ChemMedChem最新文献

The liposomal systems proved remarkably useful for the delivery of genetic materials but enhancing their efficacy remains a significant challenge. While structural alterations could result in the discovery of more effective transfecting lipids, improving the efficacy of widely used lipid carriers is also crucial in order to compete with viral vectors for gene delivery. Herein, we developed formulations of commercially available lipid, 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) with synthetic amino acid based cationic lipids. Two cationic lipids were synthesized using amino acids, with either cystine (CTT) or arginine (AT) in the head group. These lipids were used to formulate co-liposomal structures with different lipid compositions. The liposomal formulations were broadly categorised into two types: amino acid-based liposomes without DOTAP (CTTD and ATD) and those with DOTAP (DtATD and DtCTTD). Optimized lipid-DNA complexes of DOTAP-incorporated formulations (DtATD and DtCTTD) exhibited enhanced efficacy in transfection compared to formulations lacking DOTAP as well as commercial formulations such as DOTAP:DOPE. Notably, DtCTTD displayed superior transfection capabilities in prostate cancer (PC3) and lung cancer (A549) cell lines when compared to the widely used commercial transfection reagent, Lipofectamine. Collectively, the findings from this study suggest that DOTAP-incorporated formulations derived from amino acid-based liposomes, hold promise as effective tools for improving transfection efficacy with reduced toxicity, offering potential advancements in gene delivery applications.

Tyrosinases (TYRs) are copper-containing metalloenzymes present in a large diversity of species. In human, hTYR is responsible for pivotal steps in melanogenesis, catalysing the oxidation of l-tyrosine to l-DOPA and further to dopaquinone. While numerous TYR inhibitors have been reported, polyphenolic compounds tend to dominate the literature. However, many of these compounds, particularly monophenols and catechols, have been identified as alternative substrates rather than true inhibitors, given their structural similarity to natural substrates. Resorcinol-containing compounds have emerged as promising candidates to address this challenge, as the meta-dihydroxy moiety in resorcinol demonstrates resistance to TYR-mediated oxidation, while retaining the favourable interactions with copper ions provided by the hydroxy groups. Although their precise mechanism of action remains debated, resorcinol derivatives have yielded some of the most active compounds against isolated mushroom and human TYRs, as well as clinically used dermocosmetic agents like rucinol and thiamidol, which exhibited very promising effects in patients with facial melasma. This review outlines the development of resorcinol-containing TYR inhibitors, categorized by scaffold type, ranging from simple alkyl analogues to intricate synthetic derivatives. Mechanistic insights about the resorcinol-TYR interaction are also presented and debated.

Nowadays, the widespread diffusion of infections caused by opportunistic fungi represents a demanding threat for global health security. This phenomenon has also worsened by the emergence of contagious events in hospitalisation environments and by the fact that many fungi have developed harsh and serious resistance mechanisms to the traditional antimycotic drugs. Hence, the design of novel antifungal agents is a key factor to counteract mycotic infections and resistance. Within this context, nanomaterials are gaining increasing attention thanks to their biocidal character. Among these, carbon dots (CDs) represent a class of zero-dimensional, photoluminescent and quasi-spherical nanoparticles which, for their great and tuneable features, have found applications in catalysis, sensing and biomedicine. Nevertheless, only a few works define and recapitulate their antifungal properties. Therefore, we aim to give an overview about the recent advances in the synthesis of CDs active against infective fungi. We described the general features of CDs and fungal cells, by highlighting some of the most common antimycotic mechanisms. Then, we evaluated the effects of CDs, antimicrobial drugs-loaded CDs and CDs-incorporated packaging systems on different fungi and analysed the use of CDs as fluorescent nano-trackers for bioimaging, showing, to all effects, their promising application as antifungal agents.

The French Society of Medicinal Chemistry or “ Société de Chimie Thérapeutique ” (SCT) was founded in 1966. Since its inception, its mission has been to promote knowledge in the main fields of pharmaceutical research and development, in particular the research and validation of biological targets of therapeutic interest, the screening, design and optimization of drug candidates, chemical biology, medicinal chemistry, pharmacokinetics, metabolism and toxicity. Since 1964, the Society has organized an annual international congress (RICT), and later thematic days for young researchers and workshops on specific topics. The SCT is also a member of the European Federation for Medicinal Chemistry (EFMC) and organized the International Symposium on Medicinal Chemistry (ISMC) in Nice in 2022. Several new trends can be identified in the activities of the SCT, such as the organization of regular webinars, but also the recent creation of the Young MedChem Forum, as well as the distribution of a newsletter reporting scientific achievements in the French community and abroad, and an improved presence on social networks. These trends are in line with the current changes in the field in terms of scientific progress, means of communication in the community and with the public and inclusiveness.

New 4-nitrobenzyl derivatives were designed and synthesised by nucleophilic substitution reactions of 4-nitrobenzyl bromide with malonic acid and its derivatives. The synthesised molecules were characterised using mass analysis and spectroscopic techniques and tested for their antioxidant properties using various methods, such as nitric oxide, DPPH, and hydrogen peroxide radical scavenging methods. The anti-inflammatory activities of the molecules were assessed using RBC membrane stabilisation and albumin denaturation methods. We evaluated the compounds' potential anti-prostate cancer activity using the DU145 cell line. The MTT assay determined the cell viability, indicating good anti-proliferative activity. The molecule 3 c exhibited the highest potency, with a CTC₅₀ of 11.83 μg/mL. Molecular dynamics simulations were performed to study the stability of the ligand within the protein after docking and the resulting protein-ligand complex. The in vivo analysis of molecule 3 c in the DAL xenograft model demonstrated promising results. The increase in life span, reduction in tumor volume, and comparable effects to standard drugs are encouraging features that suggest that molecule 3 c may possess significant potential as an anti-cancer agent. The research also implies that these molecules might be potential lead compounds for developing new prostate cancer drugs.

