Bioorganic & Medicinal Chemistry Letters最新文献

Developing small molecule drugs to treat metastatic cancer remains challenging and relies on the identification of novel druggable targets within the multistep metastatic cascade. To this end, the pro-metastatic scaffolding protein, MDA-9/Syntenin-1 was identified and confirmed as a suitable target uniquely involved in the multiple stages of metastasis. Recently, the first-in class PDZ1 domain inhibitor for MDA-9, PDZ1i, was identified displaying significant anti-invasion activity improving survival in an in vivo glioblastoma and in multiple metastatic cancer mouse models. Herein, we report a focused library of substituted 1-(benzo[d]thiazol-2-yl)-3-phenylurea derivatives inspired by the anti-invasion and anti-metastatic agent, PDZ1i. Our studies revealed that 1-(benzo[d]thiazol-2-yl)-3-phenylurea analogs bearing 6-trifluoromethyl (3y) and 6-bromo (3aa) substituents display anti-invasion activity comparable to PDZ1i. However, compounds 3y and 3aa displayed overall decreased cancer cell selectivity and MDA-9 activity relative to PDZ1i. Nonetheless, the reported 1-(benzo[d]thiazol-2-yl)-3-phenylurea derivatives serve as promising starting points for future development of small molecule anti-invasion agents with potential to prevent and treat metastatic cancers.

Parthenolide is a natural IκB kinase β (IKKβ) inhibitor. Converting it into a PROTAC (proteolysis-targeting chimeras) may lead to improved pharmacological efficacy. Herein, we report the design, synthesis, and biological evaluation of a novel series of parthenolide-based PROTACs. Among them, compound 8 exhibited potent anti-proliferative activity, especially against triple-negative breast cancer MDA-MB-231 cells. Mechanistic studies revealed that 8 acts as an effective IKKβ degrader, inducing degradation via the ubiquitin-proteasome system (DC₅₀ = 7.15 μM, 91.24% degradation at 10 μM). Furthermore, treatment with 8 was associated with significant apoptosis and G1-phase cell cycle arrest in MDA-MB-231 cells. This work provides initial evidence that the parthenolide scaffold can be leveraged for targeted protein degradation, supporting the future development of IKKβ-directed degraders.

Covalent inhibitors have re-emerged as powerful therapeutic agents, offering the ability to modulate "undruggable" proteins including oncogenic drivers that have eluded traditional drug discovery efforts. Expanding the repertoire of electrophilic moieties remains a critical frontier in covalent drug discovery. Here, we report a Rh(I)-catalyzed cycloisomerization of N-allyl bicyclo[1.1.0]butane amides (BCB amides) to access the 5-methylene-3-azabicyclo[5.1.0]octan-4-one (MABO) scaffold via strain-release reactivity. Both N-allyl BCB amides and MABOs can react with nucleophiles, highlighting their potential as electrophilic moieties for covalent drug design. Kinetic assays against glutathione revealed that selected N-allyl BCB amides and MABOs exhibit half-lives comparable to that of (±)-sotorasib, whose enantiomerically pure form received FDA approval as an anticancer drug. Biological evaluation in human-derived head and neck squamous cell carcinoma (HNSCC) models identified specific BCB amides and MABO compounds capable of modulating cancer cell growth. The toxicity of the compounds was evaluated by flow cytometry in human peripheral blood mononuclear cells (PBMCs) and by monitoring LDH release in the monocytic cell line THP-1, both under basal and activated conditions. Together, these findings suggest that BCB amides and MABOs represent promising classes of electrophilic scaffolds for covalent drug discovery.

