RSC medicinal chemistry最新文献

This review highlights the potential of asialoglycoprotein receptor (ASGPR)-mediated targeting in advancing liver-specific treatments and underscores the ongoing progress in the field. First, we provide a comprehensive examination of the nature of ASGPR ligands, both natural and synthetic. Next, we explore various drug delivery strategies leveraging ASGPR, with a particular emphasis on the delivery of therapeutic nucleic acids such as small interfering RNAs (siRNAs) and antisense oligonucleotides (ASOs). An in-depth analysis of the current status of RNA interference (RNAi) and ASO-based therapeutics is included, detailing approved therapies and those in various stages of clinical development (phases 1 to 3). Afterwards, we give an overview of other ASGPR-targeted conjugates, such as those with peptide nucleic acids or aptamers. Finally, targeted protein degradation of extracellular proteins through ASGPR is briefly discussed.

Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory infections in babies across the world. Irrespective of progress in the development of RSV vaccines, effective small molecule drugs are still not available on the market. Based on our previous data we designed and synthesized triazole-linked coumarin-monoterpene hybrids and showed that they are indeed effective in inhibiting the RSV replication. The most effective compounds are active against both RSV serotypes, A and B, with IC₅₀ in the low micromolar or submicromolar range of concentrations. These are the most active coumarin derivatives found so far. Compound 45 combining 3,7-dimethyloctane and cyclopentane-annealed coumarin fragments has a selectivity index of 160 for serotype A and 1147 for serotype B. According to the results of the time-of-addition experiments, the conjugates are active at the early stages of the virus cycle. Based on biological evaluation and molecular modeling data, RSV F protein is a possible target.

The Wnt/β-catenin signaling pathway plays a critical role in various biological processes, including cell proliferation, differentiation, and tissue homeostasis. Aberrant activation of this pathway is strongly associated with the development of various cancers, including colorectal, pancreatic, and gastric cancers, making it a promising therapeutic target. In recent years, inhibitors targeting different components of the Wnt/β-catenin pathway, including small molecules, peptides, and nucleic acid-based therapies, have been developed to suppress cancer cell growth. These inhibitors work by disrupting key interactions within the pathway, thereby preventing tumor progression. Antibody-based therapies have also emerged as potential strategies to block ligand-receptor interactions within this pathway. Despite these advancements, challenges such as the complexity of the pathway and toxicity concerns remain. Innovative approaches, including allosteric inhibitors, proteolysis-targeting chimeras (PROTACs), and peptide-based inhibitors, offer new opportunities to address these challenges. This review provides an overview of the latest progress in the development of Wnt/β-catenin pathway inhibitors and explores future directions in cancer therapy.

Target 2035 is a global initiative that seeks to identify a pharmacological modulator of most human proteins by the year 2035. As part of an ongoing series of annual updates of this initiative, we summarise here the efforts of the EUbOPEN project whose objectives and results are making a strong contribution to the goals of Target 2035. EUbOPEN is a public-private partnership with four pillars of activity: (1) chemogenomic library collections, (2) chemical probe discovery and technology development for hit-to-lead chemistry, (3) profiling of bioactive compounds in patient-derived disease assays, and (4) collection, storage and dissemination of project-wide data and reagents. The substantial outputs of this programme include a chemogenomic compound library covering one third of the druggable proteome, as well as 100 chemical probes, both profiled in patient derived assays, as well as hundreds of data sets deposited in existing public data repositories and a project-specific data resource for exploring EUbOPEN outputs.

Inflammatory pain represents one of the unmet clinical needs for patients, as conventional therapies cause several side effects. Recently, new targets involved in inflammatory pain modulation have been identified, including the sigma-1 receptor (σ1R). Selective σ1R antagonists have demonstrated analgesic efficacy in acute and chronic inflammatory pain models. Considering these findings, a series of novel N-normetazocine derivatives has been designed and synthesized to investigate the pivotal role of N-normetazocine stereochemistry in their pharmacological fingerprint. The affinity profile of new ligands versus sigma receptors and opioid receptors was evaluated in vitro, and compound 7 showed a relevant σ1R affinity, with K _iσ1 = 27.5 ± 8.1 nM, and selectivity over sigma-2 receptor (σ2R) and opioid receptors. Furthermore, in vivo, compound 7 significantly reduced inflammatory pain in the second phase of the formalin test. Molecular modeling studies were also performed to analyze the binding mode and the key interactions between the new ligands and σ1R.

Radionuclide theranostics - a fast-growing emerging field in radiopharmaceutical sciences and nuclear medicine - offers a personalised and precised treatment approach by combining diagnosis with specific and selective targeted endoradiotherapy. This concept is based on the application of the same molecule, labelled with radionuclides possessing complementary imaging and therapeutic properties, respectively. In radionuclide theranostics, radionuclide pairs consisting of the same element, such as ^61/64Cu/⁶⁷Cu, ²⁰³Pb/²¹²Pb or ^123/124I/¹³¹I are of significant interest due to their identical chemical and pharmacological characteristics. However, such "true matched pairs" are seldom, necessitating the use of complementary radionuclides from different elements for diagnostics and endoradiotherapy with similar chemical characteristics, such as ^99mTc/^186/188Re, ⁶⁸Ga/¹⁷⁷Lu or ⁶⁸Ga/²²⁵Ac. Corresponding combinations of such two radionuclides in one and the same radioconjugate is referred to as a "matched pair". Notably, the pharmacological behavior remains consistent across both diagnostic and therapeutic applications with "true matched pairs", which may differ for "matched pairs". As "true matched pairs" of theranostic radioisotopes are rare and that some relevant radionuclides do not fit with the diagnostic or therapeutic counterpart, the radionuclide theranostic concept can be expanded and improved by the introduction of the radiohybrid approach. Radiohybrid (rh) ligands represent a new class of radiopharmaceutical bearing two different positions for the introduction of a (radio)metal and (radio)halogen in one molecule, which can be then used for both therapeutic and diagnostic purposes. The following review will give an insight into recent developments of this approach.

