124751-00-4Relevant articles and documents
Enhancement of glioblastoma multiforme therapy through a novel Quercetin-Losartan hybrid
Tsiailanis, Antonis D.,Renziehausen, Alexander,Kiriakidi, Sofia,Vrettos, Eirinaios I.,Markopoulos, Georgios S.,Sayyad, Nisar,Hirmiz, Baydaa,Aguilar, Marie-Isabel,Del Borgo, Mark P.,Kolettas, Evangelos,Widdop, Robert E.,Mavromoustakos, Thomas,Crook, Tim,Syed, Nelofer,Tzakos, Andreas G.
, p. 391 - 402 (2020)
Glioblastoma multiforme (GBM) is the most common and aggressive primary malignant brain tumor. Maximal surgical resection followed by radiotherapy and concomitant chemotherapy with temozolomide remains the first-line therapy, prolonging the survival of patients by an average of only 2.5 months. There is therefore an urgent need for novel therapeutic strategies to improve clinical outcomes. Reactive oxygen species (ROS) are an important contributor to GBM development. Here, we describe the rational design and synthesis of a stable hybrid molecule tethering two ROS regulating moieties, with the aim of constructing a chemopreventive and anticancer chemical entity that retains the properties of the parent compounds. We utilized the selective AT1R antagonist losartan, leading to the inhibition of ROS levels, and the antioxidant flavonoid quercetin. In GBM cells, we show that this hybrid retains the binding potential of losartan to the AT1R through competition-binding experiments and simultaneously exhibits ROS inhibition and antioxidant capacity similar to native quercetin. In addition, we demonstrate that the hybrid is able to alter the cell cycle distribution of GBM cells, leading to cell cycle arrest and to the induction of cytotoxic effects. Last, the hybrid significantly and selectively reduces cancer cell proliferation and angiogenesis in primary GBM cultures with respect to the isolated parent components or their simple combination, further emphasizing the potential utility of the current hybridization approach in GBM.
Synthesis and evaluation of [18F]FETLOs and [18F]AMBF3LOS as novel 18F-labelled losartan derivatives for molecular imaging of angiotensin II type 1 receptors
Ortega Pijeira, Martha Sahylí,Gon?alves Nunes, Paulo Sérgio,Dos Santos, Sofia Nascimento,Zhang, Zhengxing,Nario, Arian Pérez,Perini, Efrain Araujo,Turato, Walter Miguel,Riera, Zalua Rodríguez,Chammas, Roger,Elsinga, Philip H.,Lin, Kuo-Shyan,Carvalho, Ivone,Bernardes, Emerson Soares
, (2020/04/27)
Losartan is widely used in clinics to treat cardiovascular related diseases by selectively blocking the angiotensin II type 1 receptors (AT1Rs), which regulate the renin-angiotensin system (RAS). Therefore, monitoring the physiological and pathological biodistribution of AT1R using positron emission tomography (PET) might be a valuable tool to assess the functionality of RAS. Herein, we describe the synthesis and characterization of two novel losartan derivatives PET tracers, [18F]fluoroethyl-losartan ([18F]FEtLos) and [18F]ammoniomethyltrifluoroborate-losartan ([18F]AMBF3Los). [18F]FEtLos was radiolabeled by 18F-fluoroalkylation of losartan potassium using the prosthetic group 2-[18F]fluoroethyl tosylate; whereas [18F]AMBF3Los was prepared following an one-step 18F-19F isotopic exchange reaction, in an overall yield of 2.7 ± 0.9% and 11 ± 4%, respectively, with high radiochemical purity (>95%). Binding competition assays in AT1R-expressing membranes showed that AMBF3Los presented an almost equivalent binding affinity (Ki 7.9 nM) as the cold reference Losartan (Ki 1.5 nM), unlike FEtLos (Ki 2000 nM). In vitro and in vivo assays showed that [18F]AMBF3Los displayed a good binding affinity for AT1R-overexpressing CHO cells and was able to specifically bind to renal AT1R. Hence, our data demonstrate [18F]AMBF3Los as a new tool for PET imaging of AT1R with possible applications for the diagnosis of cardiovascular, inflammatory and cancer diseases.
[11C] Methyl-losartan as a potential ligand for PET imaging angiotensin II AT1 receptors
Hadizad, Tayebeh,Collins, Jeffrey,Antoun, Rawad E.,Beanlands, Rob S.,Dasilva, Jean N.
experimental part, p. 754 - 757 (2012/01/13)
The renin-angiotensin system regulates blood pressure via activation of the angiotensin II type 1 receptor (AT1R). The AT1R is involved in the pathology of cardiac and renal diseases such as heart failure and diabetic nephropathy. The aim of this study was to synthesize and characterize the O-[11 C]methylated derivative of the clinically used AT1 receptor blocker losartan as a novel AT1R PET imaging radioligand. [11 C]Methyl-losartan was reliably synthesized (n ≥ 40) via methylation of tetrazole-protected losartan followed by deprotection using HCl in an overall yield of 30%-60% (decay-corrected from [11 C]MeI). Radiochemical purity was >99% and specific activity 700-3600 mCi/μmol. Copyright 2011 John Wiley & Sons, Ltd. [11 C]Methyl-losartan has been synthesized in three steps: 1) protection of the tetrazole group, 2) [11 C]methylation of hydroxyl group, and 3) deprotection in acidic conditions. Copyright
