RSC medicinal chemistry最新文献

Non-small-cell lung cancer (NSCLC), which accounts for approximately eighty-five percent of lung cancer diagnoses worldwide, is a malignancy with high incidence and mortality rates. Among the various antitumor compounds, organic selenium-containing compounds have emerged as a promising class of therapeutic agents for cancer treatment. In the present study, SLL-1A-16, a new organoselenium small molecule, was discovered to exhibit antiproliferative activity against NSCLC both in vitro and in vivo. Treatment with SLL-1A-16 significantly inhibited NSCLC cell proliferation and induced apoptosis and autophagy. Mechanistically, SLL-1A-16 inhibited cell proliferation through G1-S phase arrest by reducing cyclin D1 and CDK4 expression. Additionally, SLL-1A-16 significantly induced apoptosis by upregulating cleaved caspase 3 and Bax expression, while downregulating Bcl-2 levels. Our study also demonstrated that SLL-1A-16 induced autophagy in NSCLC cells by inhibiting the Akt/mTOR pathway. Overall, our findings suggest that SLL-1A-16 could induce cell cycle arrest, apoptosis and autophagy in NSCLC cells by inhibiting the Akt/mTOR signaling pathways, providing a theoretical basis for the potential clinical application of SLL-1A-16 as a chemotherapeutic agent in NSCLC treatment.

The cell entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is mediated by the interaction between the receptor-binding domain of its spike (S) protein and human angiotensin-converting enzyme 2 (ACE2). Quercetin, a flavonoid found abundantly in plants, shows potential as a SARS-CoV-2 S:ACE2 inhibitor but is known to have low bioavailability. Modification of quercetin by capping its hydroxyl moieties could enhance the metabolic stability, solubility, and bioavailability, and reduce toxicity. In this study, sixteen (16) O-modified quercetin derivatives were synthesized by incorporating alkyl and acyl moieties of varying lengths, sizes, and polarities to the hydroxyl groups. The SARS-CoV-2 S:ACE2 inhibitory activity and toxicity of the synthesized derivatives were assessed in vitro, and their physicochemical properties, pharmacokinetics, and drug-likeness were predicted and evaluated using the SwissADME web tool. Results showed that functionalization of the hydroxyl moieties of quercetin generally resulted in more potent inhibitors (>50% inhibition). Five (5) derivatives displayed a dose-dependent inhibition against the SARS-CoV-2 S:ACE2 interaction with promising IC₅₀ values (i.e., 2e (IC₅₀ = 7.52 μM), 3a (IC₅₀ = 5.00 μM), 3b (IC₅₀ = 25.70 μM), 3c (IC₅₀ = 2.22 μM), and 4b (IC₅₀ = 3.28 μM)). Moreover, these compounds exhibited low hepato-, nephro-, and cardiotoxicity, and their SwissADME profiles indicated favorable physicochemical, pharmacokinetic, and drug-like properties, suggesting their potential as promising lead SARS-CoV-2 S:ACE2 inhibitors.

TNBC has been recognized as the most highly aggressive breast cancer without chemotherapeutic drugs. A collection of oridonin hybrids consisting of conventional antitumor pharmacophores including nitrogen mustards and adamantane-1-carboxylic acid were synthesized by deletion or blockade of multiple hydroxyl groups and structural rearrangement. Compound 11a showed the most promising anti-TNBC activity with nearly 15-fold more potent antiproliferative effects than oridonin against MDA-MB-231 and HCC1806. Moreover, 11a significantly inhibited HCC1806, MDA-MB-231 and MDA-MB-468 cell proliferation by arresting cells at the G2/M phase in a dose-dependent manner. Furthermore, 11a could trigger dose-dependently early and late apoptosis in those indicated cell lines. More importantly, 11a could significantly increase p21, γH2AX and cleaved PARP accumulation in a dose-dependent manner. Furthermore, compound 11a exhibited better stability than oridonin in a plasma assay. Taken together, all results demonstrated that 11a may warrant further investigation as a promising anticancer drug candidate for the treatment of TNBC.

Molecular glues and bifunctional small molecules, such as targeted protein degraders, induce protein proximity to mediate gain-of-function pharmacology. Emerging technologies that synthetically manipulate protein surfaces to create neoproteins, and the development of covalent chemical probes for intra- and inter-protein surface labeling are described. Ligand-directed protein surface modification strategies have the potential to enhance the induced-proximity pharmacology toolkit and expand the druggable proteome, and this Opinion considers the opportunities and challenges that lie ahead.

