ChemMedChem最新文献

The evolution of chemotherapy, especially the dawn of metal-based drugs, represents a transformative era in cancer treatment. From the serendipitous discovery of mustard gas's cytotoxic effects to the sophisticated development of targeted therapies, chemotherapy has significantly refined. Central to this progression is the incorporation of metal-based compounds, such as platinum (Pt), ruthenium (Ru), and gold (Au), which offer unique mechanisms of action, distinguishing them from organic therapeutics. Among these, Ru complexes, exemplified by BOLD-100 and TLD1433, have shown exceptional promise due to their selective activity, lower propensity for resistance, and the ability to target spescific cellular pathways. This paper explores the journey of such Ru candidates, focusing on the mechanisms, efficacy, and clinical potential of these Ru-based drugs, which stand at the forefront of current research, aiming to provide more targeted, less toxic, and highly effective cancer treatments.

Signal Amplification by Reversible Exchange (SABRE) is a relatively simple and fast hyperpolarization technique that has been used to hyperpolarize the α-ketocarboxylate pyruvate, a central metabolite and the leading hyperpolarized MRI contrast agent. In this work, we show that SABRE can readily be extended to hyperpolarize 13C nuclei at natural abundance on many other α-ketocarboxylates. Hyperpolarization is observed and optimized on pyruvate (P13C=17%) and 2-oxobutyrate (P13C=25%) with alkyl chains in the R-group, oxaloacetate (P13C=11%) and alpha-ketoglutarate (P13C=13%) with carboxylate moieties in the R group, and phenylpyruvate (P13C=2%) and phenylglyoxylate (P13C=2%) with phenyl rings in the R-group. New catalytically active SABRE binding motifs of the substrates to the hyperpolarization transfer catalyst-particularly for oxaloacetate-are observed. We experimentally explore the connection between temperature and exchange rates for all of these SABRE systems and develop a theoretical kinetic model, which is used to fit the hyperpolarization build-up and decay during SABRE activity.

The X-chromosome-linked inhibitor of apoptosis protein (XIAP) plays a crucial role in controlling cell survival across multiple regulated cell death pathways and coordinating a range of inflammatory signalling events. The discovery of selective inhibitors for XIAP-BIR2, able to disrupt the direct physical interaction between XIAP and RIPK2, offer promising therapeutic options for NOD2-mediated diseases like Crohn's disease, sarcoidosis, and Blau syndrome. The objective of this study was to design, synthesize, and evaluate small synthetic molecules with binding selectivity to XIAP-BIR2 domain. To achieve this, we applied an interdisciplinary drug design approach and firstly we have synthesized an initial fragment library to achieve a first XIAP inhibition activity. Then using a growing strategy, larger compounds were synthesized and one of them presents a good selectivity for XIAP-BIR2 versus XIAP-BIR3 domain, compound 20 c. The ability of compound 20 c to block the NOD1/2 pathway was confirmed in cell models. These data show that we have synthesized molecules capable of blocking NOD1/2 signalling pathways in cellulo, and ultimately leading to new anti-inflammatory compounds.

The Front Cover shows the identification of the new natural product aniquinazoline B from the marine fungus Aspergillus nidulans by virtual drug screening of a chemical library with 40000 compounds. Aniquinazoline B binds to the μ-opioid receptor. The amino acid sequence of the human μ opioid receptor in the background represents the basis for the 3D structure enabling virtual drug screening. Biochemical and cell culture experiments confirmed the μ-opioid receptor agonizing effect. This compound may be a promising candidate in pain-management to fight the opioid crisis. More details can be found in article 10.1002/cmdc.202400213 by Thomas Efferth and co-workers. The figure was created with biorender.com and parts of the figure were retrieved from smart servier medical art (smart.servier.com).

The Hippo pathway is deregulated in many cancers, and one approach to target these tumors is by inhibiting the interaction between YAP and TEAD. The interface between these two proteins is large and consists of several distinct contact areas. Therefore, discovering molecules that can inhibit this interaction is particularly challenging. The review 10.1002/cmdc.202400361 by Patrick Chène summarizes how the knowledge obtained from structure-function studies of the YAP:TEAD interaction was used to devise a strategy for identifying a potent low-molecular weight compound, IAG933, which is currently undergoing clinical trials.

The probing of small molecules with heterocyclic scaffolds covering unexplored chemical space and the evaluation of their biological relevance are essential parts of forward chemical genetics approaches and for the development of potential small-molecule therapeutics. In this study, we profiled sets of chromenopyrazoles (CMPs) and tetrahydroquinolines (THQs), originally developed to target the protein-RNA interaction of LIN28-let-7, in a cell painting assay (CPA) measuring cellular morphological changes. Selected LIN28-inactive CMPs and THQs induced cellular morphological changes to different extents. The most CPA-active CMPs 2 and 3 exhibited high bio-similarity with the LCH and BET clusters, while the most CPA-active THQs 13 and 20 indicated a mechanism of action beyond the currently established biosimilarity clusters. Overall, this work demonstrated that CPA is useful in revealing "hidden" biological targets and mechanisms of action for biologically inactive small molecules, which are CMPs and THQs targeting the RNA-binding protein LIN28 in this case, evaluated in target-based strategies. When compared with annotated reference compounds, CMP 3 exhibited a high biosimilarity with the dual BRD7/9 degrading PROTAC VZ185, suggesting that CPA could potentially function as a new phenotypic approach to identify degrader molecules.

