Second-generation Ligands Research Articles

Microglial Positron Emission Tomography Imaging In Vivo : Positron Emission Tomography Radioligands: Utility in Research and Clinical Practice.

Microglia, the resident immune cells of the central nervous system (CNS) play a key role in regulating and maintaining homeostasis in the brain. However, the CNS is also vulnerable to infections and inflammatory processes. In response to CNS perturbations, microglia become reactive, notably with expression of the translocator protein (TSPO), primarily on their outer mitochondrial membrane. Despite TSPO being commonly used as a marker for microglia, it is also present in other cell types such as astrocytes. Positron emission tomography (PET) ligands that target the TSPO enable the noninvasive detection and quantification of glial reactivity. While some limitations were raised, TSPO PET remains an attractive biomarker of CNS infection and inflammation. This book chapter delves into the development and application of microglial PET imaging with a focus on the TSPO PET. First, we provide an overview of the evolution of TSPO PET radioligands from first-generation to second-generation ligands and their applications in studying neuroinflammation (or CNS inflammation). Subsequently, we discuss the limitations and challenges associated with TSPO PET. Then we go on to explore non-TSPO targets for microglial PET imaging. Finally, we conclude with future directions for research and clinical practice in this field.

Protein Allostery and Ligand Design: Computational Design Meets Experiments to Discover Novel Chemical Probes

Herein we examine the determinants of the allosteric inhibition of the mitochondrial chaperone TRAP1 by a small molecule ligand. The knowledge generated is harnessed into the design of novel derivatives with interesting biological properties.TRAP1 is a member of the Hsp90 family of proteins, which work through sequential steps of ATP processing coupled to client-protein remodeling. Isoform selective inhibition of TRAP1 can provide novel information on the biomolecular mechanisms of molecular chaperones, as well as new insights into the development of small molecules with therapeutic potential.Our analysis of the interactions between an active first-generation allosteric ligand and TRAP1 shows how the small molecule induces long-range perturbations that influence the attainment of reactive poses in the active site. At the same time, the dynamic adaptation of the allosteric binding pocket to the presence of the first-generation compound sets the stage for the design of a set of second-generation ligands: the characterization of the formation/disappearance of pockets around the allosteric site that is used to guide optimize the ligands’ fit for the allosteric site and improve inhibitory activities. The effects of the newly designed molecules are validated experimentally in vitro and in vivo. We discuss the implications of our approach as a promising strategy towards understanding the molecular determinants of allosteric regulation in chemical and molecular biology, and towards speeding up the design of allosteric small molecule modulators.

Biological and Biochemical Basis of the Differential Efficacy of First and Second Generation Somatostatin Receptor Ligands in Neuroendocrine Neoplasms.

Endogenous somatostatin shows anti-secretory effects in both physiological and pathological settings, as well as inhibitory activity on cell growth. Since somatostatin is not suitable for clinical practice, researchers developed synthetic somatostatin receptor ligands (SRLs) to overcome this limitation. Currently, SRLs represent pivotal tools in the treatment algorithm of neuroendocrine tumors (NETs). Octreotide and lanreotide are the first-generation SRLs developed and show a preferential binding affinity to somatostatin receptor (SST) subtype 2, while pasireotide, which is a second-generation SRL, has high affinity for multiple SSTs (SST5 > SST2 > SST3 > SST1). A number of studies demonstrated that first-generation and second-generation SRLs show distinct functional properties, besides the mere receptor affinity. Therefore, the aim of the present review is to critically review the current evidence on the biological effects of SRLs in pituitary adenomas and neuroendocrine tumors, by mainly focusing on the differences between first-generation and second-generation ligands.

Amyloid-β Peptide Targeting Peptidomimetics for Prevention of Neurotoxicity.

A new generation of ligands designed to interact with the α-helix/β-strand discordant region of the amyloid-β peptide (Aβ) and to counteract its oligomerization is presented. These ligands are designed to interact with and stabilize the Aβ central helix (residues 13-26) in an α-helical conformation with increased interaction by combining properties of several first-generation ligands. The new peptide-like ligands aim at extended hydrophobic and polar contacts across the central part of the Aβ, that is, "clamping" the target. Molecular dynamics (MD) simulations of the stability of the Aβ central helix in the presence of a set of second-generation ligands were performed and revealed further stabilization of the Aβ α-helical conformation, with larger number of polar and nonpolar contacts between ligand and Aβ, compared to first-generation ligands. The synthesis of selected novel Aβ-targeting ligands was performed in solution via an active ester coupling approach or on solid-phase using an Fmoc chemistry protocol. This included incorporation of aliphatic hydrocarbon moieties, a branched triamino acid with an aliphatic hydrocarbon tail, and an amino acid with a 4'- N, N-dimethylamino-1,8-naphthalimido group in the side chain. The ability of the ligands to reduce Aβ1-42 neurotoxicity was evaluated by gamma oscillation experiments in hippocampal slice preparations. The "clamping" second-generation ligands were found to be effective antineurotoxicity agents and strongly prevented the degradation of gamma oscillations by physiological concentration of monomeric Aβ1-42 at a stoichiometric ratio.

Theoretical investigations of Rh-catalyzed asymmetric 1,4-addition to enones using planar-chiral phosphine-olefin ligands.

