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Molecules (Basel, Switzerland) Jun 2021Novel symmetrical bis-pyrrolo[2,3-]pyrimidines and bis-purines and their monomers were synthesized and evaluated for their antiproliferative activity in human lung...
Novel symmetrical bis-pyrrolo[2,3-]pyrimidines and bis-purines and their monomers were synthesized and evaluated for their antiproliferative activity in human lung adenocarcinoma (A549), cervical carcinoma (HeLa), ductal pancreatic adenocarcinoma (CFPAC-1) and metastatic colorectal adenocarcinoma (SW620) cells. The use of ultrasound irradiation as alternative energy input in Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) shortened the reaction time, increased the reaction efficiency and led to the formation of exclusively symmetric bis-heterocycles. DFT calculations showed that triazole formation is exceedingly exergonic and confirmed that the presence of Cu(I) ions is required to overcome high kinetic requirements and allow the reaction to proceed. The influence of various linkers and 6-substituted purine and regioisomeric 7-deazapurine on their cytostatic activity was revealed. Among all the evaluated compounds, the 4-chloropyrrolo[2,3-]pyrimidine monomer with 4,4'-bis(oxymethylene)biphenyl had the most pronounced, although not selective, growth-inhibitory effect on pancreatic adenocarcinoma (CFPAC-1) cells (IC = 0.79 µM). Annexin V assay results revealed that its strong growth inhibitory activity against CFPAC-1 cells could be associated with induction of apoptosis and primary necrosis. Further structural optimization of bis-chloropyrrolo[2,3-]pyrimidine with aromatic linker is required to develop novel efficient and non-toxic agent against pancreatic cancer.
Topics: A549 Cells; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cycloaddition Reaction; Density Functional Theory; Drug Screening Assays, Antitumor; HeLa Cells; Humans; Pyrimidines; Pyrroles
PubMed: 34206076
DOI: 10.3390/molecules26113334 -
Pharmaceutical Biology Dec 2020Naringenin and tofacitinib are often used together for treatment of rheumatoid arthritis in Chinese clinics. This experiment investigates the effect of naringenin on...
Naringenin and tofacitinib are often used together for treatment of rheumatoid arthritis in Chinese clinics. This experiment investigates the effect of naringenin on the pharmacokinetics of tofacitinib in rats. Twelve Sprague-Dawley rats were randomly divided into two groups (experimental group and control group). The experimental group was pre-treated with naringenin (150 mg/kg/day) for two weeks before dosing tofacitinib, and equal amounts of CMC-Na solution in the control group. After a single oral administration of 5 mg/kg of tofacitinib, 50 μL blood samples were directly collected into 1.5 mL heparinized tubes via the caudal vein at 0.083, 0.5, 1, 2, 3, 4, 6, 8, 10, 12 and 24 h. The plasma concentration of tofacitinib was quantified by UPLC/MS-MS. Results indicated that naringenin could significantly affect the pharmacokinetics of tofacitinib. The AUC of tofacitinib was increased from 1222.81 ± 222.07 to 2016.27 ± 481.62 ng/mL/h, and the difference was significant ( < 0.05). Compared with the control group, the was increased from 0.75 ± 0.29 to 3.00 ± 0.00 h ( < 0.05), and the MRT was increased from 4.90 ± 0.51 to 6.57 ± 0.66 h ( < 0.05), but the clearance was obviously decreased from 4.10 ± 0.72 to 2.42 ± 0.70 L/h/kg ( < 0.05) in experimental group. Although the and of tofacitinib were increased, there were no significant differences ( > 0.05). This research demonstrated a drug-drug interaction between naringenin and tofacitinib possibly when preadministered with naringenin; thus, we should pay attention to this possibility in the clinic.
Topics: Administration, Oral; Animals; Anti-Inflammatory Agents; Area Under Curve; Arthritis, Rheumatoid; Dose-Response Relationship, Drug; Drug Interactions; Female; Flavanones; Piperidines; Pyrimidines; Pyrroles; Rats, Sprague-Dawley; Signal-To-Noise Ratio
PubMed: 32202190
DOI: 10.1080/13880209.2020.1738504 -
Cephalalgia : An International Journal... Aug 2023Atogepant is an oral, small-molecule, calcitonin gene-related peptide receptor antagonist for the preventive treatment of episodic migraine. (Randomized Controlled Trial)
Randomized Controlled Trial
Patient-reported migraine-specific quality of life, activity impairment and headache impact with once-daily atogepant for preventive treatment of migraine in a randomized, 52-week trial.
