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Cancer Control : Journal of the Moffitt... 2003Multiple myeloma (MM) is an incurable malignancy that is diagnosed in approximately 15,000 people in the United States each year. The novel proteasome inhibitor... (Review)
Review
BACKGROUND
Multiple myeloma (MM) is an incurable malignancy that is diagnosed in approximately 15,000 people in the United States each year. The novel proteasome inhibitor bortezomib has shown antitumor activity in preclinical studies and has entered clinical trials, with encouraging results to date.
METHODS
We review and summarize preclinical work demonstrating the tumoricidal effects of proteasome inhibition, focusing on the potent and selective proteasome inhibitor bortezomib, the first such agent to progress to clinical trials. We also address the potential for bortezomib as a therapy for MM.
RESULTS
In preclinical studies bortezomib appears not only to have activity against MM cells, but also to downregulate protective interactions with bone marrow stromal cells and to inhibit blood vessel development. Proteasome inhibition also has been shown to interfere with protective interactions between MM cells and the bone marrow, and to restrict tumor-associated angiogenesis in preclinical models.
CONCLUSIONS
Proteasome inhibition is a promising new investigational avenue for cancer therapy. Bortezomib is currently available for the treatment of relapsed and refractory MM. Further trials are underway to assess the safety and efficacy of this agent in MM and a range of other cancers.
Topics: Antineoplastic Agents; Boronic Acids; Bortezomib; Humans; Multiple Myeloma; Protease Inhibitors; Pyrazines
PubMed: 14581890
DOI: 10.1177/107327480301000502 -
BMJ Case Reports Aug 2011The authors describe a case of episodic acute pneumonitis occurring after repeated doses of bortezomib, a drug being used increasingly to treat multiple myeloma. The...
The authors describe a case of episodic acute pneumonitis occurring after repeated doses of bortezomib, a drug being used increasingly to treat multiple myeloma. The delay in presentation each time with fever, dyspnoea, hypoxia and interstitial radiological changes contributed to under-recognition of this complication, which has so far been described in only a handful of patients, but the pattern seen may offer clues to pathogenesis and potential treatments. This case highlights the need for both physicians and patients consenting to bortezomib treatment to be more aware of this potentially fatal adverse effect.
Topics: Antineoplastic Agents; Boronic Acids; Bortezomib; Humans; Male; Middle Aged; Multiple Myeloma; Pneumonia; Pyrazines
PubMed: 22688931
DOI: 10.1136/bcr.03.2011.4028 -
Haematologica Sep 2014
Topics: Amyloidosis; Boronic Acids; Bortezomib; Cardiomyopathies; Cyclophosphamide; Dexamethasone; Female; Humans; Immunoglobulin Light-chain Amyloidosis; Male; Pyrazines
PubMed: 25176981
DOI: 10.3324/haematol.2014.113464 -
The Journal of Physical Chemistry. A Jun 2022Coelenterazine and other imidazopyrazinones are important bioluminescent substrates widespread in marine species and can be found in eight phyla of luminescent...
Coelenterazine and other imidazopyrazinones are important bioluminescent substrates widespread in marine species and can be found in eight phyla of luminescent organisms. Light emission from these systems is caused by the formation and subsequent thermolysis of a dioxetanone intermediate, whose decomposition allows for efficient chemiexcitation to singlet excited states. Interestingly, some studies have also reported the involvement of unexpected dioxetane intermediates in the chemi- and bioluminescent reactions of Coelenterazine, albeit with little information on the underlying mechanisms of these new species. Herein, we have employed a theoretical approach based on density functional theory to study for the first time the thermolysis reaction and chemiexcitation profile of two Coelenterazine dioxetanes. We have found that the thermolysis reactions of these species are feasible but with relevant energetic differences. More importantly, we found that the singlet chemiexcitation profiles of these dioxetanes are significantly less efficient than the corresponding dioxetanones. Furthermore, we identified triplet chemiexcitation pathways for the Coelenterazine dioxetanes. Given this, the chemiexcitation of these dioxetanes should lead only to minimal luminescence. Thus, our theoretical investigation of these systems indicates that the thermolysis of these dioxetanes should only provide "dark" pathways for the formation of nonluminescent degradation products of the chemi- and bioluminescent reactions of Coelenterazine and other imidazopyrazinones.
