Bioorganic Chemistry最新文献

Pulmonary fibrosis is a progressive fibrotic lung disorder in which chemical injury, inflammation, extracellular matrix deposition, and endothelial dysfunction converge to remodel lung architecture. Baicalein, a chemically defined flavonoid, has reported anti-inflammatory and antifibrotic activity, but the endothelial mechanotransduction events linked to its effects in bleomycin-induced fibrosis remain insufficiently defined. Here, we evaluated whether baicalein modulates endothelial Piezo1-associated signaling during experimental pulmonary fibrosis. A bleomycin-induced mouse model, endothelial cell-specific Piezo1 knockout mice, primary mouse pulmonary microvascular endothelial cells (PMECs), and HUVEC-based mechanistic assays were used to examine lung injury, collagen accumulation, endothelial-to-mesenchymal transition (EndMT), calcium influx, calpain activity, and MAPK activation. Baicalein reduced bleomycin-associated lung inflammation, collagen deposition, hydroxyproline accumulation, and EndMT-associated marker changes. Mechanistically, baicalein lowered Piezo1 expression and Piezo1-associated Ca²⁺ influx in endothelial cells, accompanied by reduced calpain activity and decreased phosphorylation of p38, ERK, and JNK. Endothelial Piezo1 deletion attenuated bleomycin-induced fibrotic remodeling and partially blunted the additional protective response to baicalein, supporting the functional involvement of endothelial Piezo1 while not excluding Piezo1-independent effects. These findings suggest that baicalein alleviates experimental pulmonary fibrosis, at least in part, by modulating the endothelial Piezo1/Ca²⁺/calpain-MAPK signaling axis and suppressing EndMT-associated changes. The data support endothelial mechanotransduction as a pharmacologically relevant node in fibrotic lung injury, but direct baicalein-Piezo1 binding, pathway epistasis, pharmacokinetics, and long-term safety require further validation.

The development of tumor-targeting agents is of great significance for cancer therapy. Despite the promising potential of Boron Neutron Capture Therapy (BNCT), efficient and selective accumulation of boron-10 agents in cancer cells remains challenging. Conjugation of carborane with tumor-targeting ligands provides an alternative strategy for selective accumulation in the vicinity of cancer cells. In this study, we designed and synthesized aptamer-carborane derivatives, named AS1411-CB conjugates, via covalent linkage between a dodecahydro-arachno-bis(acetonitrile)decaborane and the DNA aptamer AS1411. AS1411 specifically binds to nucleolin, which is frequently overexpressed on the surface of cancer cells, thus enables selective targeting. Circular dichroism analysis indicated that AS1411-CB conjugates retained the characteristic G-quadruplex conformation of AS1411. Incorporation of a 5-Carboxyfluorescein (FAM) fluorescent label on AS1411 allowed flow cytometry analysis, which demonstrated significantly higher association of AS1411-CB conjugates with MCF-7 breast cancer cells compared with MCF-10 A normal mammary epithelial cells. Confocal microscopy further confirmed preferential localization of AS1411-CB conjugates on the surface of MCF-7 cells, consistent with nucleolin-mediated targeting. These results demonstrated that AS1411-CB conjugates preserved the targeting capability of AS1411 and highlighted its potential as a boron delivery platform for tumor-targeting applications.

Cancer remains a leading cause of mortality worldwide, and early diagnosis and effective targeted therapy are often constrained by the lack of tumor-specific biomarkers. Overexpressed cell-surface receptors provide accessible targets for precision molecular imaging and radionuclide therapy, enabling selective visualization and treatment of malignancies while minimizing off-target effects in normal tissues. This review synthesizes the current landscape of biomarker-targeted radiopharmaceuticals, highlighting clinically approved agents, emerging molecular scaffolds, and key criteria for optimal targeting and imaging performance. Clinically approved PSMA- and SSTR2-targeted radiotracers exemplify the success of this approach, enabling highly sensitive and specific detection of prostate cancer and neuroendocrine tumors, respectively. In contrast, many other radiolabeled molecules face substantial challenges in regulatory approval and clinical translation. Overall, exploitation of overexpressed tumor biomarkers for targeted imaging and therapy holds considerable promise for transforming oncology diagnostics and improving patient outcomes through precision molecular medicine.

The site-specific functionalization of therapeutic proteins and peptides represents a significant challenge in modern synthetic chemistry due to the presence of numerous competing nucleophilic residues. Conventional chemical conjugation strategies not only suffer from poor regioselectivity-leading to high product heterogeneity and compromised bioactivity-but also frequently rely on toxic organic solvents and excessive coupling reagents, directly contradicting the principles of green chemistry. In contrast, biocatalysis has become an effective approach for precision bioconjugation. Operating under mild aqueous conditions, enzymatic transformations offer high regio- and chemoselectivity, high atom economy, and minimal environmental footprint. This review focuses on recent advances in the biocatalytic synthesis of functionalized biomacromolecules, covering four highly efficient green modification strategies: enzymatic glycosylation, lipidation, PEGylation, and macrocyclization. The catalytic mechanisms, substrate specificities, and structural engineering of diverse enzyme classes (e.g., transglutaminases, transpeptidases, ligases, and glycosyltransferases) are discussed in the context of generating homogeneous bioconjugates. Furthermore, we analyze current biocatalytic bottlenecks, such as restricted substrate scopes for unnatural polymers, and provide perspectives on how artificial intelligence (AI)-driven generative enzyme design and synthetic biology will further broaden the scope of biocatalytic methods, promoting the sustainable biomanufacturing of long-acting therapeutic proteins and peptides.

