In silico evaluation of new mangiferin-based Positron Emission Tomography radiopharmaceuticals through the inhibition of metalloproteinase-9.

Metalloproteinase-9 (MMP-9) is a key protein in cancer advancement and metastasis owing to its ability to degrade some extracellular matrix components. Mangiferin, a natural polyphenolic compound, has demonstrated through experimental and theoretical studies to be a great anticancer agent for the selective inhibition of MMP-9. This work aimed to evaluate the utility of several fluorinated compounds obtained from MF as possible Positron Emission Tomography (PET) radiopharmaceuticals oriented to MMP-9. Density Functional Theory calculations of MF were made to obtain the most active sites toward electrophilic and nucleophilic reactions and propose a synthetic route to produce its fluorinated derivatives. The reactivity study allowed us to propose a late-stage synthetic route based on click chemistry to obtain three fluorinated MF-based derivatives. Molecular docking calculations suggested that the derivative F-propyl-MF could be suitable as PET radiopharmaceutical owing to the establishment of a five-coordinated complex with the catalytic Zn atom belonging to the active site of MMP-9, crucial factor in the inhibition of MMP-9.

[18 F]Fluoropyridine-losartan: A new approach toward human Positron Emission Tomography imaging of Angiotensin II Type 1 receptors.

Angiotensin II type 1 receptors (AT1 R) blocker losartan is used in patients with renal and cardiovascular diseases. [18 F]fluoropyridine-losartan has shown favorable binding profile for quantitative renal PET imaging of AT1 R with selective binding in rats and pigs, low interference of radiometabolites and appropriate dosimetry for clinical translation. A new approach was developed to produce [18 F]fluoropyridine-losartan in very high molar activity. Automated radiosynthesis was performed in a three-step, two-pot, and two-HPLC-purification procedure within 2 h. Pure [18 F]FPyKYNE was obtained by radiofluorination of NO2 PyKYNE and silica-gel-HPLC purification (40 ± 9%), preventing the formation of nitropyridine-losartan in the second step. Conjugation with trityl-losartan azide via click chemistry, followed by acid hydrolysis, C18-HPLC purification and reformulation provided [18 F]fluoropyridine-losartan in 11 ± 2% (decay-corrected from [18 F]fluoride, EOB). Using tris[(1-(3-hydroxypropyl)-1H-1,2,3-triazol-4-yl)methyl]-amine (THPTA) as a Cu(I)-stabilizing agent for coupling [18 F]FPyKYNE to the unprotected losartan azide afforded [18 F]fluoropyridine-losartan in similar yields (11 ± 3%, decay-corrected from [18 F]fluoride, EOB). Reverse-phase HPLC was optimized by reducing the pH of the mobile phase to achieve complete purification and high molar activities (467 ± 60 GBq/µmol). The use of radioprotectants prevented tracer radiolysis for 10 h (RCP > 99%). The product passed the quality control testing. This reproducible automated radiosynthesis process will allow in vivo PET imaging of AT1 R expression in several diseases.

Explaining the interaction of mangiferin with MMP-9 and NF-ƙß: a computational study.

Mangiferin is a glycosylated xanthone widely distributed in nature, which exhibits wide pharmacological activities, highlighting its anti-cancer properties. Mangiferin interferes with inflammation, lipid, and calcium signaling, which selectively inhibits multiple NFkB target genes as interleukin-6, tumor necrosis factor, plasminogen, and matrix metalloproteinase, among others. In this work, the interactions of this polyphenol with MMP-9 and NF-κß are characterized by using computational chemistry methods. The results show MMP-9 inhibition by mangiferina is characterized for the interact with the catalytic Zn atom through a penta-coordinate structure. It is also demonstrated through a strong charge transfer established between mangiferin and Zn in the QM/MM study. Concerning the mangiferin/NF-κß system, the 92.3% of interactions between p50 sub-unity and DNA are maintained with a binding energy of - 8.04 kcal/mol. These findings indicate that mangiferin blocks the p50-p65/DNA interaction resulting in the loss of the functions of this hetero-dimeric member and suggesting inhibition of the cancer progression. Experimental results concerning the anti-cancer properties of mangiferin show that this natural compound can inhibit selectively MMP-9 and NF-ƙß. Although the anti-tumor properties of mangiferin are well defined, its molecular mechanisms of actions are not described. In this work, a computational study is carried out to characterize the interactions of mangiferin with these molecular targets. The results obtained corroborate the anti-proliferative and anti-apoptotic activity of mangiferin and provide a depiction of its mechanisms of action.

