1. Wenchao Yu, Yanlei Yu, Bingcheng Dong, Zeyu Wang, Auqi Du, Songwei Li, Buddha Bahadur Basnet, Xiaoze Bao, Xuanrong Sun, Xingnuo Li, Qi Xuan, Qihao Wu*, Hong Wang*, Bin Wei*. Targeted discovery of aromatic glycosides with dual detoxification effects via a highly customized molecular networking platform. Cell Chemical Biology, 2026, 33(1): 132-144. (https://doi.org/10.1016/j.chembiol.2025.12.001) IF:7.2
Abstract
Unlocking bioactive small molecules is essential for drug discovery, but discovering, prioritizing, and characterizing them remains difficult, as they are often found in complex biological extracts. Mass spectrometry-based untargeted metabolomics and MS2 spectral similarity are critical strategies for establishing spectra-inferred structural relationships and discovering unknown metabolites. Current analytical platforms mainly rely on comparing MS2 data using a single algorithm, which often leads to missed annotations of valuable metabolites. MSanalyst addresses this limitation by combining various mass spectral similarity algorithms, thereby enabling more comprehensive metabolite annotation. By applying MSanalyst to a well-studied strain, Kutzneria viridogrisea, we successfully discovered an undescribed class of aromatic glycosides, called kutznaposides. Integrated multi-omics and in vitro experiments further revealed that these molecules are produced through a previously uncharacterized menaquinone shunt pathway. This pathway serves as a crucial defense mechanism, enabling the host organism to eliminate reactive oxygen species and avoid self-toxicity. By demonstrating the strength of algorithmic integration, MSanalyst advances the systematic identification of hidden metabolites, metabolic pathways with essential biological functions, and potential biomedical applications.
2. Lihang Cao, Junjie Ge, Yi Hua, Xiaoze Bao, Zhikun Yang, Hong Wang,* and Hua Chen*. Strain-Release-Driven exo-Cyclization of Bicyclo[1.1.0]butyl Ketones Promoted by Brønsted Acids to Access 2,3-Diazabicyclo[3.1.1]heptenes. Organic Letters, 2026, 28, 1947-1952. (Doi: 10.1021/acs.orglett.5c04933) (IF: 5.0)
Abstract
A Brønsted acid-promoted exo-cyclization of bicyclo[1.1.0]butyl ketones with hydrazines has been established. This approach enables efficient ring expansion, leading to a diverse range of 2,3-diazabicyclo[3.1.1]heptenes. Mechanistic studies reveal that the carbonyl group is pivotal, fulfilling a dual role as both the reactive center and a latent activating group. Moreover, the unique dual nucleophilic character of hydrazines, featuring two nitrogen-based nucleophilic sites, is crucial to the success of this transformation.
3. Jianwei Chen*, Jiangwei Pan, Xingyue Lu, Lu Wang, Keli Tan, Yujie Yue, Liting Gu, Siqi Wang, Minghong Chen, Hong Jiang, Yu Pan, Yuanquan Yu, Jianwei Nai, Dahong Zhang, Hong Wang*. Phylogenomics driven metalloantibiotic engineering: Overcoming ciprofloxacin resistance in Pseudomonas aeruginosa with sideromycin bismuth synergy. Cell Reports Medicine. 2026, 7, 102637.(https://doi.org/10.1016/j.xcrm.2026.102637) (IF: 10.6)
Antimicrobial resistance exacerbates the difficultyof clinical bacterial infection treatment, as single-target antibiotics rapidlylose efficacy shortly post-clinical use. Such resistance highlights an urgentneed for multitargeted therapeutics. Metalloantibiotics, combining metal ionswith antimicrobials to disrupt diverse bacterial pathways, represent apromising strategy to circumvent resistance. Here, we engineer asideromycin-bismuth molecular nanoassembly for treating ciprofloxacin-resistantPseudomonas aeruginosa. Using phylogenomics-driven methods, we identifyfour hydroxamate siderophores from Streptomyces fradiae and rationallydesign sideromycin 7 by a structure-based strategy. Sideromycin 7 forms a 7–Bi³⁺coordination complex with bismuth citrate, exerting a three-prongedantibacterial mode of action: direct DNA binding to induce damage and arrestreplication, suppression of KdpC synthesis to block KdpFABC-mediated potassiumtransport, and inhibition of ATP production. In murine models, this combinationtherapy exhibits potent efficacy against ciprofloxacin-resistant P.aeruginosa with a considerable safety index. Our findings highlight thepotential of phylogenomics-guided metalloantibiotic engineering for overcomingdrug resistance.