New rhodanine-thiazole clubbed compounds (7a-7l) were synthesised and characterised with various spectroscopy methods. The synthesised hybrids underwent in vitro HPA, HLAG inhibition, and peroxisome proliferator-activated receptor-gamma (PPAR-γ) expression assays. Through the biological study, compound 7f showed promising inhibitory activity against HPA with an IC₅₀ value of 27.13 ± 1.02 μM and 7l exhibited better inhibition against HLAG with an IC₅₀ value of 24.21 ± 1.12 μM. In addition, Lineweaver-Burk plot analysis suggested that 7l and 7f behaved as a mixed type of HLAG and HPA inhibitor and further, compound 7f showed significant PPAR-γ expression as compared to controls in a dose dependent manner; the expression can be attributed to its mapped pharmacophoric features with a phase screen score of 1.28 and vector score of 0.62. The proteins modulated by compounds include AMY2A, PPAR, and GAA proteins via MAPK, PPAR signalling pathways identified by cluster analysis and justified by molecular docking studies and MD trajectory analysis to evaluate the binding orientation and stability of the molecules, and the energy profiles of the molecules, both in complex with the protein, were assessed using MM/GBSA and DFT calculations, respectively. Finally, the pharmacokinetic profile was determined using ADMET analysis. Thus, from the above findings, it may demonstrate that rhodanine-thiazole hybrids constitute promising candidates in the pursuit of developing newer oral antidiabetic agents.

Acinetobacter baumannii is one of the deadliest Gram-negative bacteria (GNB), responsible for 2-10% of hospital-acquired infections. Several antibiotics are used to control the growth of A. baumannii. However, in recent decades, the abuse and misuse of antibiotics to treat non-microbial diseases have led to the emergence of multidrug-resistant A. baumannii strains. A. baumannii possesses a complex cell wall structure. Cell wall-targeting agents remain the center of antibiotic drug discovery. Notably, the antibacterial drug discovery intends to target the membrane of the bacteria, offering several advantages over antibiotics targeting intracellular systems, as membrane-targeting agents do not have to travel through the plasma membrane to reach the cytoplasmic targets. Microorganisms, insects, and mammals produce antimicrobial peptides as their first line of defense to protect themselves from pathogens and predators. Importantly, antimicrobial peptides are considered potential alternatives to antibiotics. This communication summarises the recently identified peptides of natural origin and their synthetic congeners acting against the A. baumannii membrane by cell wall disruption.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder, characterized by the presence of extracellular amyloid plaques consisting of β-amyloid peptides (Aβ) and intracellular neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau (pTau) protein in the brain. Genetic and animal studies strongly indicate that Aβ, tau and neuroinflammation play important roles in the pathogenesis of AD. Several staging models showed that NFTs correlated well with the disease progression. Positron emission tomography (PET) imaging has become a widely used non-invasive technique to image NFTs for early diagnosis of AD. Despite the remarkable progress made over the past few years, tau PET imaging is still challenging due to the nature of tau pathology and the technical aspects of PET imaging. Tau pathology often coexists with other proteinopathies, such as Aβ plaques and α-synuclein aggregates. Distinguishing tau-specific signals from other overlapping pathologies is difficult, especially in the context of AD, where multiple protein aggregates are present, as well as the spectrum of different tau isoforms (3R and 4R) and conformations. Moreover, tracers should ideally have optimal pharmacokinetic properties to penetrate the blood-brain barrier (BBB) while maintaining specificity, low toxicity, low non-specific binding, rapid uptake and clearance from the brain, and formation of no radiolabeled metabolites in the brain. On the other hand, Parkinson's disease (PD) is a progressive neurodegenerative movement disorder characterized by the abnormal accumulations of α-synuclein in neurons. Heterogeneity and the unclear pathogenesis of PD hinder early and accurate diagnosis of the disease for therapeutic development in clinical use. In this review, while referring to existing reviews, we focus on the design strategies and current progress in tau (NFTs) targeting new PET tracers for AD; evolution of non-AD tau targeting PET tracers for applications including progressive supranuclear paralysis (PSP) and corticobasal degeneration (CBD); new PET tracer development for α-synuclein aggregate imaging in PD and giving an outlook for future PET tracer development.

Alzheimer's disease (AD) is estimated to affect over 55 million people across the world. Small molecule treatment options are limited to symptom management with no impact on disease progression. The need for new protein targets and small molecule hit compounds is unmet and urgent. Hydroxysteroid 17-β dehydrogenase type 10 (17β-HSD10) is a mitochondrial enzyme known to bind amyloid beta, a hallmark of AD, and potentiate its toxicity to neurons. Identification of small molecules capable of interacting with 17β-HSD10 may drive drug discovery efforts for AD. The screening compound BCC0100281 (1), was previously identified as an inhibitor of 17β-HSD10. Herein we report the first synthetic access to the hit compound following a convergent pathway starting from simple heterocyclic building blocks. The compound was found to be toxic to 'neuron-like' cells, specifically those of neuroblastoma origin, providing a potential hit compound for cancer drug discovery, wherein the protein is known to be overexpressed. However, assay of synthetic intermediates identified novel scaffolds with effect to rescue amyloid beta-induced cytotoxicity, showcasing the power of organic synthesis and medicinal chemistry to optimize hit compounds.