Overexpression of the COX-2 enzyme is a major factor in the development of various malignancies, including colorectal cancer. A new series of acetophenonic-isoxazoline derivatives was designed, synthesized, and evaluated for selective COX-2 inhibitory and anticancer effects. A synthetic route based on the 1,3-dipolar cycloaddition mechanism was employed for the regiospecific formation of the isoxazoline ring. The newly synthesized compounds were characterized by combustion analysis, IR, ¹H NMR, ¹³C NMR, and ESI-MS. Cytotoxicity was assessed using the MTT assay against HT-29 human cancer cells and HFF and HEK293 human normal cell lines. In addition, cell cycle analysis, apoptosis induction, and the expression levels of BAX, Bcl-2, caspase-3, PTGS2, and VEGF genes were evaluated in HT-29 cells treated with the most promising derivatives. The most probable binding modes were predicted by docking the 3D structures into the COX-2 binding site (PDB code: 1CX2), and the results showed hydrogen-bond formation with key residues. The fluoro-containing derivative 9b showed superior in vitro COX-2 selectivity (SI = 141.7), whereas compound 9f, bearing a 3,4-dimethoxyphenyl moiety, exhibited the highest COX-2 inhibition (IC₅₀ = 0.08 μM) and potent cytotoxicity against HT-29 cells (IC₅₀ = 7.34 ± 2.88 μM). The most potent compounds (9b, 9e, 9f, and 9 g) promoted apoptosis, with significantly increased mRNA expression of BAX and caspase-3 and decreased Bcl-2 expression. Collectively, these findings suggest that the newly designed acetophenonic-isoxazoline derivatives, as COX-2 inhibitors, may exert multitarget therapeutic effects against colorectal cancer.

Tumor-associated carbonic anhydrases IX and XII (CA IX and CA XII) are crucial regulators of extracellular acidification in hypoxic tumors, supporting cancer cell survival and progression. In this study, a novel series of dihydropyrimidine-sulfonamide hybrids was evaluated for selective inhibition of CA IX and XII and their anticancer potential. Among them, compound 7b exhibited potent dual inhibition of CA IX (IC₅₀ = 0.025 μM) and CA XII (IC₅₀ = 0.02 μM), with minimal off-target activity against CA I and II. In MTT assays, 7b demonstrated strong antiproliferative activity against HT-29 (IC₅₀ = 0.52 μM), 786-O (IC₅₀ = 0.58 μM), and MCF-7 (IC₅₀ = 0.87 μM) cancer cell lines, while showing lower cytotoxicity toward WI-38 normal fibroblasts (IC₅₀ = 23.71 μM), yielding selectivity indices of 27.25-45.60 under the present in vitro conditions. Mechanistic studies in HT-29 cells revealed that 7b induces apoptosis via upregulation of BAX and p53, downregulation of Bcl-2, and activation of caspase-3 and caspase-9, indicating involvement of the mitochondrial pathway. Molecular docking suggested plausible binding modes for 7b within the CA IX and XII active sites, including predicted Zn²⁺ coordination and hydrogen-bonding interactions, providing a structural rationale for the experimentally observed inhibitory profile. Taken together, these independent findings demonstrate potent CA IX/XII enzyme inhibition, cellular antiproliferative activity, and apoptosis-associated effects for compound 7b.

We present herein a detailed study concerning the design, synthesis, structure, stereochemistry, and anticancer activity of a new class of chimeric pyrrolodiketo-pyrrolidine-phthalazine-triazole (PPPT) derivatives. The design of the chimeric PPPT molecules integrated the biological potential of phthalazine, pyrrolidine, and triazole scaffolds using the Multiple Targeting Ligands (MTL) / molecular hybridization (MH) strategy, along with bioisosteric modifications of existing drugs. The synthesis of our chimeric PPPT derivatives was efficient and straightforward in two steps: a Huisgen 3 + 2 dipolar cycloaddition reaction of ylides with a symmetrically substituted cyclic Z-alkene, followed by a click copper-catalysed reaction. The cycloaddition reactions proceed with high stereospecificity, and NMR and single-crystal X-ray diffraction studies unambiguously established the stereochemistry of the obtained compounds. The anticancer assay reveals that the newly obtained compounds 1, 4a,b, and 6a-j have low or no cytotoxicity toward normal cells and exhibit very good to moderate activity against breast adenocarcinoma and osteosarcoma cancer cell lines. The most active compounds were proved to be the chimeric derivatives 6c, 6d, and 6j, with IC₅₀ values close to those of the standard drug doxorubicin on the MCF7 and MG-63 cancer cell lines, and with selectivity index values also indicating a good cytotoxic profile. Notable SAR correlations have been observed. The in silico Swiss-ADME evaluation indicates that our chimeric PPPT derivatives exhibit good ADME, drug-likeness, and medicinal chemistry properties. The in silico computational Swiss-Target Prediction tool predicts that our chimeric PPPT compounds will most likely act as Multiple Targeting Ligands, primarily as tyrosine kinase and PARP-1 inhibitors. The in silico molecular docking studies confirm VEGFR-2 and PARP-1 as possible binding sites for our compounds. Both the experimental anticancer assay and the in silico computational studies suggest that our chimeric pyrrolodiketo-pyrrolidine-phthalazine-triazole derivatives 6c, 6d, and 6j are promising drug candidates.