ChemMedChem最新文献

Medicinal Chemistry is a quantitative scientific discipline. Hence, it is of utmost importance that scientists working in this field pay rigorous attention to the correct representation of their quantitative data. However, browsing the Medicinal Chemistry literature, it becomes obvious that this is very often not the case. In particular, results from biological assays are too frequently reported with unreasonable numbers of significant figures. In this Perspective, it is argued that this is poor practice that sheds an unfortunate light on the discipline of Medicinal Chemistry and that therefore, more rigorous policies regarding the presentation of quantitative data in Medicinal Chemistry publications should be considered.

In this manuscript, twenty-one novel fluorinated piperazine-hydroxyethylamine analogues were synthesized and tested against Plasmodium falciparum (Pf). Among tested compounds, two 13 g and 14 g exhibited promising inhibitory activity on Pf3D7 with IC₅₀ values of 0.28 and 0.09 μM, respectively. Neither of the hits exhibited cytotoxicity on HepG2 cells up to 150 μM and Vero cells up to 20 μM. Compounds 13 g and 14 g were also evaluated against chloroquine-resistant PfDd2 and displayed IC₅₀ values of 0.11 and 0.10 μM, respectively. Next, 13 g and 14 g were administered to the Plasmodium berghei mice model at 30 mg/kg intraperitoneally for four consecutive doses, which showed 25 % and 50 % reduction in the parasitemia load, respectively. The efficacy of hits 13 g and 14 g was improved along with mean survival time when administered in combination with artesunate. On liver-stage parasites, compounds 13 g and 14 g showed >80 % inhibition at 1 μM. Compound 14 g was also tested for toxicity in mice at 100 mg/kg dose, which revealed no abnormality in mice organs. Preliminary pharmacokinetic studies of compound 14 g exhibited absorption and maintained a presence in the body for more than six hours.

Based on a clinical staged small molecular hClpP activator ONC201, a class of novel hClpP agonists with a [1,8]naphthyridinone scaffold were designed, synthesized and evaluated in a series of biochemical and biological assays. Mechanism studies for the representative compound F20 indicated that it can potently bind to and activate hClpP, efficiently promote the degradation of hClpP substrates, robustly induce ATF4/CHOP regulated integrated stress responses, strongly inhibit cell growth and effectively induce apoptosis in a subset of cancer cell lines. F20 showed good PK profiles when dosed by intravenous injection and exhibited moderate oral bioavailability in mice.

The Front Cover features a potential inhibitor targeting the protein kinase B (AKT), N-oxide hybrid triarylmethane type. The mechanism of action of its antiproliferative activity was validated through in silico studies and biological tests on colorectal cancer cells lines. More details can be found in article 10.1002/cmdc.202400151 by Bertrand Liagre, M. Sylla-Iyarreta Veitía, and co-workers. Cover design was generated using the high-performance molecular visualization software VTX (https://vtx.drugdesign.fr).

Small-molecule allosteric activators of the enzyme sarco/endoplasmic reticulum calcium ATPase (SERCA) hold promise as novel experimental tools to manipulate intracellular calcium concentrations and as therapeutic agents to treat medical conditions associated with elevated cytosolic calcium levels. Here, we synthesized and characterized 20 analogs of the known allosteric SERCA activator CDN1163 and tested their ability to stimulate SERCA activity. The structures of the compounds varied in the alkyl group of the parent scaffold's ether moiety as well as in the composition of the nitrogenous aromatic ring system. The most active compounds exhibited potencies in the sub-micromolar range while increasing enzyme activity by more than 25 %. The observed structure-activity relationships indicated that bulky alkyl groups in the ether moiety along with a quinoline ring methyl substituent were beneficial for activity. Replacement of the quinoline by a pyrimidine ring system reduced activity. To conceive a potential mechanism of action, we generated a molecular model of the transition state of SERCA when undergoing the rate-limiting step of its catalytic cycle. Subsequent blind docking with CDN1163 identified a high-affinity binding site close to the enzyme's ATP binding pocket, suggesting that the activators may accelerate SERCA's catalytic cycle by aiding in ATP binding and positioning.

KDM4A-F enzymes are a subfamily of histone demethylases containing the Jumonji C domain (JmjC) using Fe(II) and 2-oxoglutarate for their catalytic function. Overexpression or deregulation of KDM4 enzymes is associated with various cancers, altering chromatin structure and causing transcriptional dysfunction. As KDM4 enzymes have been associated with malignancy, they may represent novel targets for developing innovative therapeutic tools to treat different solid and blood tumors. KDM4A is the isozyme most frequently associated with aggressive phenotypes of these tumors. To this aim, industrial and academic medicinal chemistry efforts have identified different KDM4 inhibitors. Industrial and academic efforts in medicinal chemistry have identified numerous KDM4 inhibitors, primarily pan-KDM4 inhibitors, though they often lack selectivity against other Jumonji family members. The pharmacophoric features of the inhibitors frequently include a chelating group capable of coordinating the catalytic iron within the active site of the KDM4 enzyme. Nonetheless, non-chelating compounds have also demonstrated promising inhibitory activity, suggesting potential flexibility in the drug design. Several natural products, containing monovalent or bivalent chelators, have been identified as KDM4 inhibitors, albeit with a micromolar inhibition potency. This highlights the potential for leveraging them as templates for the design and synthesis of new derivatives, exploiting nature's chemical diversity to pursue more potent and selective KDM4 inhibitors.