Recently, planar-chiral phosphine-olefin ligands based on (η6 -arene)chromium(0) and (η5 -cyclopentadienyl)manganese(I), which are known as first- and second-generation, respectively, have been developed. These ligands were employed for Rh-catalyzed asymmetric 1,4-addition to enones. First-generation ligands involve high enantioselectivity for cyclic enones (>98% ee). Second-generation ligands involve high enantioselectivity for not only cyclic enones but also for acyclic enones (>98% ee). In this study, we have performed DFT calculations to investigate the origin of enantioselectivity. The theoretical values of enantioselectivities were found to be in good agreement with the experimental values obtained for a cyclic enone, 2-cyclopenten-1-one, using both the first- and second-generation ligands. Regarding an acyclic enone, 3-penten-2-one, it was found that the s-cis type decreases the enantioselectivity because the transition states in the s-cis type have a large steric repulsion. Energy decomposition analysis (EDA) and natural bond orbital (NBO) analysis indicate that it is important to study the orbital interactions in the transition states of the insertion step for the acyclic enone attacked from si-face with the second-generation ligand. © 2018 Wiley Periodicals, Inc.

Image-Guided Development of Heterocyclic Sulfoxides as Ligands for Tau Neurofibrillary Tangles: From First-in-Man to Second-Generation Ligands.

Positron emission tomography (PET) imaging of misfolded protein aggregates that form in neurodegenerative processes of the brain is key to providing a robust marker for improved diagnosis and evaluation of treatments. We report the development of advanced radiotracer candidates based on the sulfoxide scaffold found in proton pump inhibitors (lansoprazole, prevacid) with inherent affinity to neurofibrillary tangles in Alzheimer’s disease and related disorders (e.g., dementia with Lewy bodies and the frontotemporal degeneration syndrome). First-in-man results obtained with [18F]lansoprazole and N-methyl-[18F]lansoprazole were used to guide the design of a set of 24 novel molecules with suitable properties for neuroimaging with PET. Compounds were synthesized and characterized pharmacologically, and the binding affinity of the compounds to synthetic human tau-441 fibrils was determined. Selectivity of binding was assessed using α-synuclein and β-amyloid fibrils to address the key misfolded proteins of relevance in dementia. To complete the pharmacokinetic profiling in vitro, plasma protein binding and lipophilicity were investigated. Highly potent and selective new radiotracer candidates were identified for further study.

Phosphonite Ligand Design for Nickel‐Catalyzed 2‐Methyl‐3‐butenenitrile Isomerization and Styrene Hydrocyanation

AbstractThe synthesis of a series of novel chelating bisphosphonite ligands with a bridged dihydroanthracene scaffold is described. First‐generation derivatives showed a strong tendency for the formation of catalytically inactive Ni0 bis‐chelate complexes. The solid state structures of these complexes allowed the design of tailor‐made second‐generation ligands for nickel‐catalyzed 2‐methyl‐3‐butenenitrile isomerization with exceptionally high activity. The second‐generation catalyst also showed good catalytic performance in the hydrocyanation of styrene.

Chiral Ligands with an Isoborneol‐10‐sulfonamide Structure: A Ten‐Year Odyssey

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Chiral Ligands with an Isoborneol-10-sulfonamide Structure: A Ten-Year Odyssey

The isoborneol-10-sulfonamide unit represents a new type of chiral structure that has been successfully prepared and used in different reactions of organometallic addition to aldehydes and ketones. The obtained results were excellent in some cases, and this type of ligand is unique as it is able to promote the enantioselective addition of dialkylzinc reagents to simple ketones. The scope of these catalyzed reactions, together with some synthetic applications, is outlined. References to important related work from others are also included. 1 Introduction 2 First-Generation Ligands 2.1 Enantioselective Addition of Organozinc Reagents to -Aldehydes 2.2 Enantioselective Addition to Ketones 3 Second-Generation Ligands 3.1 Enantioselective Addition of Organozinc Reagents to -Aldehydes 3.2 Enantioselective Addition to Ketones 4 Third-Generation Ligands 5 Outlook

Second‐Generation Paracyclophane Imine Ligands for the Dialkylzinc Addition to Aldehydes. Optimization of the Branched Side Chain leads to Improvement for Aliphatic Aldehydes

AbstractTwo novel diastereomeric [2.2]paracyclophane ketimine ligands (SP,S)‐2 and (RP,S)‐2, which unite a planar chiral element and a central chiral element, were used towards the enantioselective diethylzinc addition onto aliphatic aldehydes. These improved second‐generation ligands, which are stable in air and water and are easy to obtain, showed significant improvements with respect to the ligands that were previously used.

A Combinatorial and Informatics Approach to CdS Nanoclusters

The stabilization of size-specific monodisperse CdS nanoclusters has received much attention. However, the development of matrices, e.g., polymers, micelles, zeolites, for this purpose has remained largely empirical. Here a combinatorial and informatics approach to the discovery of ligands for CdS nanocluster stabilization is introduced. It is shown that combinatorially derived peptide and peptidomimetic ligands based on phytochelatins can stabilize CdS nanoclusters and that an informatics analysis of the library used yields design parameters critical for obtaining second-generation ligands.