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Angewandte Chemie (International Ed. in... Jul 2024Electron transfers in multinuclear metal complexes are the origin of their unique functionalities both in natural and artificial systems. However, electron transfers in...
Electron transfers in multinuclear metal complexes are the origin of their unique functionalities both in natural and artificial systems. However, electron transfers in multinuclear metal complexes are generally complicated, and predicting and controlling these electron transfers is extremely difficult. Herein, we report the precise manipulation of the electron transfers in multinuclear metal complexes. The development of a rational synthetic strategy afforded a series of pentanuclear metal complexes which composed of metal ions and 3,5-bis(2-pyridyl)pyrazole (Hbpp) as a platform to probe the phenomena. Electrochemical and spectroscopic investigations clarified overall picture of the electron transfers in the pentanuclear complexes. In addition, unique electron transfer behaviors, in which the reduction of a metal center occurs during the oxidation of the overall complex, were identified. We also elucidated the two dominant factors that determine the manner of the electron transfers. Our results provide comprehensive guidelines for interpreting the complicated electron transfers in multinuclear metal complexes.
PubMed: 38954391
DOI: 10.1002/anie.202408514 -
Organic & Biomolecular Chemistry Jul 2024An efficient method for the construction of 5-arylpyrazolo[1,5-]pyrimidines using calcium carbide as a solid alkyne source instead of flammable and explosive gaseous...
An efficient method for the construction of 5-arylpyrazolo[1,5-]pyrimidines using calcium carbide as a solid alkyne source instead of flammable and explosive gaseous acetylene, pyrazole-3-amine and (hetero)aromatic aldehydes as starting materials in the presence of a copper mediator is described. Meanwhile, 2-arylpyrimido[1,2-]indazoles are also synthesized under similar conditions using indazole-3-amine as a substitute for pyrazole-3-amine as a starting material. The method has salient features such as the use of an inexpensive and easy-to-handle alkyne source, commercially available substrates, wide functional group tolerance, a low-cost mediator, and simple workup procedures. This protocol can also be extended to gram-scale synthesis.
PubMed: 38953741
DOI: 10.1039/d4ob00881b -
Clinical Advances in Hematology &... 2024Neurotrophic tyrosine receptor kinase (NTRK) gene fusions are implicated in various cancers, including those of the lung and thyroid. The prevalence of NTRK fusions is... (Review)
Review
Neurotrophic tyrosine receptor kinase (NTRK) gene fusions are implicated in various cancers, including those of the lung and thyroid. The prevalence of NTRK fusions is 0.1 to 0.3% in non-small cell lung cancer (NSCLC) and as high as 26% in pediatric papillary thyroid carcinoma. Detection methods include immunohistochemistry, fluorescence in situ hybridization, reverse transcription polymerase chain reaction, and next-generation sequencing. Management of NTRK fusion-positive lung cancer primarily involves targeted therapies, notably the tyrosine receptor kinase (TRK) inhibitors larotrectinib and entrectinib. Both agents demonstrate high response rates and durable disease control, particularly in metastatic adenocarcinoma of the lung. They are preferred as first-line treatments because of their efficacy over immunotherapy. Possible adverse events include dizziness, weight gain, neuropathy-like pain, and liver enzyme elevation. Larotrectinib and entrectinib also produce robust and durable responses in NTRK fusion-positive thyroid cancer that is refractory to radioactive iodine. Second-generation TRK inhibitors that have been designed to overcome acquired resistance are under investigation.
Topics: Humans; Protein Kinase Inhibitors; Thyroid Neoplasms; Lung Neoplasms; Indazoles; Pyrazoles; Oncogene Proteins, Fusion; Pyrimidines; Receptor, trkA; Benzamides; Treatment Outcome
PubMed: 38953725
DOI: No ID Found -
The Journal of Organic Chemistry Jul 2024An efficient [3 + 2] cycloaddition reaction between generated nitrile imines from hydrazonoyl halides and vinylsulfonium salts is developed. The nitrile imines are...
An efficient [3 + 2] cycloaddition reaction between generated nitrile imines from hydrazonoyl halides and vinylsulfonium salts is developed. The nitrile imines are demonstrated to be a new class of reaction partner for vinylsulfonium salts to conduct the [3 + 2] cycloaddition reaction. The process provides a concise and efficient method for the construction of pyrazole derivatives under mild reaction conditions with broad substrate scope, good product yields, and high regioselectivity.