4. Zhikun Yang, Jiajia Han, Yanhong Yang, Xue Yang, Yijing Du, Zimeng Huang, Leyi Ying, Xin Yu, Yi Hua, Qihao Wu, Xiaozhou Mou, Hong Wang*. Rational discovery of novel phenylindole-bisamide derivatives as potent P-glycoprotein inhibitors for cancer multidrug resistance. RSC Medicinal Chemistry, 2026. (DOI: 10.1039/d6md00030d). (IF: 3.6)
Abstract
Overcoming multidrug resistance (MDR) remains a major challenge in cancer chemotherapy, largely mediated by the efflux pump P-glycoprotein (P-gp). To address this, we designed and synthesized a series of novel phenylindole-bisamide derivatives using receptor-based drug design and empirical modifications. The MDR reversal activities of target compounds were systematically evaluated in MCF-7/ADR cells. Among them, compound l1 exhibited enhanced reversal potency and significantly reduced cytotoxicity compared to the third-generation P-gp inhibitor tariquidar. Furthermore, l1 demonstrated excellent broad-spectrum chemosensitization effects when used in combination with front-line anticancer drugs. Mechanistic studies (including western blotting, cellular thermal shift assay and Rh123 accumulation assays) demonstrated that l1 effectively inhibited P-gp efflux function without affecting protein expression. Molecular docking analysis revealed that l1 binds tightly within the P-gp active pocket through π-π stacking and hydrogen-bond interactions. Importantly, in 3D tumor spheroid assays, the co-administration of l1 with doxorubicin significantly suppressed spheroid growth. Collectively, these findings identify l1 as a promising P-gp inhibitor and provide a rational scaffold for further optimization in the development of MDR modulators.
5. Yixian Qiu, Weikang Xie, Shenghui Zhu, Ligong Yao, Hong Wang, Mingzhi Su, Songwei Li, Yuewei Guo*, Youmin Ying*. DeepSAT-guided discovery of new eunicellin-type diterpenoids from Cladiella krempfi and Sinularia ornata. Bioorganic Chemistry, 2026, 176, 109880. （https://doi.org/10.1016/j.bioorg.2026.109880）（IF: 4.5）
Abstract
Guided by HSQC-based DeepSAT technology, six new eunicellin-type diterpenoids litophynols E–J (1–6), together with two known related ones 7–8, were isolated and characterized from the diethyl ether extracts of the soft corals Cladiella krempfi and Sinularia ornata. Among them, compounds 1–3, 7, and 8 were derived from C. krempfi, whereas compounds 4–6 originated from S. ornata. The structures and absolute configurations of these compounds were determined by comprehensive spectroscopic analysis, X-ray crystallography, and time-dependent density dunctional dheory electronic circular dichroism (TDDFT-ECD) calculations. Compounds 1–7 were found to possess a highly oxidized cembrane skeleton featuring a unique C-2–O–C-9 transannular ether bridge. Compound 8 was identified as having a 2,11-cyclized cembrane skeleton with an unusual C-6–O–C-9 ether bridge. All isolates were evaluated for their in vitro anti-inflammatory and antibacterial activities. Compounds 3 and 7 exhibited moderate anti-inflammatory potential by inhibiting nitric oxide (NO) production in LPS-induced RAW264.7 macrophages. In an in vitro antibacterial assay, compound 4 inhibited the growth of Streptococcus agalactiae GSB with an MIC value of 25 μM. Notably, it also exhibited significant inhibition of Staphylococcus aureus SS119-induced hemolysis. Preliminary structure-activity relationship (SAR) analysis indicated that substitutions at C-8 and C-13, particularly the presence of a free hydroxy group at C-8, played a critical role in modulating the antibacterial activity of eunicellin-type diterpenoids. These findings not only expanded the structural diversity of marine-derived eunicellin-type diterpenoids but also highlighted their potential as promising drug leads.
