enzymes sets the stage for further understanding the functions of in bacterial cell-to-cell signaling.
Topics: Aldehydes; Amino Acids; Biological Products; Carboxylic Acids; Cyclic N-Oxides; Dipeptides; Imidazoles; Peptide Synthases; Pseudomonas; Pyrazines; Virulence Factors
PubMed: 34767712
DOI: 10.1021/acschembio.1c00623 -
International Journal of Molecular... Aug 2019There is a need for an efficient and low-cost leading compound discovery mode. However, drug development remains slow, expensive, and risky. Here, this manuscript...
There is a need for an efficient and low-cost leading compound discovery mode. However, drug development remains slow, expensive, and risky. Here, this manuscript proposes a leading compound discovery strategy based on a combination of traditional Chinese medicine (TCM) formulae and pharmacochemistry, using a ligustrazine-betulinic acid derivative (BA-12) in the treatment of angiogenesis as an example. Blocking angiogenesis to inhibit the growth and metastasis of solid tumors is currently one recognized therapy for cancer in the clinic. Firstly, based on a traditional plaster, BA-12 was synthesized according to our previous study, as it exhibited better antitumor activities than other derivatives on human bladder carcinoma cells (T24); it was then uploaded for target prediction. Secondly, the efficacy and biotoxicity of BA-12 on angiogenesis were evaluated using human umbilical vein endothelial cells (HUVECs), a quail chick chorioallantoic membrane, and . According to the prediction results, the main mechanisms of BA-12 were metabolic pathways. Thus, multiple metabolomics approaches were applied to reveal the mechanisms of BA-12. Finally, the predictive mechanisms of BA-12 on glutathione metabolism and glycerophospholipid metabolism activation were validated using targeted metabolomics and pharmacological assays. This strategy may provide a reference for highly efficient drug discovery, with the aim of sharing TCM wisdom for unmet clinical needs.
Topics: Animals; Caenorhabditis elegans; Chorioallantoic Membrane; Drug Discovery; Human Umbilical Vein Endothelial Cells; Humans; Metabolomics; Neovascularization, Pathologic; Pentacyclic Triterpenes; Pyrazines; Triterpenes; Betulinic Acid
PubMed: 31434286
DOI: 10.3390/ijms20164062 -
European Journal of Medicinal Chemistry Jul 2022Acetylation of histone lysine residues by histone acetyltransferase (HAT) p300 and its paralog CBP play important roles in gene regulation in health and diseases. The...
Acetylation of histone lysine residues by histone acetyltransferase (HAT) p300 and its paralog CBP play important roles in gene regulation in health and diseases. The HAT domain of p300/CBP has been found to be a potential drug target for cancer. Compound screening followed by structure-activity relationship studies yielded a novel series of 1,4-pyrazine-containing inhibitors of p300/CBP HAT with their ICs as low as 1.4 μM. Enzyme kinetics and other studies support the most potent compound 29 is a competitive inhibitor of p300 HAT against the substrate histone. It exhibited a high selectivity for p300 and CBP, with negligible activity on other classes of HATs in human. Compound 29 inhibited cellular acetylation of several histone lysine residues and showed strong activity against proliferation of a panel of solid and blood cancer cells. These results indicate it is a novel pharmacological lead for drug development targeting these cancers as well as a useful chemical probe for biological studies of p300/CBP.