PubMed: 38953547
DOI: 10.1021/acs.joc.4c00910 -
Beilstein Journal of Organic Chemistry 2024A series of 4-thio/seleno-cyanated pyrazoles was conveniently synthesized from 4-unsubstituted pyrazoles using NHSCN/KSeCN as thio/selenocyanogen sources and PhICl as...
A series of 4-thio/seleno-cyanated pyrazoles was conveniently synthesized from 4-unsubstituted pyrazoles using NHSCN/KSeCN as thio/selenocyanogen sources and PhICl as the hypervalent iodine oxidant. This metal-free approach was postulated to involve the in situ generation of reactive thio/selenocyanogen chloride (Cl-SCN/SeCN) from the reaction of PhICl and NHSCN/KSeCN, followed by an electrophilic thio/selenocyanation of the pyrazole skeleton.
PubMed: 38952956
DOI: 10.3762/bjoc.20.128 -
BMC Urology Jul 2024The ARASENS trial recruited 1306 men with metastatic hormone sensitive prostate cancer. It investigated the effect of androgen deprivation therapy (ADT) and systemic...
The ARASENS trial recruited 1306 men with metastatic hormone sensitive prostate cancer. It investigated the effect of androgen deprivation therapy (ADT) and systemic therapy docetaxel in combination with a third novel drug - daralutamide, compared with placebo on overall survival. Triple therapy with ADT, docetaxel and darolutamide resulted in improved overall survival rates as compared with ADT, docetaxel and placebo (HR 0.68; 95% CI, 0.57-0.80; p < 0.001). The side effect profile for both treatments was similar. This randomised, double blinded, placebo controlled study, was assessed to have a low risk of bias using the Cochrane Risk of Bias 2 tool.
Topics: Male; Humans; Prostatic Neoplasms; Benzamides; Randomized Controlled Trials as Topic; Survival Rate; Androgen Antagonists; Docetaxel; Pyrazoles
PubMed: 38951868
DOI: 10.1186/s12894-024-01507-7 -
International Journal of Gynecological... Jul 2024To identify characteristics associated with long-term progression-free survival (≥2 years) in patients with advanced ovarian cancer treated with niraparib first-line... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
To identify characteristics associated with long-term progression-free survival (≥2 years) in patients with advanced ovarian cancer treated with niraparib first-line maintenance therapy in the phase III PRIMA/ENGOT-OV26/GOG-3012 study.
METHODS
In this post hoc analysis of PRIMA, patients randomized to niraparib were grouped based on investigator-assessed progression-free survival (progressive disease/censoring <2 years or ≥2 years after randomization). Variables assessed for predictive value were Eastern Cooperative Oncology Group performance status, International Federation of Gynecology and Obstetrics (FIGO) stage at diagnosis, clinical response to platinum-based chemotherapy, number of prior chemotherapy cycles, primary tumor location, body mass index, categorical age, debulking surgery type, number of baseline target lesions, number of baseline non-target lesions, /homologous recombination-deficiency status, residual disease status, and duration from end of chemotherapy to randomization. Logistic regression modeling using backward elimination (significance level=0.15) identified covariates associated with long-term progression-free survival (clinical cut-off date November 17, 2021).
RESULTS
Of 487 patients randomized to niraparib, 152 (31%) had progressive disease/censoring ≥2 years after randomization. Multivariable logistic regression modeling using backward elimination identified mutation/homologous recombination deficiency status (p<0.0001), FIGO stage (p=0.041), primary tumor location (p=0.095), and number of baseline non-target lesions (p=0.0001) to be associated with long-term progression-free survival. Patients significantly more likely to achieve progression-free survival of ≥2 years in the final model were those with - and -mutated/homologous recombination-deficient tumors or wild-type/not determined/homologous recombination-deficient tumors (vs wild-type/homologous recombination-proficient/not determined tumors), FIGO stage III (vs IV), and 0 or 1 baseline non-target lesions (vs ≥2 baseline non-target lesions).
CONCLUSIONS
The hypothesis-generating results of this analysis suggest that mutation/homologous recombination-deficiency status, FIGO stage, and number of baseline non-target lesions may predict progression-free survival of ≥2 years in patients with advanced ovarian cancer receiving niraparib first-line maintenance therapy.
TRIAL REGISTRATION NUMBER
NCT02655016.
Topics: Humans; Female; Indazoles; Piperidines; Progression-Free Survival; Ovarian Neoplasms; Middle Aged; Poly(ADP-ribose) Polymerase Inhibitors; Adult; Aged
PubMed: 38950925
DOI: 10.1136/ijgc-2024-005356 -
Melanoma Research Jul 2024Melanoma is the most serious and deadly form of skin cancer and with progression to advanced melanoma, the intrinsically disordered protein α-synuclein is upregulated...