We describe the synthesis and evaluation of six halogenated nitrophenyl glycosides for detection of β-galactosidase and β-glucuronidase enzyme activity among Enterobacterales ("coliforms") and Escherichia coli, respectively. These were evaluated alongside the established substrates; o-nitrophenyl-β-D-galactopyranoside (ONPG), p-nitrophenyl-β-D-galactopyranoside (PNPG) and p-nitrophenyl-β-D-glucuronide (PNP-GUR). The evaluation was performed using 30 isolates of Enterobacterales including 19 isolates of E. coli. Hydrolysis of 2-fluoro-p-nitrophenyl-β-D-galactopyranoside (2-fluoro-PNPG) yielded a significantly stronger yellow coloration after a six-hour incubation period compared to hydrolysis of ONPG and PNPG, potentially allowing for a more sensitive detection of Enterobacterales. Similarly, hydrolysis of the novel substrate 2-fluoro-p-nitrophenyl-β-D-glucuronide sodium salt (2-fluoro-PNP-GUR Na) by producers of β-glucuronidase also yielded a significantly stronger yellow colouration, potentially allowing for a more sensitive detection of E. coli. The yellow chromophore 2-fluoro-PNP retained high colour intensity at reduced pH when compared to o-nitrophenol and p-nitrophenol. Both substrates potentially offer enhanced sensitivity for the detection of Enterobacterales and E. coli in environmental samples as markers of faecal pollution.

Hepatocellular carcinoma (HCC) remains one of the leading causes of cancer-related mortality and disease burden worldwide, and its clinical management continues to face substantial challenges. Sorafenib, a widely used systemic therapy for advanced HCC, frequently develops acquired resistance upon long-term treatment, in part due to the overexpression of anti-apoptotic Bcl-2 family proteins. Herein, guided by the structural features of Sorafenib, the selective Bcl-2 inhibitor Venetoclax, and the selective Mcl-1 inhibitor AZD5991, we designed and synthesized a series of novel Sophocarpine-derived analogues bearing a pyridylethyl moiety via a molecular-hybridization strategy. Molecular docking suggested a favorable binding mode, in which the resulting scaffold could occupy the hydrophobic binding pockets of both Bcl-2 and Mcl-1 and engage key residues through hydrogen-bond interactions. In vitro antiproliferative screening (MTT assay) against three human HCC cell lines (Huh-7, MHCC-97H, and HepG2) showed that most compounds exhibited moderate to good activity. Notably, compound S6 emerged as the most potent analogue, with IC₅₀ values of 9.13 ± 0.29 μM (Huh-7), 6.76 ± 0.06 μM (MHCC-97H), and 15.9 ± 0.98 μM (HepG2). Mechanistic studies demonstrated that S6 markedly suppressed proliferation and migration of MHCC-97H cells, induced G1-phase arrest, and promoted apoptosis. Western blot analysis revealed that S6 downregulated anti-apoptotic proteins Bcl-2 and Mcl-1, induced mitochondrial membrane potential (ΔΨm) depolarization, and activated the caspase-dependent apoptotic cascade, as evidenced by caspase-3 activation and PARP1 cleavage. In parallel, a 3D-QSAR (CoMFA) model was constructed to rationalize the structure-activity relationship and to inform further lead optimization. Collectively, these findings identify S6 as a promising Sophocarpine derivative with a putative dual Bcl-2/Mcl-1 targeting profile, with significant anti-HCC activity and potential for preclinical development.

This study addresses drug resistance in castration-resistant prostate cancer by developing novel inhibitors of CYP11A1, the key rate-limiting enzyme in androgen synthesis. Based on the clinical candidate Opevesostat, two series of 23 new compounds were designed and synthesized using a 4H-pyran-4-one core to explore structure-activity relationships at the C2 and C6 positions.Compound II-4 exhibited potent inhibitory activity (95.2% at 100 nM; IC₅₀ = 26.7 nM), comparable to Opevesostat (IC₅₀ = 20.4 nM). Importantly, II-4 showed superior selectivity against CYP1A2, 2C9, and 2D6 (2- to 4-fold improvement), attributed to hydrophobic interactions between its C6 methyl group and Ile 84.These results highlight II-4 as a promising lead compound with optimized activity and selectivity, providing valuable insights for overcoming resistance in prostate cancer therapy.

