RSC medicinal chemistry最新文献

A series of sulfonamides incorporating a 1,2,3-triazolyloxime substituted 1,2,3-triazolyl moiety were conceptualized and synthesized as human carbonic anhydrase (hCA) inhibitors. The synthesized small structures, denoted 7a through 7o, exhibited moderate inhibitory effects against the tumor-associated isoforms hCA IX and hCA XII compared to the well-known hCA inhibitor acetazolamide. In contrast, these molecules demonstrated higher potency and a diverse range of selectivity against the cytosolic isoforms hCA I and hCA II. Notably, the 4-hydroxyphenyl derivative (compound 7dversus cytosolic isoforms), the 4-acetylphenyl derivative (compound 7o), and the phenyl derivative (compound 7a) emerged as the most potent and selective inhibitors in this series, with inhibition constants (K _I) of 47.1, 35.9, 170.0, and 149.9 nM, respectively, against hCA I, II, IX, and XII. Further cytotoxicity assays of compounds 7a-o against cancer cell lines Hep3B and A549, as well as normal cell line L929, were conducted to assess their selectivity towards malignant cells. Compounds 7d, 7g, and 7k exhibited selective cytotoxicity towards the Hep3B cell line, with reduced selectivity towards A549, whereas compound 7j demonstrated higher selectivity for the A549 cell line. Additionally, molecular docking studies were performed to elucidate the binding modes of these compounds within the active sites of hCAs, revealing crucial interactions that underpin their significant activity and selectivity for the tumor-specific isoforms.

Pimasertib, a potent antiproliferative drug, has been extensively studied for treating cancers characterized by dysregulation in the ERK/MAPK signaling pathway, such as melanoma. However, its therapeutic efficacy would greatly benefit from an increased selectivity for tumour cells and a longer half-life. Such improvements may be achieved by combining the rational design of a prodrug with its encapsulation in a potential nanodelivery system. For this reason, we synthesized a glutathione (GSH)-responsive putative prodrug of pimasertib (PROPIMA), which contains a redox-sensitive disulphide linker that can be processed by GSH to activate pimasertib. The synthesis of PROPIMA and its in vitro biological activity on a human melanoma cell line as a model are described. The results showed that PROPIMA, either free or embedded in liposomes, selectively inhibits cell proliferation and cell viability, reducing by about 5-fold the levels of pERK. Additionally, PROPIMA shows stronger inhibition of the cancer cell migration than the parent drug.

Alzheimer's disease (AD) is a prevalent degenerative disorder affecting the central nervous system of the elderly. Patients primarily manifest cognitive decline and non-cognitive neuro-psychiatric symptoms. Currently, western medications for AD primarily include cholinesterase inhibitors and glutamate receptor inhibitors, which have limited efficacy and accompanied by significant toxic side effects. Given the intricate pathogenesis of AD, the use of single-target inhibitors is limited. In recent years, as research on AD has progressed, traditional Chinese medicine (TCM) and its active ingredients have increasingly played a crucial role in clinical treatment. Numerous studies demonstrate that TCM and its active ingredients can exert anti-Alzheimer's effects by modulating pathological protein production and deposition, inhibiting tau protein hyperphosphorylation, apoptosis, inflammation, and oxidative stress, while enhancing the central cholinergic system, protecting neurons and synapses, and optimizing energy metabolism. This article summarizes extracts from TCM and briefly elucidates their pharmacological mechanisms against AD, aiming to provide a foundation for further research into the specific mechanisms of TCM in the prevention and treatment of the disease, as well as the identification of efficacious active ingredients.