Topics: Acetylation; Acetyltransferases; Enzyme Inhibitors; Histone Acetyltransferases; Histones; Humans; Lysine; Neoplasms; Pyrazines; Structure-Activity Relationship
PubMed: 35512565
DOI: 10.1016/j.ejmech.2022.114407 -
Cancer Immunology, Immunotherapy : CII Jan 2006Apoptosis has an essential role in embryogenesis, adult tissue homeostasis and cellular responses to stressful stimuli. Therefore, increased apoptosis is involved in the... (Review)
Review
Apoptosis has an essential role in embryogenesis, adult tissue homeostasis and cellular responses to stressful stimuli. Therefore, increased apoptosis is involved in the pathogenesis of various ischaemic, degenerative and immune disorders. Conversely, genetic aberration that results in a reduction or abolition of apoptosis can promote tumorigenesis and underlie the resistance of cancer cells to various genotoxic anticancer agents. Therefore, a detailed knowledge of the control of apoptotic pathways could aid in the rational design of effective therapeutics for a variety of human diseases including cancer. One major way to promote apoptosis involves signaling through members of the tumor necrosis factor (TNF) superfamily. On binding to their appropriate receptors, some TNF family members can promote caspase activation and apoptosis. Early studies on TNF indicated that a limited number of tumor cell lines could be induced to undergo apoptosis on exposure to TNF. Another member of the TNF family Fas ligand (FasL) is also known to induce apoptosis in a variety of tumor cells. Although TNF and FasL can efficiently induce apoptosis in a limited number of tumor cells, administration of either of these agents is associated with extreme toxicity. This toxicity has precluded further development of either TNF or FasL for cancer therapy. However, within the last 8 years another member of the TNF family, TNF-related apoptosis-inducing ligand (Apo2L/TRAIL) has been characterized, which induces apoptosis of a wider range of cancer cells than either TNF or FasL. Surprisingly, most normal non-transformed cells are quite resistant to the apoptotic effects of Apo2L/TRAIL. This selective toxicity for cancer cells is the basis for the current enthusiasm for Apo2L/TRAIL as a potential novel anticancer therapy. In this symposium report, we provide a brief overview of Apo2L/TRAIL, its receptors and their signaling pathways. We discuss findings on the antitumor effects of Apo2L/TRAIL alone or in combination with radiotherapy or chemotherapy. In addition, we present recent information from our groups concerning the possible therapeutic benefits of combining Apo2L/TRAIL with the proteasome inhibitor bortezomib.
Topics: Apoptosis; Apoptosis Regulatory Proteins; Boronic Acids; Bortezomib; Humans; Membrane Glycoproteins; Neoplasms; Protease Inhibitors; Pyrazines; Signal Transduction; TNF-Related Apoptosis-Inducing Ligand; Tumor Necrosis Factor-alpha
PubMed: 15864587
DOI: 10.1007/s00262-005-0676-3 -
The Oncologist Mar 2007As therapy for hematologic malignancy evolves, new regimens and novel agents that target specific cellular processes allow a more optimistic prognosis for many patients.... (Review)
Review
As therapy for hematologic malignancy evolves, new regimens and novel agents that target specific cellular processes allow a more optimistic prognosis for many patients. Bortezomib and tipifarnib are two new, targeted treatments for hematologic malignancies. Bortezomib, a proteasome inhibitor, has shown impressive efficacy in patients with relapsed multiple myeloma and as initial treatment, including before autologous stem cell transplantation. It has been studied as monotherapy and in combination with standard treatments such as dexamethasone, and with newer agents such as the immunomodulators thalidomide and lenalidomide; response is encouraging, even in patients who have relapsed after previously receiving components of a regimen as single agents. Bortezomib is generally well tolerated, including in combination with novel and conventional agents. Tipifarnib is a specific inhibitor of farnesyltransferase. Clinical trials in patients with high-risk acute leukemias and myelodysplastic syndromes have demonstrated good efficacy with tipifarnib. Continued investigation with these new, targeted treatments will further define their use as treatment options in patients with hematologic cancer.
Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Hematologic Neoplasms; Humans; Pyrazines; Quinolones
PubMed: 17405892
DOI: 10.1634/theoncologist.12-3-281 -
Drug Discoveries & Therapeutics Jun 2014As a RNA polymerase inhibitor, 6-fluoro-3-hydroxypyrazine-2-carboxamide commercially named favipiravir has been proved to have potent inhibitory activity against RNA...
