-
Journal of Hematology & Oncology Nov 2010Discovery of new treatments for lymphoma that prolong survival and are less toxic than currently available agents represents an urgent unmet need. We now have a better... (Review)
Review
Discovery of new treatments for lymphoma that prolong survival and are less toxic than currently available agents represents an urgent unmet need. We now have a better understanding of the molecular pathogenesis of lymphoma, such as aberrant signal transduction pathways, which have led to the discovery and development of targeted therapeutics. The ubiquitin-proteasome and the Akt/mammalian target of rapamycin (mTOR) pathways are examples of pathological mechanisms that are being targeted in drug development efforts. Bortezomib (a small molecule protease inhibitor) and the mTOR inhibitors temsirolimus, everolimus, and ridaforolimus are some of the targeted therapies currently being studied in the treatment of aggressive, relapsed/refractory lymphoma. This review will discuss the rationale for and summarize the reported findings of initial and ongoing investigations of mTOR inhibitors and other small molecule targeted therapies in the treatment of lymphoma.
Topics: Boronic Acids; Bortezomib; Everolimus; Humans; Lymphoma; Molecular Targeted Therapy; Pyrazines; Signal Transduction; Sirolimus; Survival Analysis
PubMed: 21092307
DOI: 10.1186/1756-8722-3-45 -
Molecules (Basel, Switzerland) Mar 2020According to the World Health Organization, tuberculosis is still in the top ten causes of death from a single infectious agent, killing more than 1.7 million people...
According to the World Health Organization, tuberculosis is still in the top ten causes of death from a single infectious agent, killing more than 1.7 million people worldwide each year. The rising resistance developed by against currently used antituberculars is an imperative to develop new compounds with potential antimycobacterial activity. As a part of our continuous research on structural derivatives of the first-line antitubercular pyrazinamide, we have designed, prepared, and assessed the in vitro whole cell growth inhibition activity of forty-two novel 5-alkylamino--phenylpyrazine-2-carboxamides with various length of the alkylamino chain (propylamino to octylamino) and various simple substituents on the benzene ring. Final compounds were tested against H37Ra and four other mycobacterial strains (, , , ) in a modified Microplate Alamar Blue Assay. We identified several candidate molecules with micromolar MIC against H37Ra and low in vitro cytotoxicity in HepG2 cell line, for example, -(4-hydroxyphenyl)-5-(pentylamino)pyrazine-2-carboxamide (, MIC = 3.91 µg/mL or 13.02 µM, SI > 38) and 5-(heptylamino)--(-tolyl)pyrazine-2-carboxamide (, MIC = 0.78 µg/mL or 2.39 µM, SI > 20). In a complementary screening, we evaluated the in vitro activity against bacterial and fungal strains of clinical importance. We observed no antibacterial activity and sporadic antifungal activity against the genus.
Topics: Antitubercular Agents; Drug Design; Drug Development; Humans; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Pyrazinamide; Pyrazines; Structure-Activity Relationship
PubMed: 32231166
DOI: 10.3390/molecules25071561 -
Molecules (Basel, Switzerland) Nov 2020Pulcherriminic acid is a cyclic dipeptide found mainly in and yeast. Due to the ability of pulcherriminic acid to chelate Fe to produce reddish brown pulcherrimin,... (Review)
Review
Pulcherriminic acid is a cyclic dipeptide found mainly in and yeast. Due to the ability of pulcherriminic acid to chelate Fe to produce reddish brown pulcherrimin, microorganisms capable of synthesizing pulcherriminic acid compete with other microorganisms for environmental iron ions to achieve bacteriostatic effects. Therefore, studying the biosynthetic pathway and their enzymatic catalysis, gene regulation in the process of synthesis of pulcherriminic acid in can facilitate the industrial production, and promote the wide application in food, agriculture and medicine industries. After initially discussing, this review summarizes current research on the synthesis of pulcherriminic acid by , which includes the crystallization of key enzymes, molecular catalytic mechanisms, regulation of synthetic pathways, and methods to improve efficiency in synthesizing pulcherriminic acid and its precursors. Finally, possible applications of pulcherriminic acid in the fermented food, such as Chinese Baijiu, applying combinatorial biosynthesis will be summarized.