Topics: Imidazoles; Luminescent Measurements; Models, Theoretical; Pyrazines
PubMed: 35612291
DOI: 10.1021/acs.jpca.2c01835 -
Molecules (Basel, Switzerland) Oct 2023As a new approach, pyrrolo[1,2-]pyrazines were synthesized through the cyclization of 2-formylpyrrole-based enaminones in the presence of ammonium acetate. The...
As a new approach, pyrrolo[1,2-]pyrazines were synthesized through the cyclization of 2-formylpyrrole-based enaminones in the presence of ammonium acetate. The enaminones were prepared with a straightforward method, reacting the corresponding alkyl 2-(2-formyl-1-pyrrol-1-yl)acetates, 2-(2-formyl-1-pyrrol-1-yl)acetonitrile, and 2-(2-formyl-1-pyrrol-1-yl)acetophenones with DMFDMA. Analogous enaminones elaborated from alkyl ()-3-(1-pyrrol-2-yl)acrylates were treated with a Lewis acid to afford indolizines. The antifungal activity of the series of substituted pyrroles, pyrrole-based enaminones, pyrrolo[1,2-]pyrazines, and indolizines was evaluated on six spp., including two multidrug-resistant ones. Compared to the reference drugs, most test compounds produced a more robust antifungal effect. Docking analysis suggests that the inhibition of yeast growth was probably mediated by the interaction of the compounds with the catalytic site of HMGR of the species.
Topics: Antifungal Agents; Pyrroles; Indolizines; Pyrazines; Microbial Sensitivity Tests; Candida
PubMed: 37894702
DOI: 10.3390/molecules28207223 -
Oncology (Williston Park, N.Y.) Nov 2011The ubiquitin-proteasome pathway was first validated as a target for cancer therapy with the demonstration of the activity of the boronic acid proteasome inhibitor (PI)... (Review)
Review
The ubiquitin-proteasome pathway was first validated as a target for cancer therapy with the demonstration of the activity of the boronic acid proteasome inhibitor (PI) bortezomib (Velcade) against relapsed and relapsed/refractory multiple myeloma. Another generation of PIs is now entering the clinical arena; this includes intravenous agents such as carfilzomib, CEP-18770, and marizomib, and oral drugs such as MLN9708 and ONX 0912. These novel agents will likely first be used for patients with disease that has either relapsed or been refractory to prior therapy (including bortezomib-based regimens) because of their ability to overcome drug resistance, or will be used in patients who are intolerant of, or are not candidates for bortezomib. Preclinical studies also suggest that PIs may act synergistically with other conventional and novel agents, or even with one another in rationally designed combination regimens. In addition, other inhibitors that selectively target only the immunoproteasome and not the constitutive proteasome, as well as agents that bind to noncatalytic proteasome subunits, are emerging as potential drug candidates. Taken together, it seems likely that we have only begun to appreciate the full potential of inhibition of the proteasome. This article extrapolates our current knowledge into an algorithm for the future use of these inhibitors against multiple myeloma.
Topics: Boronic Acids; Bortezomib; Humans; Multiple Myeloma; Proteasome Inhibitors; Pyrazines; Recurrence
PubMed: 25188482
DOI: No ID Found -
Scientific Reports Feb 2019Large-scale microalgae cultivations are increasingly used for the production of animal feed, nutritional supplements and various high-value bioproducts. Due to the...
Large-scale microalgae cultivations are increasingly used for the production of animal feed, nutritional supplements and various high-value bioproducts. Due to the process size and other limitations, contaminations of microalgae fermentations with other photoautotrophic microorganism are frequently observed. In the present study, we explored the applicability of 5-isobutyl-2,3-dimethylpyrazine for the removal of contaminating microalgae from industrial photobioreactors. In order to select a representative microbial population for susceptibility experiments, reactor samples were obtained from a multi-stage cultivation process. Assignments of 18S rRNA gene fragment amplicons indicated that Haematococcus, Chlorella, and Scenedesmus were the three most frequently occurring microalgae genera in the selected reactors. Following the isolation of representative algae cultures, susceptibility tests were conducted with the antimicrobial pyrazine. It was demonstrated that all isolated contaminants are highly susceptible to the bioactive compound. The highest tolerance towards the alkylpyrazine was observed with Scenedesmus vacuolatus; solutions with 1.66% (v/v) of the active compound were required for its deactivation. Further tests with the vaporized pyrazine showed consistent reductions in the viability of treated microalgae. This pilot study provides evidence for the applicability of a novel, nature-based alternative for bioreactor decontaminations.