Non-small cell lung cancer (NSCLC), the leading cause of cancer-related mortality worldwide, poses a formidable challenge due to its heterogeneity and the emergence of resistance to targeted therapies. While initially effective, first- and third-generation EGFR-tyrosine kinase inhibitors (TKIs) often fail to control disease progression, leaving patients with limited treatment options. To address this unmet medical need, we explored the therapeutic potential of multitargeting agents that simultaneously inhibit two key signalling pathways, the mesenchymal-epithelial transition factor (c-MET) and the G protein-coupled receptor Smoothened (SMO), frequently dysregulated in NSCLC. By employing a combination of in silico drug repurposing and structure-based structure-activity relationship (SAR) studies, we identified and developed novel c-MET/SMO-targeting agents with antiproliferative activity against first- as well as third-generation EGFR-TKI-resistant NSCLC cells suggesting a synergistic effect arising from the simultaneous inhibition of c-MET and SMO.

Enveloped viruses enter the host cells by endocytosis and subsequently fuse with the endosomal membranes, or fuse with the plasma membrane at the cell surface. The crucial stage of viral infection, regardless of the route taken to enter the host cell, is membrane fusion. The present work aims to develop a peptide-based fusion inhibitor that prevents membrane fusion by modifying the properties of the participating membranes, without targeting a protein. This would allow us to develop a fusion inhibitor that might work against a larger spectrum of enveloped viruses as it does not target any specific viral fusion protein. With this goal in mind, we have designed a novel peptide by modifying a native sequence derived from coronin 1, a phagosomal protein, that helps to avoid lysosomal degradation of mycobacterium-loaded phagosomes. The designed peptide, mTG-23, inhibits ∼30-40% fusion between small unilamellar vesicles containing varying amounts of cholesterol by modulating the biophysical properties of the participating bilayers. As a proof of principle, we have further demonstrated that the mTG-23 inhibits Influenza A virus infection in A549 and MDCK cells (with ∼EC₅₀ of 20.45 μM and 21.55 μM, respectively), where viral envelope and endosomal membrane fusion is a crucial step. Through a gamut of biophysical and biochemical methods, we surmise that mTG-23 inhibits viral infection by inhibiting viral envelope and endosomal membrane fusion. We envisage that the proposed antiviral strategy can be extended to other viruses that employ a similar modus operandi, providing a novel pan-antiviral approach.

Coronaviruses rely on the viral-encoded chymotrypsin-like main protease (M^pro or 3CL^pro) for replication and assembly. Our previous research on M^pro of SARS-CoV-2 identified cysteine 300 (Cys300) as a potential allosteric site of M^pro inhibition. Here, we identified tixocortol (TX) as a covalent modifier of Cys300 which inhibits M^pro activity in vitro as well as in a cell-based M^pro expression assay. Most importantly TX inhibited SARS-CoV-2 replication in ACE2 expressing HeLa cells. Biochemical analysis and kinetic assays were consistent with TX acting as a non-competitive inhibitor. By contrast, TX was a weaker inhibitor and modifier of C300S M^pro, confirming a role for Cys300 in inhibition of WT M^pro but also providing evidence for an additional Cys target. TX pivalate (TP), a prodrug for TX that was previously marketed as a nasal spray, also inhibited SARS-CoV-2 replication in HeLa-ACE2 cells at low micromolar IC₅₀s. These studies suggest that TX and/or TP could possibly be repurposed for the prevention and/or treatment of SARS-CoV-2 infection.

VEGFR2 inhibition has been established as a therapeutic approach for managing cancer. A series of curcumin-based analogues were designed, synthesized, and screened for their anticancer activity against MCF-7 and HepG-2 cell lines and WISH normal cells. Compounds 4b, 4d, 4e, and 4f showed potent cytotoxicity against MCF-7 with IC₅₀ values of 0.49, 0.14, 0.01, and 0.32 μM, respectively, compared to curcumin (IC₅₀ = 13.8 μM) and sorafenib (IC₅₀ = 2.13 μM). Interestingly, compound 4e, the most active compound, exhibited potent VEGFR2 inhibition with an IC₅₀ value of 11.6 nM (96.5% inhibition) compared to sorafenib with an IC₅₀ value of 30 nM (94.8% inhibition). Additionally, compound 4e significantly induced apoptotic cell death in MCF-7 cells by 41.1% compared to a control group (0.8%), halting cell division during the G2/M phase by 39.8% compared to the control (21.7%). Molecular docking-coupled dynamics simulations highlighted the bias of the VEGFR2 pocket towards compound 4e compared to other synthesized compounds. Predicting superior binding affinities and relevant interactions with the pocket's key residues recapitulated in vitro findings towards higher inhibition activity for compound 4e. Furthermore, compound 4e with adequate pharmacokinetic and drug-likeness profiles in terms of ADME and safety characteristics can serve as a promising clinical candidate for future lead optimization and development. Notably, 4e-Fe₂O₃-humic acid NPs exhibited potent cytotoxicity with IC₅₀ values of 2.41 and 13.4 ng mL^-1 against MCF-7 and HepG-2 cell lines, respectively. Hence, compound 4e and its Fe₂O₃-humic acid-NPs could be further developed as promising anti-breast cancer agents.