Synthesis and Evaluation of [18F]FEtLos and [18F]AMBF3Los as Novel 18F-Labelled Losartan Derivatives for Molecular Imaging of Angiotensin II Type 1 Receptors.

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.

Insight into the structure and stability of Tc and Re DMSA complexes: A computational study.

Meso-2,3-dimercaptosuccinic acid (DMSA) is used in nuclear medicine as ligand for preparation of diagnostic and therapy radiopharmaceuticals. DMSA has been the subject of numerous investigations during the past three decades and new and significant information of the chemistry and pharmacology of DMSA complexes have emerged. In comparison to other ligands, the structure of some DMSA complexes is unclear up today. The structures and applications of DMSA complexes are strictly dependent on the chemical conditions of their preparation, especially pH and components ratio. A computational study of M-DMSA (M=Tc, Re) complexes has been performed using density functional theory. Different isomers for M(V) and M(III) complexes were studied. The pH influence over ligand structures was taken into account and the solvent effect was evaluated using an implicit solvation model. The fully optimized complex syn-endo Re(V)-DMSA shows a geometry similar to the X-ray data and was used to validate the methodology. Moreover, new alternative structures for the renal agent 99mTc(III)-DMSA were proposed and computationally studied. For two complex structures, a larger stability respect to that proposed in the literature was obtained. Furthermore, Tc(V)-DMSA complexes are more stable than Tc(III)-DMSA proposed structures. In general, Re complexes are more stable than the corresponding Tc ones.

Influence of the chelator structures on the stability of Re and Tc tricarbonyl complexes with iminodiacetic acid tridentate ligands: a computational study.

The development of novel radiopharmaceuticals for nuclear medicine based on M(CO)3 (M = Tc, Re) complexes has attracted great attention. The versatility of this core and the easy production of the fac-[M(CO)3(H2O)3](+) precursor could explain this interest. The main characteristics of these tricarbonyl complexes are the high substitution stability of the three CO ligands and the corresponding lability of the coordinated water molecules, yielding, via easy exchange of a variety of bi- and tridentate ligands, complexes xof very high kinetic stability. Here, a computational study of different tricarbonyl complexes of Re(I) and Tc(I) was performed using density functional theory. The solvent effect was simulated using the polarizable continuum model. These structures were used as a starting point to investigate the relative stabilities of tricarbonyl complexes with various tridentate ligands. These complexes included an iminodiacetic acid unit for tridentate coordination to the fac-[M(CO)3](+) moiety (M = Re, Tc), an aromatic ring system bearing a functional group (-NO2, -NH2, and -Cl) as a linking site model, and a tethering moiety (a methylene, ethylene, propylene butylene, or pentylene bridge) between the linking and coordinating sites. The optimized complexes showed geometries comparable to those inferred from X-ray data. In general, the Re complexes were more stable than the corresponding Tc complexes. Furthermore, using NH2 as the functional group, a medium length carbon chain, and ortho substitution increased complex stability. All of the bonds involving the metal center presented a closed shell interaction with dative or covalent character, and the strength of these bonds decreased in the sequence Tc-CO > Tc-O > Tc-N.

Tizolidinadionas: una nueva familia de Hipoglicemiantes Orales / Thizolidinediones: a new family of oral hypoglycemic agents

A partir de un estudio de la literatura más actualizada se presenta una revisión bibliográfica de una nueva serie de compuestos conocidos como tiazolidinadionas. Se consultaron las bases de datos Medline (1989-8/96), Excerpta Médica (1990-7/96), Predicast (1992-6/96), Medical Research Division (1991) y Life Science (1993-95). Se resumen los resultados obtenidos en los estudios preclínicos y clínicos de los derivados de esta familia conocidos hasta el momento

Tizolidinadionas: una nueva familia de Hipoglicemiantes Orales / Thizolidinediones: a new family of oral hypoglycemic agents

A partir de un estudio de la literatura más actualizada se presenta una revisión bibliográfica de una nueva serie de compuestos conocidos como tiazolidinadionas. Se consultaron las bases de datos Medline (1989-8/96), Excerpta Médica (1990-7/96), Predicast (1992-6/96), Medical Research Division (1991) y Life Science (1993-95). Se resumen los resultados obtenidos en los estudios preclínicos y clínicos de los derivados de esta familia conocidos hasta el momento(AU)