Topics: Bioreactors; Decontamination; Microalgae; Pyrazines
PubMed: 30814601
DOI: 10.1038/s41598-019-39673-6 -
The Oncologist 2003Bortezomib (formerly PS-341), a promising new drug for the treatment of multiple myeloma, recently received accelerated approval from the U.S. Food and Drug... (Review)
Review
Bortezomib (formerly PS-341), a promising new drug for the treatment of multiple myeloma, recently received accelerated approval from the U.S. Food and Drug Administration (FDA) for the therapy of patients with progressive myeloma after previous treatment. Two phase II studies of bortezomib used the same schedule of twice-weekly i.v. dosing for the first 2 weeks of each 3-week cycle. In a randomized study of 54 patients, two doses were compared (1.0 and 1.3 mg/m2) and objective responses occurred at both dose levels (23% versus 35%), including one complete response in each arm. In the other phase II study, 202 heavily pretreated patients (median of six prior therapies) all received the same schedule at 1.3 mg/m2. Of 188 evaluable patients, complete responses occurred in five (3%) and partial responses occurred in 47 (25%). The median duration of response was 365 days. The most clinically relevant adverse events were asthenic conditions, nausea, vomiting, diarrhea, thrombocytopenia, and a peripheral neuropathy that often was painful. This report highlights the FDA analysis supporting the accelerated approval.
Topics: Antineoplastic Agents; Boronic Acids; Bortezomib; Drug Approval; Humans; Multiple Myeloma; Pyrazines; Randomized Controlled Trials as Topic; United States; United States Food and Drug Administration
PubMed: 14657528
DOI: 10.1634/theoncologist.8-6-508 -
Science Advances Apr 2017Bioluminescent fungi are spread throughout the globe, but details on their mechanism of light emission are still scarce. Usually, the process involves three key...
Bioluminescent fungi are spread throughout the globe, but details on their mechanism of light emission are still scarce. Usually, the process involves three key components: an oxidizable luciferin substrate, a luciferase enzyme, and a light emitter, typically oxidized luciferin, and called oxyluciferin. We report the structure of fungal oxyluciferin, investigate the mechanism of fungal bioluminescence, and describe the use of simple synthetic α-pyrones as luciferins to produce multicolor enzymatic chemiluminescence. A high-energy endoperoxide is proposed as an intermediate of the oxidation of the native luciferin to the oxyluciferin, which is a pyruvic acid adduct of caffeic acid. Luciferase promiscuity allows the use of simple α-pyrones as chemiluminescent substrates.
Topics: Fungal Proteins; Fungi; Indoles; Luciferases; Luminescence; Pyrazines; Pyrones
PubMed: 28508049
DOI: 10.1126/sciadv.1602847 -
Drug Design, Development and Therapy 2013Sitagliptin is the first dipeptidylpeptidase-4 inhibitor to be used in the management of type 2 diabetes. It is widely used as an add-on therapy to ongoing management or... (Review)
Review
Sitagliptin is the first dipeptidylpeptidase-4 inhibitor to be used in the management of type 2 diabetes. It is widely used as an add-on therapy to ongoing management or as monotherapy where it is deemed necessary. It has been found to be beneficial in improving β-cell function and glycemic control, and also is used in special circumstances like chronic kidney disease, with appropriate dose reductions. Overall, cardiovascular outcomes are no different from other oral hypoglycemic agents. In this review article we have summarized all the previous studies relevant to sitagliptin use in clinical practice and emphasized its use in various stages of chronic kidney disease.
Topics: Animals; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dose-Response Relationship, Drug; Humans; Hypoglycemic Agents; Pyrazines; Renal Insufficiency, Chronic; Severity of Illness Index; Sitagliptin Phosphate; Triazoles
PubMed: 24039399
DOI: 10.2147/DDDT.S32331