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European Journal of Medicinal Chemistry Dec 2022A set of fifteen triterpenoid pyrazines and pyridines was prepared from parent triterpenoid 3-oxoderivatives (betulonic acid, dihydrobetulonic acid, oleanonic acid,...
A set of fifteen triterpenoid pyrazines and pyridines was prepared from parent triterpenoid 3-oxoderivatives (betulonic acid, dihydrobetulonic acid, oleanonic acid, moronic acid, ursonic acid, heterobetulonic acid, and allobetulone). Cytotoxicity of all compounds was tested in eight cancer and two non-cancer cell lines. Evaluation of the structure-activity relationships revealed that the triterpenoid core determined whether the final molecule is active or not, while the heterocycle is able to increase the activity and modulate the specificity. Five compounds (1b, 1c, 2b, 2c, and 8) were found to be preferentially and highly cytotoxic (IC ≈ 1 μM) against leukemic cancer cell lines (CCRF-CEM, K562, CEM-DNR, or K562-TAX). Surprisingly, compounds 1c, 2b, and 2c are 10-fold more active in multidrug-resistant leukemia cells (CEM-DNR and K562-TAX) than in their non-resistant analogs (CCRF-CEM and K562). Pharmacological parameters were measured for the most promising candidates and two types of prodrugs were synthesized: 1) Sugar-containing conjugates, most of which had improved cell penetration and retained high cytotoxicity in the CCRF-CEM cell line, unfortunately, they lost the selectivity against resistant cells. 2) Medoxomil derivatives, among which compounds 26-28 gained activities of IC 0.026-0.043 μM against K562 cells. Compounds 1b, 8, 21, 22, 23, and 24 were selected for the evaluation of the mechanism of action based on their highest cytotoxicity against CCRF-CEM cell line. Several experiments showed that the majority of them cause apoptosis via the mitochondrial pathway. Compounds 1b, 8, and 21 inhibit growth and disintegrate spheroid cultures of HCT116 and HeLa cells, which would be important for the treatment of solid tumors. In summary, compounds 1b, 1c, 2b, 2c, 24, and 26-28 are highly and selectively cytotoxic against cancer cell lines and were selected for future in vivo tests and further development of anticancer drugs.
Topics: Humans; Prodrugs; Pyrazines; Membrane Potential, Mitochondrial; Antineoplastic Agents, Phytogenic; HeLa Cells; Drug Resistance, Neoplasm; Cell Line, Tumor; Triterpenes; Antineoplastic Agents; Pyridines
PubMed: 36174412
DOI: 10.1016/j.ejmech.2022.114777 -
Molecules (Basel, Switzerland) Feb 2022There are numerous pyrazine and phenazine compounds that demonstrate biological activities relevant to the treatment of disease. In this review, we discuss pyrazine and... (Review)
Review
There are numerous pyrazine and phenazine compounds that demonstrate biological activities relevant to the treatment of disease. In this review, we discuss pyrazine and phenazine agents that have shown potential therapeutic value, including several clinically used agents. In addition, we cover some basic science related to pyrazine and phenazine heterocycles, which possess interesting reactivity profiles that have been on display in numerous cases of innovative total synthesis approaches, synthetic methodologies, drug discovery efforts, and medicinal chemistry programs. The majority of this review is focused on presenting instructive total synthesis and medicinal chemistry efforts of select pyrazine and phenazine compounds, and we believe these incredible heterocycles offer promise in medicine.
Topics: Chemistry, Pharmaceutical; Drug Discovery; Heterocyclic Compounds; Humans; Phenazines; Pyrazines
PubMed: 35164376
DOI: 10.3390/molecules27031112 -
Molecules (Basel, Switzerland) Apr 2021A radical approach to late-stage functionalization using photoredox and Diversinate chemistry on the Open Source Malaria (OSM) triazolopyrazine scaffold (Series 4)...
A radical approach to late-stage functionalization using photoredox and Diversinate chemistry on the Open Source Malaria (OSM) triazolopyrazine scaffold (Series 4) resulted in the synthesis of 12 new analogues, which were characterized by NMR, UV, and MS data analysis. The structures of four triazolopyrazines were confirmed by X-ray crystal structure analysis. Several minor and unexpected side products were generated during these studies, including two resulting from a possible disproportionation reaction. All compounds were tested for their ability to inhibit the growth of the malaria parasite (3D7 and Dd2 strains) and for cytotoxicity against a human embryonic kidney (HEK293) cell line. Moderate antimalarial activity was observed for some of the compounds, with IC values ranging from 0.3 to >20 µM; none of the compounds displayed any toxicity against HEK293 at 80 µM.