TGR5, a receptor that interacts with bile acids on cell surfaces, has become a promising therapeutic target for type II diabetes due to its ability to regulate energy expenditure and blood sugar levels. While several TGR5 agonists have been identified, only a few are currently in clinical trials. This article reviews the promising TGR5 agonists discovered in recent years, highlighting the chemical structure and pharmacological profile of the most effective compounds. With the limited number of effective drugs available for treating type II diabetes, the search for a potent TGR5 agonist with high efficacy and fewer side effects continues. The goal of this article is to provide an overview of the latest advancements in TGR5 agonists and offer insights for the future development of novel, potent TGR5 agonists for diabetes treatment. A noteworthy aspect addressed in the discussion is the common side effect associated with TGR5 agonist treatment – gallbladder filling. The review also explores potential strategies to mitigate this side effect, with the goal of improving the overall safety and tolerability of TGR5-targeted therapies.

Cancer is the uncontrolled proliferation of abnormal cells that invade other areas, spread to other organs, and cause metastases, which is the most common cause of death. A review of all FDA-approved new molecular entities (NMEs) shows that natural products and derivatives account for over one-third of all NMEs. Before 1940, unmodified products and derivatives accounted for 43% and 14% of NME registrations, respectively. Since then, the share of unmodified products has decreased to 9.5% of all approved NMEs, while the share of derivatives has increased to 28%. Since the 1940s, semi-synthetic and synthetic derivatives of natural substances have gained importance, and this trend continues to date. In this study, we have discussed in detail isolated phytoconstituents with chemical modifications that are either FDA-approved or under clinical trials, such as podophyllotoxin, Taxol (paclitaxel, docetaxel), vinca alkaloids (vincristine, vinblastine), camptothecin, genistein, cephalotaxine, rohitukine, and many more, which may act as essential leads to the development of novel anticancer agents. Furthermore, we have also discussed recent developments in the most potent semisynthetic phytoconstituents, their unique properties, and their importance in cancer treatment.

PKMYT1, a member of the WEE family, plays a crucial role in the cell cycle by specifically phosphorylating CDK1-CyclinB at Tyr15 and Thr14. Recent investigations have revealed that the amplification of CCNE1 and the inhibition of PKMYT1 kinase collectively result in synthetic lethality, further indicating that PKMYT1 is promising as an effective target for tumor therapy. Existing PKMYT1 inhibitors are mostly derivatives of RP-6306 or pan-inhibitors, limiting their further development. Herein, we conducted virtual screening of a natural product library, and in vitro enzyme experiments demonstrated that EGCG, GCG, and luteolin exhibited potent inhibitory activities with IC₅₀ values of 0.137 μM, 0.159 μM, and 1.5 μM, respectively. Subsequently, analysis of the hit compounds and RP-6306, using different molecular simulation methods, revealed that stable hydrogen bonds with Asp251 and Glu157 in the DFG region were vital for binding to PKMYT1, more so than hydrogen bonds in the hinge and loop regions.

Correction for ‘Rosavin improves insulin resistance and alleviates hepatic and kidney damage via modulating the cGAS-STING pathway and autophagy signaling in HFD/STZ-induced T2DM animals’ by Hebatallah S. Ali et al., RSC Med. Chem., 2024, 15, 2098–2113, https://doi.org/10.1039/D4MD00023D.

Colorectal cancer represents the over-expression of TMEM16A and COX-2, offering a promising therapeutic strategy. Two Pt(IV) conjugates derived from Pt(II) drug (cisplatin or oxaliplatin) and niflumic acid, complexes 1 and 2, were designed and prepared to exert the positive impact of multiple biological targets of DNA/TMEM16A/COX-2 against colorectal cancer. Complex 2 afforded higher cytotoxicity than 1 and the combination of an intermediate of oxidized oxaliplatin and NFA against cancer cells A549, HeLa, MCF-7, and HCT116. Especially for colorectal cancer cells HCT116, 2 was significantly more toxic (22-fold) and selective to cancer cells against normal HUVEC cells (4-fold) than first-line oxaliplatin. The outstanding anticancer activity of 2 is partly attributed to its dramatic increase in cellular uptake, DNA damage, and apoptosis. Mechanistic studies indicated that 2 inhibited HCT116 cell metastasis by triggering TMEM16A, COX-2, and their downstream signaling pathways, including EGFR, STAT3, E-cadherin and N-cadherin.

The emergence of SARS-CoV-2, the causative agent of COVID-19, has highlighted the need for advanced antiviral strategies. Targeting the coronaviral methyltransferase nsp14, which is essential for RNA capping, offers a promising approach for the development of small-molecule inhibitors. We designed and synthesized a series of adenosine 5′-carboxamide derivatives as potential nsp14 inhibitors and identified coumarin analogs to be particularly effective. Structural modifications revealed the importance of the 5′-carboxyl moiety for the inhibitory activity, showing superior efficacy compared to other modifications. Notably, compound 18l (HK370) demonstrated high selectivity and favorable in vitro pharmacokinetic properties and exhibited moderate antiviral activity in cell-based assays. These findings provide a robust foundation for developing targeted nsp14 inhibitors as a potential treatment for COVID-19 and related diseases.