Multicomponent reactions (MCRs) have emerged as a powerful strategy in synthetic organic chemistry due to their widespread applications in drug discovery and development. MCRs are flexible ...transformations in which three or more substrates react to form structurally complex products with high atomic efficiency. They are being increasingly appreciated as a highly exploratory and evolutionary tool by the medicinal chemistry community, opening the door to more sustainable, cost-effective and rapid synthesis of biologically active molecules. In recent years, MCR-based synthetic strategies have found extensive application in the field of drug discovery, and several anticancer drugs have been synthesized through MCRs. In this review, we present an overview of representative and recent literature examples documenting different approaches and applications of MCRs in the development of new anticancer drugs.
Abstract
The four adenosine receptors (ARs) A
1
AR, A
2A
AR, A
2B
AR
,
and A
3
AR are G protein-coupled receptors (GPCRs) for which an exceptional amount of experimental and structural data is ...available. Still, limited success has been achieved in getting new chemical modulators on the market. As such, there is a clear interest in the design of novel selective chemical entities for this family of receptors. In this work, we investigate the selective recognition of ISAM-140, a recently reported A
2B
AR reference antagonist. A combination of semipreparative chiral HPLC, circular dichroism and X-ray crystallography was used to separate and unequivocally assign the configuration of each enantiomer. Subsequently affinity evaluation for both A
2A
and A
2B
receptors demonstrate the stereospecific and selective recognition of (
S
)-ISAM140 to the A
2B
AR. The molecular modeling suggested that the structural determinants of this selectivity profile would be residue V250
6.51
in A
2B
AR, which is a leucine in all other ARs including the closely related A
2A
AR. This was herein confirmed by radioligand binding assays and rigorous free energy perturbation (FEP) calculations performed on the L249V
6.51
mutant A
2A
AR receptor. Taken together, this study provides further insights in the binding mode of these A
2B
AR antagonists, paving the way for future ligand optimization.
Two 3D-hybrid monolithic catalysts containing immobilized copper and palladium species on a silica support were synthesized by 3D printing and a subsequent surface functionalization protocol. The ...resulting 3D monoliths provided a structure with pore sizes around 300 μm, high mechanical strength, and easy catalyst recyclability. The devices were designed to perform heterogeneous multicatalytic multicomponent reactions (MMCRs) based on a copper alkyne–azide cycloaddition (CuAAC) + palladium catalyzed cross-coupling (PCCC) strategy, which allowed the rapid assembly of variously substituted 1,2,3-triazoles using a mixture of tBuOH/H2O as solvent. The reusable multicatalytic system developed in this work is an example of a practical miniaturized and compartmental heterogeneous 3D-printed metal catalyst to perform MMCRs for solution chemistry.
The identification of new modulators for Cannabinoid Receptors (CBRs) has garnered significant attention in drug discovery over recent years, owing to their manifold pathophysiological implications. ...In the context of hit identification, the availability of robust and sensitive high-throughput screening assays is essential to enhance the likelihood of success. In this study, we present the development and validation of a Tag-lite
binding assay designed for screening hCB
/hCB
binding, employing a dual fluorescent ligand, CELT-335. Representative ligands for CBRs, exhibiting diverse affinity and functional profiles, were utilized as reference compounds to validate the robustness and efficiency of the newly developed Tag-lite
binding assay protocol. The homogeneous format, coupled with the sensitivity and optimal performance of the fluorescent ligand CELT-335, establishes this assay as a viable and reliable method for screening in hit and lead identification campaigns.
The family of adenosine receptors (ARs) is focus of several medicinal chemistry programs aimed to find new potent and selective drugs. Each receptor subtype has been proposed as a relevant drug ...target in the treatment of, e.g., cardiovascular or inflammatory diseases, asthma or Parkinson's disease. Until recently, most of these efforts have been dominated by ligand-based or empirical approaches. However, the latest advances in G protein-coupled receptor (GPCR) crystallography allowed for a thorough structural characterization of the A2AAR subtype, which has been crystalized with a number of agonists and antagonists. Consequently, the ligand discovery of AR ligands has been enriched with a number of structure-based approaches. These include the generation of higher-confident homology models for the remaining AR subtypes, virtual screening identification of novel chemotypes, structure-based lead-optimization programs, rationalization of selectivity profiles, or the structural characterization of novel binding sites that enable the design of novel allosteric modulators. Computational methodologies have importantly contributed to the success of these structure-based approaches, and the recent advances in the field are also analyzed in this review. We conclude that the design of adenosine receptor ligands has improved dramatically with the consideration of structure- based approaches, which is paving the way to a better understanding of the biology and pharmacological modulation of this relevant family of receptors.