MicroRNAs (miRNAs) play a crucial role in ovarian cancer (OC) pathogenesis and miRNA processing can be the object of pharmacological intervention. By exploiting our in-house quinolone library, we combined a cell-based screening with medicinal chemistry efforts, ultimately leading to derivative 33 with anti-OC activity against distinct cell lines (GI₅₀ values 13.52-31.04 μM) and CC_{50 Wi-38} = 142.9 μM. Compound 33 retained anticancer activity against additional cancer cells and demonstrated a synergistic effect with cisplatin against cisplatin-resistant A2780 cells. Compound 33 bound TRBP by SPR (K _D = 4.09 μM) and thermal shift assays and its activity was TRBP-dependent, leading to modulation of siRNA and miRNA maturation. Derivative 33 exhibited augmented potency against OC cells and a stronger binding affinity for TRBP compared to enoxacin, the sole quinolone identified as a modulator of miRNA maturation. Consequently, 33 represents a promising template for developing novel anti-OC agents with a distinctive mechanism of action.

The application of nanoparticles is promising for the purposes of nuclear medicine due to the possibilities of using them as vectors and transporters of radionuclides. In this study, we have successfully synthesised conjugates of CeO₂ nanoparticles and azacrown ligands. Then, the radiolabelling conditions with radionuclides ⁶⁵Zn, ⁴⁴Sc and ²⁰⁷Bi were selected and the kinetic stability of the complexes in biologically significant media was evaluated. Optimum conditions for CeO₂-APTES-L and CeO₂-APTES-DOTA labelling were found: 0.1 g l^-1 conjugate and 10^-9 M metal cations at 90 °C for complexes with [⁶⁵Zn]Zn²⁺, [⁴⁴Sc]Sc³⁺ and [²⁰⁷Bi]Bi³⁺. CeO₂-APTES-L-⁴⁴Sc (radiochemical purity more than 90%) was stable in fetal bovine serum. The obtained results enabled us to choose the most promising complex for biomedical applications for carrying out in vitro and in vivo biodistribution research. Nanoceria and its derivative showed no obvious toxicity to human endothelial cells EA.hy926. Then, the in vivo stability of the studied scandium complex was demonstrated. Taken together, our studies show that functionalised cerium oxide nanoparticles lead to stable radiolabelled nanosystems that may be used for targeted drug delivery, diagnosis and treatment of oncological diseases.

The regioselective synthesis of functionalized naphthoquinones via the formation and capture of naphthoquinonynes has been used to prepare trypanocidal compounds. The target compounds are functionalized on the aromatic ring, leaving the quinoidal ring intact. Using this technique, eighteen functionalized naphthoquinones were succesfull obtained, divided in two main groups: the first scope using N-nucleophiles, and the second scope using pyridine N-oxides, with yields up to 74%. Evaluation against bloodstream trypomastigotes of T. cruzi has identified fourteen compounds that are more potent than benznidazole (Bz); for instance, compounds 29b-I and 30b, with IC₅₀/24 h values of 10.5 and 10.1 μM, respectively, are approximately 10-fold more active than Bz. This study provides the first examples of the application of naphthoquinonyne chemistry for the synthesis of new compounds with potent trypanocidal activities.