Topics: Anti-Bacterial Agents; Bacillus; Biosynthetic Pathways; Pyrazines
PubMed: 33260656
DOI: 10.3390/molecules25235611 -
Preventive Medicine Sep 1993Oltipraz (4-methyl-5-(2-pyrazinyl)-1,2-dithiole-3-thione) is an antischistosomal drug presently under evaluation as a possible chemoprotective agent in humans. To date,... (Review)
Review
Oltipraz (4-methyl-5-(2-pyrazinyl)-1,2-dithiole-3-thione) is an antischistosomal drug presently under evaluation as a possible chemoprotective agent in humans. To date, oltipraz has proved effective as an inhibitor of carcinogenesis in experimental models for breast, bladder, liver, forestomach, colon, tracheal, lung, and skin cancer. Studies on the mechanisms of action of oltipraz indicate that it affects the metabolism and disposition of chemical carcinogens, principally through the induction of electrophile detoxication enzymes. While this feature is common to many different classes of both natural and synthetic experimental chemoprotectors (i.e., phenolic antioxidants, isothiocyanates, flavonoids, indoles, cinnamates, coumarins, terpenes, and others), oltipraz may offer the earliest and easiest prospect for examining the role of enzyme induction as a protective strategy in humans. Unlike the situation with many of the anutrients, substantial preclinical research has already been conducted with oltipraz to establish its safety and efficacy in animals. Hopefully, Phase I investigations will demonstrate a high tolerance for oltipraz in the chemoprotective dose range of the drug. A major concern for the success of any trial is selecting participants who are likely to adhere to the intervention as well as to all aspects of the protocol. Factors influencing participation and adherence in a trial include the design of the trial, the nature of the disease under study as well as the nature of the intervention, in particular the toxicities of the intervention (J. A. Tangrea, M. E. Adrianza, and W. E. Helsel, Cancer Epi Biomarkers Prev 1992; 1:325-330). Chemoprotection trials with oltipraz have an excellent prospect for success. Individuals with known carcinogenic exposures are likely to be interested in participation in trials designed to reduce the risks of the exposures. Moreover, the availability of intermediate markers reflecting the modulation of the biologically effective dose of environmental carcinogens as study end points will enable efficient trials to be designed.
Topics: Animals; Anticarcinogenic Agents; Clinical Trials as Topic; Drug Screening Assays, Antitumor; Female; Humans; Male; Neoplasms; Neoplasms, Experimental; Pyrazines; Thiones; Thiophenes
PubMed: 8234218
DOI: 10.1006/pmed.1993.1072 -
Oncology (Williston Park, N.Y.) Dec 2004Bortezomib (PS-341, Velcade) is a novel, first-in-class proteasome inhibitor with antitumor activity against a number of hematologic and nonhematologic malignancies.... (Review)
Review
Bortezomib (PS-341, Velcade) is a novel, first-in-class proteasome inhibitor with antitumor activity against a number of hematologic and nonhematologic malignancies. Based on the results of phase II clinical trials, bortezomib received accelerated US Food and Drug Administration approval on May 13, 2003, for the treatment of multiple myeloma patients whose disease has progressed after they have received at least two prior conventional therapies. The results of phase III studies evaluating bortezomib as first- or second-line therapy, or in combination with other commonly prescribed therapies in multiple myeloma patients, are eagerly awaited. Studies assessing the antitumor effects of bortezomib in other hematologic malignancies and solid tumors are also under way. A thorough understanding of the pharmacology, pharmacodynamics, and pharmacokinetics of this novel compound is essential for appropriate prescribing and monitoring of bortezomib therapy. Bortezomib is rapidly distributed into tissues after administration of a single dose, with an initial plasma distribution half-life of less than 10 minutes, followed by a terminal elimination half-life of more than 40 hours. Maximum proteasome inhibition occurs within 1 hour and recovers close to baseline within 72 to 96 hours after administration. Bortezomib is primarily metabolized by oxidative deboronation to one of two inactive enantiomers that are further processed and eliminated, both renally and in bile. Bortezomib has been shown to be a substrate of several cytochrome P450 isoenzymes using in vitro systems. Adverse effects of bortezomib are generally mild and effectively managed with supportive care. Bortezomib should be administered with caution to patients with preexisting fluid retention and patients with baseline platelet counts of less than 70,000/microL. Dose reductions are recommended for patients experiencing peripheral neuropathy, grade 3 or higher nonhematologic toxicities, or grade 4 hematologic toxicities. Formal drug interaction studies have not been performed, but bortezomib has been administered in combination with a variety of antitumor agents without significant alterations to its pharmacokinetic or pharmacodynamic profile.
