RSC medicinal chemistry最新文献

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.

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.

Pyruvate kinase M2 (PKM2), a crucial enzyme in the glycolysis pathway, is commonly documented as being overexpressed in cancer cells. Inhibiting PKM2, a strategy to mitigate cancer cell-dependent glycolysis, has demonstrated efficacy in anticancer treatment. In this study, plumbagin, which was originally extracted from the plant Plumbago zeylanica L., was discovered as a novel PKM2 inhibitor and it could bind to PKM2 to inhibit the enzymatic activity. Treatment with plumbagin in HepG2 cells resulted in the decrease of PKM2 expression, which in turn reduced the protein kinase function. The mRNA levels of its downstream genes, such as LDHA and MYC, were suppressed. Additionally, plumbagin downregulated the expression of intracellular antioxidant proteins, which induced oxidative stress and mitochondrial damage, ultimately triggering apoptosis. Moreover, plumbagin also reduced the migration and proliferation of HepG2 cells. This study offered valuable insights into the molecular mechanism of plumbagin and advocated for the exploration of PKM2 inhibitors as viable possibilities for anticancer therapeutics.

Due to its essential roles in cell proliferation and apoptosis, the precise regulation of the Hippo pathway through LATS presents a viable biological target for developing new drugs for cancer and regenerative diseases. However, currently available probes for selective and highly drug-like inhibition of LATS require further improvement in terms of both activity, selectivity and drug-like properties. Through scaffold hopping aided by docking studies and AI-assisted prediction of metabolic stabilities, we successfully identified an advanced LATS inhibitor demonstrating potent kinase activity, exceptional selectivity against other kinases, and superior oral pharmacokinetic profiles.

The norepinephrine transporter (NET), encoded by the SLC6A2 gene, is one of three key monoamine neurotransmitter transporters. Inhibition of NET-mediated reuptake of norepinephrine by monoamine reuptake inhibitors has been the main therapeutic strategy to treat disorders such as depression, ADHD and Parkinson's disease. Nevertheless, lack of efficacy as well as risk of adverse effects are still common for these treatments underscoring the necessity to improve drug discovery efforts for this target. In this study, we developed new inhibitors based on 4-((2-(3,4-dichlorophenyl)cyclopentyl)amino)butan-1-ol (8), a potent NET inhibitor, which emerged from earlier virtual screening efforts using a predictive proteochemometric model. Hence, we optimized the N,2-substituted cycloalkylamine scaffold in three regions to design twenty new derivatives. To establish structure-activity relationships for these NET inhibitors, all novel compounds were tested utilizing an impedance-based 'transporter activity through receptor activation' assay. Moreover, all stereoisomers of the most potent compound (27) were synthesized and evaluated for their inhibitory potencies. Initial screening indicated that modifications in the cyclopentylamine moiety and phenyl substitutions decreased NET inhibition compared to 8, emphasizing the importance of the five-membered ring, secondary amine and dichloro-substitution pattern in NET binding. Substituting the original butylalcohol at the R ² position with a rigid cyclohexanol yielded lead compound 27, with potency similar to reference inhibitor nisoxetine. Pharmacological characterization of all eight stereoisomers of 27 revealed varying inhibitory potencies, favoring a trans-orientation of the N,2-substituted cyclopentyl moiety. Molecular docking highlighted key interactions and the impact of a hydrophilic region in the binding pocket. This study presents a novel set of moderate to highly potent NET inhibitors, elucidating the influence of molecular orientation in the NET binding pocket and offering valuable insights into drug discovery efforts for monoamine transport-related treatments.