Topics: Alcohols; Antimalarials; Chemistry Techniques, Synthetic; Crystallography, X-Ray; Humans; Magnetic Resonance Spectroscopy; Models, Molecular; Molecular Structure; Parasitic Sensitivity Tests; Plasmodium falciparum; Pyrazines; Structure-Activity Relationship
PubMed: 33919319
DOI: 10.3390/molecules26092421 -
Expert Opinion on Pharmacotherapy Nov 2014Bortezomib , the first proteasome inhibitor (PI) to be evaluated in humans, is approved in the USA and Europe for the treatment of patients with multiple myeloma, and in... (Review)
Review
INTRODUCTION
Bortezomib , the first proteasome inhibitor (PI) to be evaluated in humans, is approved in the USA and Europe for the treatment of patients with multiple myeloma, and in the USA for patients with relapsed mantle cell lymphoma (MCL).
AREAS COVERED
This review examines the role of bortezomib in the therapy of non-Hodgkin's lymphoma (NHL). Bortezomib may be particularly effective against the NF-κB-dependent activated B-cell subtype of diffuse large B-cell lymphoma. The combination of bortezomib with rituximab and dexamethasone represents a standard approach for the treatment of Waldenström's macroglobulinemia, and that with bendamustine and rituximab has demonstrated excellent efficacy in follicular lymphoma. Combinations with other novel agents, such as inhibitors of cyclin-dependent kinases or histone deacetylases, also hold substantial promise in NHL. Unmet needs in NHL, competitor compounds, chemistry, pharmacokinetics, pharmacodynamics and safety and tolerability of bortezomib are also discussed.
EXPERT OPINION
The success of bortezomib in MCL has validated the proteasome as a therapeutic target in NHL. Rational combinations, for example, with Bruton's tyrosine kinase inhibitors or BH3-mimetics, may hold the key to optimizing the therapeutic potential of PIs in NHL. Future trials are likely to involve newer agents with improved pharmacodynamic (e.g., carfilzomib, marizomib) or pharmacokinetic (e.g., ixazomib, oprozomib) properties.
Topics: Antineoplastic Agents; Boronic Acids; Bortezomib; Humans; Lymphoma, Non-Hodgkin; Multiple Myeloma; Proteasome Inhibitors; Pyrazines
PubMed: 25263936
DOI: 10.1517/14656566.2014.965142 -
Archives of Pharmacal Research Nov 2021The site-selective and metal-free C-H nitration reaction of quinoxalinones and pyrazinones as biologically important N-heterocycles with t-butyl nitrite is described. A...
The site-selective and metal-free C-H nitration reaction of quinoxalinones and pyrazinones as biologically important N-heterocycles with t-butyl nitrite is described. A wide range of quinoxalinones were efficiently applied in this transformation, providing C7-nitrated quinoxalinones without undergoing C3-nitration. From the view of mechanistic point, the radical addition reaction exclusively occurred at the electron-rich aromatic region beyond electron-deficient N-heterocycle ring. This is a first report on the C7-H functionalization of quinoxalinones under metal-free conditions. In contrast, the nitration reaction readily takes place at the C3-position of pyrazinones. This transformation is characterized by the scale-up compatibility, mild reaction conditions, and excellent functional group tolerance. The applicability of the developed method is showcased by the selective reduction of NO functionality on the C7-nitrated quinoxalinone product, providing aniline derivatives. Combined mechanistic investigations aided the elucidation of a plausible reaction mechanism.
Topics: Aniline Compounds; Chemistry Techniques, Synthetic; Nitrites; Pyrazines; Quinoxalines
PubMed: 34664211
DOI: 10.1007/s12272-021-01351-5 -
British Journal of Haematology Feb 2017
Topics: Boronic Acids; Bortezomib; Humans; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Pyrazines
PubMed: 28145575
DOI: 10.1111/bjh.14503 -
Chemistry, An Asian Journal Nov 2019Eight different compounds, all nucleoside analogues, could presently be considered as potential drug candidates for the treatment of Ebola virus (EBOV) and/or other... (Review)
Review
Eight different compounds, all nucleoside analogues, could presently be considered as potential drug candidates for the treatment of Ebola virus (EBOV) and/or other hemorrhagic fever virus (HFV) infections. They can be considered as either (i) adenine analogues (3-deazaneplanocin A, galidesivir, GS-6620 and remdesivir) or (ii) guanine analogues containing the carboxamide entity (ribavirin, EICAR, pyrazofurin and favipiravir). All eight owe their mechanism of action to hydrogen bonded base pairing with either (i) uracil or (ii) cytosine. Four out of the eight compounds (galidesivir, GS-6620, remdesivir and pyrazofurin) are C-nucleosides, and two of them (GS-6620, remdesivir) also contain a phosphoramidate part. The C-nucleoside and phosphoramidate (and for the adenine analogues the 1'-cyano group as well) may be considered as essential attributes for their antiviral activity.