As a RNA polymerase inhibitor, 6-fluoro-3-hydroxypyrazine-2-carboxamide commercially named favipiravir has been proved to have potent inhibitory activity against RNA viruses in vitro and in vivo. A four-step synthesis of the compound is described in this article, amidation, nitrification, reduction and fluorination with an overall yield of about 8%. In addition, we reported the crystal structure of the title compound. The molecule is almost planar and the intramolecular O-H(•••)O hydrogen bond makes a 6-member ring. In the crystal, molecules are packing governed by both hydrogen bonds and stacking interactions.
Topics: Amides; Crystallization; Hydrogen Bonding; Pyrazines
PubMed: 25031043
DOI: 10.5582/ddt.2014.01028 -
American Journal of Transplantation :... Mar 2010When new agents such as bortezomib appear, it is important to maintain scientific rigor regarding off-label use of medications.
When new agents such as bortezomib appear, it is important to maintain scientific rigor regarding off-label use of medications.
Topics: Boronic Acids; Bortezomib; Drug Approval; Drug Labeling; Drug Prescriptions; Humans; Immunosuppressive Agents; Off-Label Use; Organ Transplantation; Pyrazines; Research Design; United States; United States Food and Drug Administration
PubMed: 20415896
DOI: 10.1111/j.1600-6143.2010.03025.x -
Blood Aug 2012Proteasome inhibition has emerged as an important therapeutic strategy in multiple myeloma (MM). Since the publication of the first phase 1 trials of bortezomib 10 years... (Review)
Review
Proteasome inhibition has emerged as an important therapeutic strategy in multiple myeloma (MM). Since the publication of the first phase 1 trials of bortezomib 10 years ago, this first-in-class proteasome inhibitor (PI) has contributed substantially to the observed improvement in survival in MM patients over the past decade. Although first approved as a single agent in the relapsed setting, bortezomib is now predominantly used in combination regimens. Furthermore, the standard twice-weekly schedule may be replaced by weekly infusion, especially when bortezomib is used as part of combination regimens in frontline therapy. Indeed, bortezomib is an established component of induction therapy for patients eligible or ineligible for autologous stem cell transplantation. Bortezomib has also been incorporated into conditioning regimens before autologous stem cell transplantation, as well as into post-ASCT consolidation therapy, and in the maintenance setting. In addition, a new route of bortezomib administration, subcutaneous infusion, has recently been approved. Recently, several new agents have been introduced into the clinic, including carfilzomib, marizomib, and MLN9708, and trials investigating these "second-generation" PIs in patients with relapsed/refractory MMs have demonstrated positive results. This review provides an overview of the role of PIs in the treatment of MM, focusing on developments over the past decade.
Topics: Animals; Antineoplastic Agents; Boronic Acids; Bortezomib; Cysteine Proteinase Inhibitors; Humans; Medical Oncology; Multiple Myeloma; Proteasome Inhibitors; Pyrazines; Time Factors
PubMed: 22645181
DOI: 10.1182/blood-2012-04-403733 -
Revista Espanola de Quimioterapia :... Apr 2017Favipiravir (T-705) is a new antiviral drug with strong inhibitory activity on RNA-dependent RNA polymerase of most RNA virus genome. All the influenza viruses have been... (Review)
Review
Favipiravir (T-705) is a new antiviral drug with strong inhibitory activity on RNA-dependent RNA polymerase of most RNA virus genome. All the influenza viruses have been shown fully sensitive to this new antiviral, including genetic strains to neuraminidase inhibitors (oseltamivir) resistance. Its mechanism of action lies in blocking viral replication and induction of lethal mutagenesis which determines the loss of infective activity of influenza viruses. Its activity is particularly intense in the respiratory tract, decreasing the viral load to non-infectious levels. Clinical trials in humans have not yet completed but have very favourable results. It seems that the best therapy would be the combination of favipiravir with oseltamivir; both antivirals are synergistic and avoid the emergence of resistance.
Topics: Amides; Animals; Antiviral Agents; Humans; Influenza, Human; Orthomyxoviridae; Pyrazines
PubMed: 28176519
DOI: No ID Found