Neglected tropical diseases are a group of infectious diseases with a high endemicity in developing countries of Africa, Asia, and the Americas. Treatment for these diseases depends solely on chemotherapy, which is associated with severe side effects, toxicity, and the development of parasitic resistance. This highlights a critical need to develop new and effective drugs to curb these diseases. As a result, a series of novel isatinylhydantoin derivatives were synthesized and evaluated for in vitro anti-kinetoplastid activity against seven human- or animal-infective Trypanosoma and two human-infective Leishmania species. The synthesized derivatives were tested for potential cytotoxicity against human, animal, and parasite host-related cell lines. The isatinylhydantoin hybrid 4 b bearing 5-chloroisatin and p-bromobenzyl moieties, showed strong trypanocidal activity against blood-stage T. congolense parasites; however, the promising in vitro trypanocidal potency of 4 b could not be translated to in vivo treatment efficacy in a preliminary animal study. Compounds 5, 2 b, and 5 b, were the most active against amastigotes of L. donovani, showing higher leishmanicidal activity than the reference drug, amphotericin B. These compounds were identified as early antileishmanicidal leads, and future investigations will focus on confirming their antileishmanial potential through in vivo efficacy evaluation as well as their exact mechanism of action.

Melanoma has emerged as a significant threat to human life and health. Microneedle (MN)-mediated transdermal drug delivery (TDD) has garnered attention in melanoma treatment for bypassing the first-pass effect. However, the propensity of melanoma to metastasize presents substantial challenges for MN mediated local treatment. Developing systemic therapies, such as immunotherapy in combination with TDD, is crucial for achieving effective melanoma treatment. Herein, a polyvinyl alcohol (PVA) MN-mediated multifunctional TDD system, designated MN@PDA@1-MT/CUR/DOX@HA (MN@PMCDH), was developed for synergetic chemotherapy/photothermal/immunotherapy of melanoma. PMCDH nanomedicines penetrate deep skin layers through MNs, accumulate at tumor sites guided by hyaluronic acid (HA), and selectively release drugs in response to the acidic tumor microenvironment and near-infrared (NIR) stimulation. Released curcumin (CUR) significantly enhances the efficacy of photothermal therapy (PTT) and chemotherapy, as well as improves the induction of immunogenic cell death (ICD) by increasing melanoma sensitivity to polydopamine (PDA)-mediated photothermal effects and doxorubicin (DOX). Moreover, the incorporation of 1-methyltryptophan (1-MT) to reverse the tumor immunosuppressive microenvironment can further enhance the effects of immunotherapy. In vitro studies revealed that the MN@PMCDH system can effectively induce ICD and inhibit tumor cell growth. Additionally, remarkable deep tumor cell inhibition effects are also achieved in 3D tumor models.

In liposomal drug delivery development, the delicate balance of membrane stability is a major challenge to prevent leakage (during shelf-life and blood circulation), and to ensure efficient payload release at the therapeutic destination. Our composite screening approach uses the processing by dual centrifugation technique to speed up the identification of de novo formulations of intermediate membrane stability. By screening binary lipid combinations at systemically varied ratios we highlight liposomal formulations of intermediate stability, what we termed "the edge of stability", requiring moderate stimuli for destabilization. Supplementation with a pH-sensitive cholesterol derivative (to obtain acid labile liposomes) and renewed assessment with cargo load led to the discovery of three formulations with sufficient shelf-life stability, acceptable cargo retention and efficient pH-responsive cargo release in vitro. The "lead candidates" exhibited promising in cellulo uptake with increased intracellular cargo release and revealed in vivo performance advantages compared to a control liposome. Our approach filters lipid compositions on "the edge of stability" that were introduced with a pH-sensitive cholesterol derivate leading pH-responsive liposomes, out of a multidimensional parameter space. Their discovery by rational approaches would have been highly unlikely, thus highlighting the potential of our screening approach.

Despite a wide range of available wound treatments, hard-to-heal wounds still pose a challenge. Hydrogels are often used as dressings for these wounds, because they sustain moisture in the wound environment, supporting the natural healing process. However, it is still not fully understood how physicochemical properties of hydrogel matrix affect the drug release process. Thus, detailed swelling kinetics examination coupled with modeling is needed together with studies on drug release. In this regard, several hydrogels based on plant-derived agar and modified with amikacin sulfate were investigated. The main properties of hydrogels were examined focusing on detailed swelling kinetics. Drug release was studied as microbiological activity against E. coli and S. Epidermidis strains. The obtained hydrogels were characterized by high swelling, reaching values in range from 465-1300 %, fitting the second order kinetics mode and exhibiting the quasi-Fickian diffusion properties. Furthermore, there was no correlation found between swelling properties and antibacterial activity against tested strains. The results confirmed that presented hydrogel materials have desirable properties for application as dressings for hard-to-heal wounds. The suggested compositions are a promising base for modification with other active substances (e. g., regenerative, anti-inflammatory) and studying the broader correlation between swelling and drug release.