Catalysts are substances that increase the reaction rate of a chemical reaction without being consumed in the process. 150728-13-5, Name is 4,6-Dichloro-5-(2-methoxyphenoxy)-2,2′-bipyrimidine, SMILES is ClC1=NC(=NC(=C1OC2=C(C=CC=C2)OC)Cl)C3=NC=CC=N3, belongs to pyrimidines compound. In a document, author is Hill, Brian, introduce the new discover, Application In Synthesis of 4,6-Dichloro-5-(2-methoxyphenoxy)-2,2′-bipyrimidine.
A pilot clinical trial of oral tetrahydrouridine/decitabine for noncytotoxic epigenetic therapy of chemoresistant lymphoid malignancies
One mechanism by which lymphoid malignancies resist standard apoptosis-intending (cytotoxic) treatments is genetic attenuation of the p53/p16-CDKN2A apoptosis axis. Depletion of the epigenetic protein DNA methyltransferase 1 (DNMT1) using the deoxycytidine analog decitabine is a validated approach to cytoreduce malignancy independent of p53/p16. In vivo decitabine activity, however, is restricted by rapid catabolism by cytidine deaminase (CDA). We, therefore, combined decitabine with the CDA-inhibitor tetrahydrouridine and conducted a pilot clinical trial in patients with relapsed lymphoid malignancies: the doses of tetrahydrouridine/decitabine used (similar to 10/0.2 mg/kg orally (PO) 2x/week) were selected for the molecular pharmacodynamic objective of non-cytotoxic, S-phase dependent, DNMT1-depletion, guided by previous Phase 1 studies. Patients with relapsed/refractory B- or T-cell malignancies (n = 7) were treated for up to 18 weeks. Neutropenia without concurrent thrombocytopenia is an expected toxicity of DNMT1-depletion and occurred in all patients (Grade 3/4). Subjective and objective clinical improvements occurred in 4 of 7 patients, but these responses were lost upon treatment interruptions and reductions to manage neutropenia. We thus performed parallel experiments in a preclinical in vivo model of lymphoma to identify regimen refinements that might sustain DNMT1-targeting in malignant cells but limit neutropenia. We found that timed-alternation of decitabine with the related molecule 5-azacytidine, and combination with inhibitors of CDA and de novo pyrimidine synthesis could leverage feedback responses of pyrimidine metabolism to substantially increase lymphoma cytoreduction but with less neutropenia. In sum, regimen innovations beyond incorporation of a CDA-inhibitor are needed to sustain decitabine DNMT1-targeting and efficacy against chemo-resistant lymphoid malignancy. Such potential solutions were explored in preclinical in vivo studies. (C) 2020 Elsevier Inc. All rights reserved.
The proportionality constant is the rate constant for the particular unimolecular reaction. the reaction rate is directly proportional to the concentration of the reactant. I hope my blog about 150728-13-5 is helpful to your research. Application In Synthesis of 4,6-Dichloro-5-(2-methoxyphenoxy)-2,2′-bipyrimidine.
Reference:
Pyrimidine | C4H4N2 – PubChem,
,Pyrimidine – Wikipedia