BACKGROUND
Atogepant is an oral, small-molecule, calcitonin gene-related peptide receptor antagonist for the preventive treatment of episodic migraine.
METHODS
In this 52-week, multicenter, randomized, open-label trial, adults with 4-14 monthly migraine days received atogepant 60 mg once-daily or standard care. Health outcome endpoints collected from participants randomized to atogepant included change from baseline in Migraine-Specific Quality of Life Questionnaire version 2.1 (MSQ v2.1) Role Function-Restrictive (RFR), Role Function-Preventive (RFP) and Emotional Function (EF) domain scores, change in Activity Impairment in Migraine-Diary (AIM-D) Performance of Daily Activities (PDA) and Physical Impairment (PI) domain scores, and change in Headache Impact Test-6 (HIT-6) total score.
RESULTS
Of 744 randomized participants, 521 received atogepant 60 mg in the modified intent-to-treat population. Least-squares mean changes from baseline in MSQ-RFR score were 30.02 (95% confidence interval = 28.16-31.87) at week 12 and 34.70 (95% confidence interval = 32.74-36.66) at week 52. Improvements were also observed in other MSQ domains, AIM-D PDA, PI and HIT-6 total scores. A ≥5-point improvement from baseline in HIT-6 score was observed in 59.9% of participants at week 4 and 80.8% of participants at week 52.
CONCLUSION
Over 52 weeks, atogepant 60 mg once-daily was associated with sustained improvements in quality of life and reductions in activity impairment and headache impact. NCT03700320.
Topics: Humans; Quality of Life; Piperidines; Pyridines; Pyrroles; Spiro Compounds; Calcitonin Gene-Related Peptide Receptor Antagonists; Migraine Disorders; Patient Reported Outcome Measures; Drug Administration Schedule
PubMed: 37638400
DOI: 10.1177/03331024231190296 -
Molecules (Basel, Switzerland) Aug 2019The main goal of this mini review is to summarise the most recent progress in the field of conjugated graft copolymers featuring conjugation across the main chain,... (Review)
Review
The main goal of this mini review is to summarise the most recent progress in the field of conjugated graft copolymers featuring conjugation across the main chain, across side chains or across both. The main approaches to the synthesis of conjugated graft copolymers are highlighted, and the various trends in the development of new copolymer materials and the intended directions of their applications are explored.
Topics: Biosensing Techniques; Chemistry Techniques, Synthetic; Corrosion; Drug Delivery Systems; Hydrogels; Polymers; Polysaccharides, Bacterial; Pyrroles; Waste Disposal, Fluid
PubMed: 31434298
DOI: 10.3390/molecules24163019 -
Journal of Natural Products Mar 2021Metabolomics analysis detected tambjamine alkaloids in aqueous and EtOAc extracts of the marine invertebrates , , , and . Among several tambjamines, the new amino acid...
Metabolomics analysis detected tambjamine alkaloids in aqueous and EtOAc extracts of the marine invertebrates , , , and . Among several tambjamines, the new amino acid derivatives tambjamines M-O (-) were identified by Marfey's advanced analysis, UPLC-MS/MS analyses, and total synthesis. The tambjamine diversity increased from the bryozoan to its nudibranch predators and and attained a higher diversity in , the nudibranch that preys upon and . The total tambjamine content also increases among the trophic levels, probably due to biomagnification. Tambjamines A (), C (), and D () are the major metabolites in the tissues of , , , and and are likely the main chemical defenses of these marine invertebrates.
Topics: Alkaloids; Animals; Aquatic Organisms; Brazil; Chromatography, High Pressure Liquid; Food Chain; Gastropoda; Metabolomics; Molecular Structure; Pyrroles; Tandem Mass Spectrometry
PubMed: 33371682
DOI: 10.1021/acs.jnatprod.0c01043 -
Arthritis Research & Therapy Aug 2021During rheumatoid arthritis (RA), the angiogenic processes, occurring with pannus-formation, may be a therapeutic target. JAK/STAT-pathway may play a role and the aim of...