This study reports a structure-guided design, synthesis, and biological evaluation of a novel class of hybrid molecules combining indole and pyrazole scaffolds-both known for their broad pharmacological profiles. A series of 5-indolyl-pyrazole derivatives (n = z1-z44) were synthesized and characterized through ¹H/¹³C NMR and HR-MS analysis. The synthesized compounds were screened against H37Rv and two multidrug-resistant clinically isolated strains M.tb* and M.tb**. Several derivatives (notably z1 and z8) showed potent inhibition at concentrations as low as 25 μg/mL may be even more potent at lower concentrations and a comparative analysis could be possible. Complementary molecular docking studies were conducted using the InhA enzyme (PDB ID: 4TZK), a validated target in mycolic acid biosynthesis. Lead compounds demonstrated favorable binding energies (e.g., -6.35 kcal/mol for z1), engaging key active-site residues (PHE97, MET103, PHE149, TYR158) through hydrophobic, π-stacking, and van der Waals interactions, alongside critical contact with the NAD⁺ cofactor. Interaction fingerprint analysis correlated ligand-residue contacts with biological activity, underscoring the importance of aromatic planarity and substituent modulation for effective InhA inhibition. This integrated synthetic-biological-computational workflow lays a promising foundation for the development of next-generation anti-TB agents with improved efficacy against resistant strains.

Inspired by the known anticancer activities of hydroxychalcones and acetamidochalcones, a series of novel hybrid molecules integrating these motifs with a paracetamol core were designed and synthesized. The synthesized chalcone-paracetamol hybrids were evaluated for their antiproliferative activity against a panel of eight human cancer cell lines. Compounds 6a, 6b, and 9, showed good activity against four cancer cell lines (U937, Jurkat, HCT-116 and MCF-7 cells). Notably, derivative 9 was the most potent with IC₅₀ ranging from 1.50 to 4.50 μM, while showing no significant toxicity toward normal cells. Mechanistic investigations revealed that compound 9 induced cell cycle arrest at G0/G1 phase and stimulated apoptosis. Further biochemical analysis identified it (9) as a multi-target agent, with significant inhibitory activity against EGFR (0.62 ± 0.02 μM), VEGFR-2 (2.26 ± 0.01 μM), COX-2 (17.38 ± 0.13 μM), and tubulin polymerization (19.31 ± 0.29 μM). Molecular docking analysis supported these results, showing strong binding affinities for the respective target proteins, with high binding scores of compound 9 ranging from (-9.2 to -10.0) kcal/mol. Collectively, these findings highlight that compound 9 is worthy of further investigation as a potential anticancer lead.

Targeted therapies have pioneered a more effective new pathway in cancer treatment by leveraging their precision-targeting advantages. Spiro tetramic acids are a kind of unique pyrrolidine-2,4-dione core structure containing a spiro ring structure, primarily employed as agro-chemicals with limited application in the field of anti-cancer. In this paper, fourteen novel 3-acetyl and 3-phenyl spiro tetramic acids were designed, synthesized, and evaluated for anti-proliferation in cancer cells. 3-Acetyl and 3-phenyl spirotetramic acids exhibited toxic effects against tested cancer cell lines. Among the 14 compounds, compound 8d was the most effective against RKO and H1299 with Half Maximal Inhibitory Concentration (IC₅₀) 3 ± 1 and 19 ± 2 μM. Further molecular structural prediction, bioinformatics analysis, and molecular docking revealed that compound 8d may target MMP1, MMP7 and PLK1. Additionally, 8d induced cell cycle arrest in G1 phase by increasing the expression of p21 protein and decreasing the expression of CCND1 and CCNB1 proteins. 8d also induced cell apoptosis through the mitochondrial pathways, as evidenced by alterations in the expressions of pertinent proteins, including Bcl-2 and Bax. These results indicated that the novel spirotetramine derivative 8d is a potential anti-cancer candidate drug and provides a new structural basis for the development of anti-cancer drugs.