Melanoma is the most serious and deadly form of skin cancer and with progression to advanced melanoma, the intrinsically disordered protein α-synuclein is upregulated to high levels. While toxic to dopaminergic neurons in Parkinson's disease, α-synuclein is highly beneficial for primary and metastatic melanoma cells. To gain detailed insights into this exact opposite role of α-synuclein in advanced melanoma, we performed proteomic studies of high-level α-synuclein-expressing human melanoma cell lines that were treated with the diphenyl-pyrazole small-molecule compound anle138b, which binds to and interferes with the oligomeric structure of α-synuclein. We also performed proteomic and transcriptomic studies of human melanoma xenografts that were treated systemically with the anle138b compound. The results reveal that interfering with oligomerized α-synuclein in the melanoma cells in these tumor xenografts led to a substantial upregulation and expression of major histocompatibility complex proteins, which are pertinent to enhancing anti-melanoma immune responses.
PubMed: 38950202
DOI: 10.1097/CMR.0000000000000982 -
Journal of Managed Care & Specialty... Jul 2024Neurotrophic tyrosine receptor kinase () gene fusions are rare oncogenic drivers prevalent in 0.3% of solid tumors. They are most common in salivary gland cancer (2.6%),...
BACKGROUND
Neurotrophic tyrosine receptor kinase () gene fusions are rare oncogenic drivers prevalent in 0.3% of solid tumors. They are most common in salivary gland cancer (2.6%), thyroid cancer (1.6%), and soft-tissue sarcoma (1.5%). Currently, there are 2 US Food and Drug Administration-approved targeted therapies for gene fusions: larotrectinib, approved in 2018, and entrectinib, approved in 2019. To date, the real-world uptake of tyrosine receptor kinase inhibitor (TRKi) use for -positive solid tumors in academic cancer centers remains largely unknown.
OBJECTIVE
To describe the demographics, clinical and genomic characteristics, and testing and treatment patterns of patients with -positive solid tumors treated at US academic cancer centers.
METHODS
This was a retrospective chart review study conducted in academic cancer centers in the United States. All patients diagnosed with an fusion-positive (1, 2, 3) solid tumor (any stage) and who received cancer treatment at participating sites between January 1, 2012, and July 1, 2023, were included in this study. Patient demographics, clinical characteristics, genomic characteristics, testing data, and treatment patterns were collected from electronic medical records and analyzed using descriptive statistics as appropriate.
RESULTS
In total, 6 centers contributed data for 55 patients with -positive tumors. The mean age was 49.3 (SD = 20.5) years, 51% patients were female, and the majority were White (78%). The median duration of time from cancer diagnosis to testing was 85 days (IQR = 44-978). At the time of testing, 64% of patients had stage IV disease, compared with 33% at cancer diagnosis. Prevalent cancer types in the overall cohort included head and neck (15%), thyroid (15%), brain (13%), lung (13%), and colorectal (11%). 1 fusions were most common (45%), followed by 3 (40%) and 2 (15%). Across all lines of therapy, 51% of patients (n = 28) received a TRKi. Among TRKi-treated patients, 71% had stage IV disease at TRKi initiation. The median time from positive test to initiation of TRKi was 48 days (IQR = 9-207). TRKis were commonly given as first-line (30%) or second-line (48%) therapies. Median duration of therapy was 610 (IQR = 182-764) days for TRKi use and 207.5 (IQR = 42-539) days for all other first-line therapies.
CONCLUSIONS
This study reports on contemporary real-world testing patterns and use of TRKis in solid tumors, including time between testing and initiation of TRKi therapy and duration of TRKi therapy.
Topics: Humans; Female; Male; Retrospective Studies; Middle Aged; United States; Neoplasms; Receptor, trkC; Aged; Receptor, trkA; Adult; Protein Kinase Inhibitors; Receptor, trkB; Academic Medical Centers; Membrane Glycoproteins; Oncogene Proteins, Fusion; Cohort Studies; Pyrimidines; Pyrazoles; Benzamides; Young Adult; Indazoles
PubMed: 38950155
DOI: 10.18553/jmcp.2024.30.7.672 -
Circulation Jul 2024
Randomized Controlled Trial
Topics: Humans; Pyridones; Pyrazoles; COVID-19; COVID-19 Drug Treatment; Female; Treatment Outcome; Male; Outpatients; Factor Xa Inhibitors; SARS-CoV-2; Aged; Middle Aged
PubMed: 38950107
DOI: 10.1161/CIRCULATIONAHA.123.066709