OBJECTIVE
During rheumatoid arthritis (RA), the angiogenic processes, occurring with pannus-formation, may be a therapeutic target. JAK/STAT-pathway may play a role and the aim of this work was to investigate the inhibiting role of a JAK-inhibitor, tofacitinib, on the angiogenic mechanisms occurring during RA.
METHODS
After ethical approval, JAK-1, JAK-3, STAT-1, STAT-3 and VEGF expression was evaluated on RA-synovial-tissues. In vitro, endothelial cells (ECs), stimulated with 20 ng/ml of VEGF and/or 1 μM of tofacitinib, were assessed for tube formation, migration and proliferation, by Matrigel, Boyden chamber assay and ki67 gene-expression. In vivo, 32 mice received collagen (collagen-induced arthritis (CIA)) and 32 mice PBS (control). At day 19, CIA and controls mice were divided: 16 mice receiving vehicle and 16 mice receiving tofacitinib. At day 35, the arthritis score, the thickness of paw joints and the serum levels of VEGF and Ang-2 were evaluated.
RESULTS
The expression of JAK-1, JAK-3, STAT-1, STAT-3 and VEGF in synovial tissue of RA-patients were significantly higher than healthy controls. In vitro, tofacitinib inhibited the ECs ability to form vessels, to proliferate and to migrate. In vivo, administration of tofacitinib prevented the increase of the arthritis score, the paw thickness, the synovial vessels and VEGF and Ang-2 serum-accumulation, when compared to CIA without tofacitinib.
CONCLUSIONS
We explored the anti-angiogenic role of tofacitinib, reporting its ability to inhibit in vitro the angiogenic mechanisms of ECs and in vivo the formation of new synovial vessels, occurring in CIA model. These findings suggest that the therapeutic effect of tofacitinib during RA may be also related to its anti-angiogenic activity.
Topics: Animals; Arthritis, Experimental; Endothelial Cells; Humans; Mice; Piperidines; Pyrimidines; Pyrroles; Synovial Membrane
PubMed: 34391476
DOI: 10.1186/s13075-021-02587-8 -
Clinical Cancer Research : An Official... Feb 2022We report final antitumor efficacy results from a phase II study of trilaciclib, an intravenous cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, administered prior to... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
We report final antitumor efficacy results from a phase II study of trilaciclib, an intravenous cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, administered prior to gemcitabine plus carboplatin (GCb) in patients with metastatic triple-negative breast cancer (NCT02978716).
PATIENTS AND METHODS
Patients were randomized (1:1:1) to group 1 [GCb (days 1, 8); n = 34], group 2 [trilaciclib prior to GCb (days 1, 8); n = 33], or group 3 [trilaciclib (days 1, 8) and trilaciclib prior to GCb (days 2, 9); n = 35]. Subgroup analyses were performed according to CDK4/6 dependence, level of programmed death-ligand 1 (PD-L1) expression, and RNA-based immune signatures using proportional hazards regression. T-cell receptor (TCR) β CDR3 regions were amplified and sequenced to identify, quantify, and compare the abundance of each unique TCRβ CDR3 at baseline and on treatment.
RESULTS
Median overall survival (OS) was 12.6 months in group 1, not reached in group 2 (HR = 0.31; P = 0.0016), 17.8 months in group 3 (HR = 0.40; P = 0.0004), and 19.8 months in groups 2 and 3 combined (HR = 0.37; P < 0.0001). Efficacy outcomes were comparable regardless of cancer CDK4/6 dependence status and immune signatures. Administering trilaciclib prior to GCb prolonged OS irrespective of PD-L1 status but had greater benefit in the PD-L1-positive population. T-cell activation was enhanced in patients receiving trilaciclib.
CONCLUSIONS
Administering trilaciclib prior to GCb enhanced antitumor efficacy, with significant improvements in OS. Efficacy outcomes in immunologic subgroups and enhancements in T-cell activation suggest these improvements may be mediated via immunologic mechanisms.
Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Pyrimidines; Pyrroles; Triple Negative Breast Neoplasms
PubMed: 34887261
DOI: 10.1158/1078-0432.CCR-21-2272 -
Marine Drugs Mar 2022Two new cyclized thiolopyrrolone derivatives, namely, thiolopyrrolone A () and 2,2-dioxidothiolutin (), together with the kn own compound, thiolutin () were identified...
Two new cyclized thiolopyrrolone derivatives, namely, thiolopyrrolone A () and 2,2-dioxidothiolutin (), together with the kn own compound, thiolutin () were identified from a marine-derived sp. BTBU20218885, which was isolated from a mud sample collected from the coastal region of Xiamen, China. Their chemical structures were determined using spectroscopic data, including HRESIMS, 1D and 2D NMR techniques. possessed a unique unsymmetrical sulfur-containing thiolopyrrolone structure. All the compounds were tested for bioactivities against , , Bacille Calmette-Guérin (BCG), , and . displayed antibacterial activities against BCG, , and with minimum inhibitory concentration (MIC) values of 10, 10, and 100 μg/mL, respectively. Thiolutin () showed antibacterial activities against , BCG, , and with MIC values of 6.25, 0.3125, 0.625, and 3.125 μg/mL, respectively.
Topics: Anti-Infective Agents; Aquatic Organisms; Biological Products; Candida albicans; Cyclization; Microbial Sensitivity Tests; Pyrroles; Streptomyces
PubMed: 35323513
DOI: 10.3390/md20030214 -
Nature Chemical Biology May 2022The marine microbial natural product salinosporamide A (marizomib) is a potent proteasome inhibitor currently in clinical trials for the treatment of brain cancer....
The marine microbial natural product salinosporamide A (marizomib) is a potent proteasome inhibitor currently in clinical trials for the treatment of brain cancer. Salinosporamide A is characterized by a complex and densely functionalized γ-lactam-β-lactone bicyclic warhead, the assembly of which has long remained a biosynthetic mystery. Here, we report an enzymatic route to the salinosporamide core catalyzed by a standalone ketosynthase (KS), SalC. Chemoenzymatic synthesis of carrier protein-tethered substrates, as well as intact proteomics, allowed us to probe the reactivity of SalC and understand its role as an intramolecular aldolase/β-lactone synthase with roles in both transacylation and bond-forming reactions. Additionally, we present the 2.85-Å SalC crystal structure that, combined with site-directed mutagenesis, allowed us to propose a bicyclization reaction mechanism. This work challenges our current understanding of the role of KS enzymes and establishes a basis for future efforts toward streamlined production of a clinically relevant chemotherapeutic.
Topics: Biological Products; Lactams; Lactones; Proteasome Inhibitors; Pyrroles
PubMed: 35314816
DOI: 10.1038/s41589-022-00993-w -
Journal of the American Chemical Society Jan 2024Bilirubin is the principal product of heme catabolism. High concentrations of the pigment are neurotoxic, yet slightly elevated levels are beneficial. Being a potent...
Bilirubin is the principal product of heme catabolism. High concentrations of the pigment are neurotoxic, yet slightly elevated levels are beneficial. Being a potent antioxidant, oxidative transformations of bilirubin occur in vivo and lead to various oxidized fragments. The mechanisms of their formation, intrinsic biological activities, and potential roles in human pathophysiology are poorly understood. Degradation methods have been used to obtain samples of bilirubin oxidation products for research. Here, we report a complementary, fully synthetic method of preparation. Our strategy leverages repeating substitution patterns in the parent tetracyclic pigment. Functionalized ready-to-couple γ-lactone, γ-lactam, and pyrrole monocyclic building blocks were designed and efficiently synthesized. Subsequent modular combinations, supported by metal-catalyzed borylation and cross-coupling chemistries, translated into the concise assembly of the structurally diverse bilirubin oxidation products (BOXes, propentdyopents, and biopyrrins). The discovery of a new photoisomer of biopyrrin A named lumipyrrin is reported. Synthetic bilirubin oxidation products made available in sufficient purity and quantity will support future in vitro and in vivo investigations.
Topics: Humans; Bilirubin; Oxidation-Reduction; Pyrroles; Oxidative Stress
PubMed: 38165253
DOI: 10.1021/jacs.3c11778