6. Zhenyi Zhou, Yutian Guan, Ziyang Li, Xiaowen Wu, Jixiang Xin, Hong Wang*, Bin Wei*. Towards the targeted activation of silent biosynthetic gene clusters by chemical elicitors. Biotechnology Advances, 2026, 89: 108870. (中科院一区TOP, IF=12.5)
Abstract
Systematic genome mining has revealed that microbes encode numerous uncharacterized secondary metabolite biosynthetic gene clusters (BGCs). The efficient and selective activation of these silent or cryptic BGCs is crucial for the high-throughput discovery of novel natural products. Recent influential studies have demonstrated that using small chemical elicitors is a practical and cost-effective method to unlock the secondary metabolic potential of microbes. However, the current approach mainly relies on high-throughput, non-targeted screening methods to discover chemical elicitors capable of activating these silent BGCs. Therefore, this study comprehensively reviews reported cases of small molecules that activate silent BGCs, covering the chemical structures of elicitors, resulting natural products, and target BGCs, thereby constructing an integrated knowledge graph. We also summarize the underlying activation mechanisms. Leveraging relationships captured in this graph, we outline directions for targeted activation of silent pathways using small molecules, thereby facilitating more efficient natural product discovery.
7. Zimeng Huang, Yijing Du, Junzhe Hu, Leyi Ying, Binying Zhou, Yi Hua, Hong Wang*, Zhikun Yang*. Marine Natural Products as Potent Anticancer Agents (2020–2024): Structural Diversity, SARs and Target Prediction. Marine Drugs, 2026, 24:173. (DOI: 10.3390/md24050173). (IF=5.4)
Abstract
In recent years, Marine Natural Products (MNPs) have emerged as a significant source for anticancer drug discovery, as many natural products can offer structural diversity, unique mechanisms of action, and relatively low toxicity. This article provides a systematic review of MNPs with reported anticancer activities from 2020 to 2024. These compounds are classified into seven major categories: terpenoids, alkaloids, sterols, polyketides, peptides and proteins, polysaccharides, and macrolides. For each category, we elaborate on the marine sources, structural identification, in vitro anticancer activity, and preliminary structure-activity relationships. We found that sponges and marine-derived fungi are the most abundant sources of highly active compounds. Furthermore, knowledge graph-based analysis reveals that oxygen- and nitrogen-containing heterocycles constitute the core pharmacophores, and target prediction further indicates that MNPs exert anticancer effects through coordinated modulation of a multi-target network involving kinases, proteasomes, and nuclear receptors. This review contributes significantly to a deeper understanding of recent advances (2020-2024) in MNPs and provides critical guidance for promoting the development of innovative anticancer drugs derived from marine resources.
8. Hua Chen*, Junmin Zhang, Lihang Cao, Chen He, Hui Guo, Yi Hua, Xiaoze Bao, Zhikun Yang and Hong Wang*. Lewis-Acid-Catalyzed Cyclization of Bicyclo[1.1.0]butanes with Alkenyl Cyclic Dithioacetals for the Synthesis of 11-Membered Bicyclic Medium-Sized Rings. Organic Letters, 2026, DOI: 10.1021/acs.orglett.6c01548. (IF: 5.0)
Abstract
Medium-sized rings arevaluable synthetic scaffolds yet challenging to construct. Herein, we report aLewis acid-catalyzed (8+3) cycloaddition of bicyclo[1.1.0]butanes with alkenylcyclic dithioacetals that provides efficient access to previously inaccessible 11-memberedbicyclo[8.1.1] skeletons. Driven by strain release and catalyzed by Lu(OTf)3,this ring expansion proceeds under mild conditions, exhibits broad substratescope, and delivers products in excellent yields (46 examples, with yields upto 94%). Mechanistic studies and DFT calculations support a pathway involvingsequential nucleophilic attack, ring opening and regioselective intramolecular1,4-addition.