Topics: Animals; Antineoplastic Agents; Boronic Acids; Bortezomib; Cell Cycle; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Dose-Response Relationship, Drug; Drug Administration Schedule; Humans; Lymphoma, Non-Hodgkin; Multiple Myeloma; Protease Inhibitors; Proteasome Inhibitors; Pyrazines; Time Factors
PubMed: 15688598
DOI: No ID Found -
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 -
Antiviral Research Jun 2009A series of pyrazinecarboxamide derivatives T-705 (favipiravir), T-1105 and T-1106 were discovered to be candidate antiviral drugs. These compounds have demonstrated... (Review)
Review
A series of pyrazinecarboxamide derivatives T-705 (favipiravir), T-1105 and T-1106 were discovered to be candidate antiviral drugs. These compounds have demonstrated good activity in treating viral infections in laboratory animals caused by various RNA viruses, including influenza virus, arenaviruses, bunyaviruses, West Nile virus (WNV), yellow fever virus (YFV), and foot-and-mouth disease virus (FMDV). Treatment has in some cases been effective when initiated up to 5-7 days after virus infection, when the animals already showed signs of illness. Studies on the mechanism of action of T-705 have shown that this compound is converted to the ribofuranosyltriphosphate derivative by host enzymes, and this metabolite selectively inhibits the influenza viral RNA-dependent RNA polymerase without cytotoxicity to mammalian cells. Interestingly, these compounds do not inhibit host DNA and RNA synthesis and inosine 5'-monophosphate dehydrogenase (IMPDH) activity. From in vivo studies using several animal models, the pyrazinecarboxamide derivatives were found to be effective in protecting animals from death, reducing viral burden, and limiting disease manifestations, even when treatment was initiated after virus inoculation. Importantly, T-705 imparts its beneficial antiviral effects without significant toxicity to the host. Prompt development of these compounds is expected to provide effective countermeasures against pandemic influenza virus and several bioweapon threats, all of which are of great global public health concern given the current paucity of highly effective broad-spectrum drugs.
Topics: Amides; Animals; Antiviral Agents; Nucleosides; Pyrazines; RNA Virus Infections; RNA Viruses; RNA-Dependent RNA Polymerase; Viral Proteins
PubMed: 19428599
DOI: 10.1016/j.antiviral.2009.02.198 -
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 -
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 -
Dermatology (Basel, Switzerland) 2008Bortezomib (Velcad) is a proteasome inhibitor recently developed and mainly used for the treatment of multiple myeloma. Bortezomib represents a novel class of drugs...
Bortezomib (Velcad) is a proteasome inhibitor recently developed and mainly used for the treatment of multiple myeloma. Bortezomib represents a novel class of drugs functioning as proteasome inhibitors. Skin complications of bortezomib treatment are very frequent but poorly characterized. We describe the case of a patient who developed erythematous and edematous plaques after treatment with bortezomib. This case illustrates one of the potential reactions associated with bortezomib administration and underlines the need to recognize and report cutaneous side effects of this new drug.
Topics: Antineoplastic Agents; Biopsy; Boronic Acids; Bortezomib; Diagnosis, Differential; Dose-Response Relationship, Drug; Drug Eruptions; Humans; Male; Middle Aged; Multiple Myeloma; Pyrazines; Skin
PubMed: 18216478
DOI: 10.1159/000111513