Photo-induced chemotherapy offers the best option for the selective treatment of cancer among all the prevailing modalities. Iridium (III) complexes, flourished with excellent photophysical and photochemical properties, have been considered to be superior for undergoing photo-responsive cancer therapy. Large Stokes shift, long-lived triplet excited state, photostability, and tuneable emission have rendered its excellence as a phototheranostic agent. In particular, the cyclometalated Ir (III) complexes and their respective nanoparticles have made a strong niche in the arena of cancer therapy. In recent years, Ir (III) based complexes have shown promising utilities as both imaging and therapeutic agents as well. Therefore, this review summarises the recent advances in the strategic designing of cyclometalated Ir(III) complexes to augment their phototheranostic applications in precision medicine.

Novel 1,10-phenanthroline-2,9-bistriazoles derivatives have been synthesized by copper-catalyzed azide/alkyne cycloaddition reactions and assessed for their ability to bind and stabilize G-quadruplex (G4) structures. Ten novel compounds were evaluated using Förster resonance energy transfer (FRET) melting, circular dichroism (CD), and fluorescence spectroscopy on several G4 sequences. Biophysical characterization led to the identification of compounds 4 a, 4 b, and 5 b as good G4 ligands of KRAS G4 sequences. The impact on cell viability of all derivatives was also assessed, revealing weak effects. However, compound 2 a exhibited cytotoxicity activity on A549 and H1299 cancer cells and low cytotoxicity towards MRC-5 non-malignant cells MRC-5 not connected with its G4-binding ability. Flow cytometry showed that 2 a induced a cell viability decrease in S and G2/M phases for A549 and H1299; thus, more studies should be performed to explore the proteins involved in cell cycle regulation.

GlcNAcylation is a prevalent protein modification in eukaryotic cells and increasing evidences indicated that over-expressed O-GlcNAcylation are intimately linked to the development and prognosis of prostate cancer. Thus, exploring this modification in the context of prostate cancer is vital for understanding the underlying mechanisms and hopefully used for future targeted therapies. In this paper, we use our previously established metabolic probes to comprehensively compare the labeling efficiency of O-GlcNAc modified proteins in PC3 cells. Our results demonstrated that all the tested probes were non-toxic to PC3 cells and only Ac₄GlcNAz, Ac₄GalNAz and Ac₃4deoGlcNAz exhibited robust labeling signals amongst the probes. Further investigations by western blot and flow cytometry analysis revealed that Ac₃4deoGlcNAz was a specific and efficient probe for intracelluar protein labeling with negligible S-glyco-modification signal. In addition, proteomic analysis further confirmed that 94 % of the proteins identified by Ac₃4deoGlcNAz were in the form of O-linked GlcNAc rather than S-glyco-modification, these enriched O-GlcNAcylated proteins were mainly involved in the regulated processes of prostate cancer. Our results here together prove Ac₃4deoGlcNAz is a safe and reliable probe for metabolic labeling O-GlcNAc modified proteins in prostate cancer, providing a mean to fully exploit the regulatory mechanism of O-GlcNAcylation in the process of prostate cancer.

Relieving severe pains is an unmet medical need, in which opioids are of prime importance and in the focus of pharmaceutical companies. The objective of this study is to characterize the physicochemical properties, namely basicity, lipophilicity and permeability of thirty opioid ligands, which include eleven newly synthesized compounds. pH-potentiometry and the shake-flask method were used for the characterization of species-specific basicity and lipophilicity. The effective permeability was determined using a brain-specific parallel artificial membrane permeability assay. Structural modifications, namely O-methylation in position 3, isomerization in position 6, saturation of the double bond in position 7, 14-hydroxylation, and the substitution of N-(β-phenylethyl) and N-cyclobutylmethyl side chains all have various effects on these physicochemical properties, and these are explained and compared to computationally predicted values. Computational predictions inadequately capture hydrogen bond formation with the tertiary amino group in case of 14-hydroxylation, just as the effects of hydroxy oxidation at position 6 and N-methyl substitution with N-(β-phenylethyl). The relationship between lipophilicity, permeability and potency is presented by lipophilic efficiency plots that reveal the most promising compounds. This study emphasizes the importance of experimental determination of these essential physicochemical parameters, furthermore, it can contribute to a more thorough understanding of the pharmacokinetic properties.