Topics: Adenine; Adenosine; Alanine; Amides; Antiviral Agents; Base Pairing; Ebolavirus; Guanine; Hemorrhagic Fevers, Viral; Humans; Nucleotides; Phosphoric Acids; Pyrazines; Triazines
PubMed: 31389664
DOI: 10.1002/asia.201900841 -
Biomolecules Oct 2021Alkyl-methoxypyrazines are an important class of odor-active molecules that contribute green, 'unripe' characters to wine and are considered undesirable in most wine... (Review)
Review
Alkyl-methoxypyrazines are an important class of odor-active molecules that contribute green, 'unripe' characters to wine and are considered undesirable in most wine styles. They are naturally occurring grape metabolites in many cultivars, but can also be derived from some Coccinellidae species when these 'ladybugs' are inadvertently introduced into the must during harvesting operations. The projected impacts of climate change are discussed, and we conclude that these include an altered alkyl-methoxypyrazine composition in grapes and wines in many wine regions. Thus, a careful consideration of how to manage them in both the vineyard and winery is important and timely. This review brings together the relevant literatures on viticultural and oenological interventions aimed at mitigating alkyl-methoxypyrazine loads, and makes recommendations on their management with an aim to maintaining wine quality under a changing and challenging climate.
Topics: Climate Change; Food Contamination; Fruit; Gas Chromatography-Mass Spectrometry; Humans; Odorants; Pyrazines; Vitis; Wine
PubMed: 34680154
DOI: 10.3390/biom11101521 -
Current Pharmaceutical Design 2013The cancer drug discovery field has placed much emphasis on the identification of novel and cancer-specific molecular targets. A rich source of such targets for the... (Review)
Review
The cancer drug discovery field has placed much emphasis on the identification of novel and cancer-specific molecular targets. A rich source of such targets for the design of novel anti-tumor agents is the ubiqutin-proteasome system (UP-S), a tightly regulated, highly specific pathway responsible for the vast majority of protein turnover within the cell. Because of its critical role in almost all cell processes that ensure normal cellular function, its inhibition at one point in time was deemed non-specific and therefore not worth further investigation as a molecular drug target. However, today the proteasome is one of the most promising anti-cancer drug targets of the century. The discovery that tumor cells are in fact more sensitive to proteasome inhibitors than normal cells indeed paved the way for the design of its inhibitors. Such efforts have led to bortezomib, the first FDA approved proteasome inhibitor now used as a frontline treatment for newly diagnosed multiple myeloma (MM), relapsed/refractory MM and mantle cell lymphoma. Though successful in improving clinical outcomes for patients with hematological malignancies, relapse often occurs in those who initially responded to bortezomib. Therefore, the acquisition of bortezomib resistance is a major issue with its therapy. Furthermore, some neuro-toxicities have been associated with bortezomib treatment and its efficacy in solid tumors is lacking. These observations have encouraged researchers to pursue the next generation of proteasome inhibitors, which would ideally overcome bortezomib resistance, have reduced toxicities and a broader range of anti-cancer activity. This review summarizes the success and limitations of bortezomib, and describes recent advances in the field, including, and most notably, the most recent FDA approval of carfilzomib in July, 2012, a second generation proteasome inhibitor. Other proteasome inhibitors currently in clinical trials and those that are currently experimental grade will also be discussed.
Topics: Animals; Antineoplastic Agents; Boronic Acids; Bortezomib; Humans; Neoplasms; Proteasome Endopeptidase Complex; Pyrazines
PubMed: 23181572
DOI: 10.2174/1381612811319220012 -
EBioMedicine Oct 2021Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease with high mortality, however with no effective therapy available. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease with high mortality, however with no effective therapy available.
METHODS
The effect of favipiravir (FPV) in treating SFTS was evaluated by an integrated analysis on data collected from a single-arm study (n=428), a surveillance study (n=2350) and published data from a randomized controlled trial study (n=145). A 1:1 propensity score matching was performed to include 780 patients: 390 received FPV and 390 received supportive therapy only. Case fatality rates (CFRs), clinical progress, and adverse effects were compared.
FINDINGS
FPV treatment had significantly reduced CFR from 20.0% to 9.0% (odds ratio 0.38, 95% confidence interval 0.23-0.65), however showing heterogeneity when patients were grouped by age, onset-to-admission interval, initial viral load and therapy duration. The effect of FPV was significant only among patients aged ≤70 years, with onset-to-admission interval ≤5 days, therapy duration ≥5 days or baseline viral load ≤1 × 10 copies/mL. Age-stratified analysis revealed no benefit in the aging group >70 years, regardless of their sex, onset-to-admission interval, therapy duration or baseline viral load. However, for both ≤60 and 60-70 years groups, therapy duration and baseline viral load differentially affected FPV therapy efficiency. Hyperuricemia and thrombocytopenia, as the major adverse response of FPV usage, were observed in >70 years patients.
INTERPRETATION
FPV was safe in treating SFTS patients but showed no benefit for those aged >70 years. Instant FPV therapy could highly benefit SFTS patients aged 60-70 years.
FUNDING
China Natural Science Foundation (No. 81825019, 82073617 and 81722041) and China Mega-project for Infectious Diseases (2018ZX10713002 and 2015ZX09102022).
Topics: Aged; Amides; Antiviral Agents; Female; Humans; Male; Middle Aged; Pyrazines; Severe Fever with Thrombocytopenia Syndrome; Treatment Outcome; Viral Load
PubMed: 34563924
DOI: 10.1016/j.ebiom.2021.103591