The Front Cover shows the clinical demands that drive the development of novel imaging agents for positron emission tomography (PET) or single-photon emission computed tomography (SPECT). Multiple pathways lead from the initial concept to a practically useful compound. The process for the discovery and development of imaging agents follows a well-documented path; however, variations are possible and provide some flexibility depending on the resources and technologies available to the project team. According to the question asked, the properties of the imaging agents will vary, and the requirements for their development will differ. Understanding the target profile required to address the clinical questions, as well as the possible steps enabling the discovery, optimization, and validation of imaging agents is critical. Like when climbing a mountain, resource efficiency and speed should be optimized to guarantee the optimal development of novel imaging agent candidates. More details can be found in article 10.1002/cmdc.202400094 by Yves P. Auberson and co-workers.

Isoflavones are phenolic natural compounds with a C₆C₃C₆ framework. They possess a plethora of biological activities that are associated with putative benefits to human health. In particular, the cancer chemopreventive and chemotherapeutic potential of isoflavones has attracted the interest of researchers. Several isoflavone derivatives have been synthesised and probed for their anticancer activities. The isoflavone analogues are mainly synthesised by molecular hybridisation and other strategies that enable diversification through early or late-stage functionalisation of A-, B- and C-rings of the isoflavones. This has resulted in the discovery of isoflavone analogues with improved antiproliferative activities against several cancer cells and different mechanisms of action. In this review, the synthesis of isoflavone derivatives and their anticancer activity studies are discussed.

Hearing loss (HL) affects more than 5% of the global population, with projections indicating an impact of up to 50% on young individuals in the next years. HL treatments remain limited due to the inner ear's hermeticism. HL often involves inflammatory processes, underscoring the need for enhanced delivery of antiinflammatory agents to the inner ear. Our research focuses on the development of a directed therapy based on magnetic nanoparticles (MNPs). We previously synthesized biocompatible folic acid-coated iron oxide-core nanoparticles (MNPs@FA) as potential carriers for the anti-inflammatory Diclofenac (Dfc). This study aims to incorporate Dfc onto MNPs@FA to facilitate targeted drug delivery to the inner ear. Through optimizing the loading procedure, we achieved optimal loading capacity. Dfc release was studied in the simulated target fluid and the administration vehicle. Complete characterization is also shown. In vitro biocompatibility testing ensured the biosafety of the resulting formulation. Subsequent ex vivo targeting assays on murine cochleae validated the nanosystems' ability to penetrate the round window membrane, one of the main HL therapy barriers. These findings serve as validation before continuing to more complex in vivo studies. Together, the data here presented represent an advancement in addressing unmet medical needs in HL therapy.

Many current cancer immunotherapies function by redirecting immune system components to recognize cancer biomarkers and initiate a cytotoxic attack. The lack of a universal tumor biomarker limits the therapeutic potential of these approaches. However, one feature characteristic of nearly all solid tumors is extracellular acidity. This inherent acidity provides the basis for targeted drug delivery via the pH-low insertion peptide (pHLIP), which selectively accumulates in tumors in vivo due to a pH-dependent membrane insertion propensity. Previously, we established that we could selectively decorate cancer cells with antigen-pHLIP conjugates to facilitate antibody recruitment and subsequent killing by engineered effector cells via antibody-depended cellular cytotoxicity (ADCC). Here, we present a novel strategy for opsonizing antibodies on target cell surfaces using click chemistry. We utilize pHLIP to facilitate selective tetrazine - trans-cyclooctene ligation of human IgGs to the cancer cell surface and induce ADCC. We demonstrate that our approach activates the primary ADCC signaling pathway via CD16a (FcγRIIIa) receptors on effector cells and induces the killing of cancer cell targets by engineered NK cells.

Tumor progression depends on angiogenesis, which is stimulated by growth factors like VEGF, targeting VEGFR kinase with small molecules is an effective anti-angiogenic therapeutic approach. The rational modification of sunitinib (VEGFR-2 inhibitor) to spirocyclopropyloxindoline carboxamides have been performed and their in vitro cytotoxic profiling was evaluated. The molecular modelling studies enabled the screening of designed analogues and identifying the possible interactions within the type III allosteric inhibitor binding site of VEGFR-2. The biological screening of synthesized compounds 15 a-y, revealed the ability of compound 15 w to inhibit the cell growth in MCF-7 cell line with IC₅₀ value of 3.87±0.19 μM and alongside inhibition of VEGFR-2 kinase at a IC₅₀ concentration of 4.34±0.13 μM was observed. Also, VEGFR-2 inhibition was validated through HUVEC tube formation inhibition assay. The qualitative assessment of apoptosis induction by 15 w in MCF-7 cells was evaluated through staining studies such as AO/EB and DAPI staining, whereas quantification of apoptosis and cell cycle analysis were performed through FACS analysis. The metastatic ability of the cancer cells was evaluated through inhibition of cell migration by a scratch wound healing assay. The current study strives to sequentially optimize the structural attributes of the 3-alkenyl oxindole core to surpass the existing challenges of well-known VEGFR-2 inhibitors. The findings observed from this study highlights that compound 15 w to be a prominent lead towards the development of clinical drug candidates.