New supported catalysts for the Huisgen’s 3+2 azide‐alkyne cycloaddition have been prepared by immobilization of copper species on commercially available polymeric matrixes incorporating the ...1,5,7‐triazabicyclo4.4.0dec‐5‐ene (TBD) template. The synergic exploitation of the exceptional copper chelating ability and basicity profile of the TBD framework, in addition to ensuring effective immobilization and stabilization of copper species, allows the implementation of three‐component strategies. The new catalytic systems enabled the development of regioselective, efficient, modular, mild and eco‐friendly multicomponent syntheses of diversely decorated 1,2,3‐triazoles, contributing to expand the scope and versatility of the Cu‐catalyzed Huisgen 1,3‐dipolar cycloaddition.
G-protein coupled receptors (GPCRs) have been largely targeted in a wide range of diseases, but few therapies have been directed against GPCRs in the field of cancer, partly because of the lack of ...effective target identification strategies. Here, using colorectal cancer (CRC) as a model, we explored the gene expression of a panel of GPCRs in tumor and stromal cells, identifying specific gene sets defining each cellular compartment. We selected the adenosine receptor 2B (A2BAR), specifically expressed in cancer cell lines compared with stromal cells, to explore the use of fluorescent ligands that can be used for target visualization. Fluorescent probes allowed semi-quantitative receptor mapping in living cells and validated the specific expression of A2BAR in CRC cell lines. As well, fluorescent ligands were effective at monitoring real-time A2BAR receptor labeling using live-imaging modalities, and displayed high efficiency when used to label complex 3D cellular systems such as tumor spheroids. Finally, we validated A2BAR as a potential pharmacological tool in CRC, using selective antagonists, finding a reduction in tumor cell proliferation. This proof-of-concept study suggests the use of fluorescent ligands for GPCR characterization through imaging, and as possible new tools used for target validation in drug screening methodologies.
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•We explored the expression of a panel of GPCRs in colorectal cancer, and found tumor and stromal-specific signatures.•We validated A2BAR as a tumor-specific GPCR using novel fluorescent ligands.•A2BAR labeling can be performed in living cells, and receptor binding monitored in real time.•Fluorescent ligands technology allows efficient A2BAR labeling in complex 3D cellular models.•Specific targeting of A2BAR decreases cell proliferation.
Nearly 90 years ago, Drury and Szent-Györgyi revealed that adenosine produced profound hypotension and bradycardia, and it affected kidney function in mammals 1. ....
Synthetic cannabinoid receptor agonists (SCRAs) constitute the largest and most defiant group of abuse designer drugs. These new psychoactive substances (NPS), developed as unregulated alternatives ...to cannabis, have potent cannabimimetic effects and their use is usually associated with episodes of psychosis, seizures, dependence, organ toxicity and death. Due to their ever-changing structure, very limited or nil structural, pharmacological, and toxicological information is available to the scientific community and the law enforcement offices. Here we report the synthesis and pharmacological evaluation (binding and functional) of the largest and most diverse collection of enantiopure SCRAs published to date. Our results revealed novel SCRAs that could be (or may currently be) used as illegal psychoactive substances. We also report, for the first time, the cannabimimetic data of 32 novel SCRAs containing an (R) configuration at the stereogenic center. The systematic pharmacological profiling of the library enabled the identification of emerging Structure-Activity Relationship (SAR) and Structure-Selectivity Relationship (SSR) trends, the detection of ligands exhibiting incipient cannabinoid receptor type 2 (CB2R) subtype selectivity and highlights the significant neurotoxicity of representative SCRAs on mouse primary neuronal cells. Several of the new emerging SCRAs are currently expected to have a rather limited potential for harm, as the evaluation of their pharmacological profiles revealed lower potencies and/or efficacies. Conceived as a resource to foster collaborative investigation of the physiological effects of SCRAs, the library obtained can contribute to addressing the challenge posed by recreational designer drugs.
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•Functional and binding data from the largest and most diverse collection of SCRAs published to date are presented.•We document 32 previously unexplored SCRAs that elicit the (R) configuration on the pendant amino acid chain.•New structural features defining SAR and SSR trends were identified.•Primary neuronal cells assessment evidenced an eventual neurotoxicity of tested SCRAs.
The four receptors that signal for adenosine, A₁, A
, A
and A₃ ARs, belong to the superfamily of G protein-coupled receptors (GPCRs). They mediate a number of (patho)physiological functions and have ...attracted the interest of the biopharmaceutical sector for decades as potential drug targets. The many crystal structures of the A
, and lately the A₁ ARs, allow for the use of advanced computational, structure-based ligand design methodologies. Over the last decade, we have assessed the efficient synthesis of novel ligands specifically addressed to each of the four ARs. We herein review and update the results of this program with particular focus on molecular dynamics (MD) and free energy perturbation (FEP) protocols. The first in silico mutagenesis on the A₁AR here reported allows understanding the specificity and high affinity of the xanthine-antagonist 8-Cyclopentyl-1,3-dipropylxanthine (DPCPX). On the A
AR, we demonstrate how FEP simulations can distinguish the conformational selectivity of a recent series of partial agonists. These novel results are complemented with the revision of the first series of enantiospecific antagonists on the A
AR, and the use of FEP as a tool for bioisosteric design on the A₃AR.
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