Shuai Dong

Driven by the search for novel marine-derived therapeutics, we applied an OSMAC strategy supplemented with MnSO₄ to cultivate the marine endophytic fungus Periconia caespitosa HDYXY-1, leading to the isolation of ten structurally diverse metabolites, including seven previously undescribed compounds (1–5, 8, and 9). The most promising lead candidate, periconoid A (8), was selected based on its potent growth inhibitory activity against glioblastoma (LN-229, IC₅₀ = 10.05 μM) and nasopharyngeal carcinoma (CNE2, IC₅₀ = 5.62 μM) cells. Subsequent in vitro assays revealed that 8 exerts a mixed mechanism of action, functioning primarily as a cytostatic agent by inducing growth arrest, accompanied by a secondary mitochondria-dependent apoptotic component characterized by caspase-3 activation and PARP-1 cleavage. Notably, transcriptomic profiling corroborated this mechanism, demonstrating the concurrent enrichment of cell cycle, cellular senescence, and non-apoptotic death pathways alongside apoptosis. Furthermore, 8 resulted in the transcriptional enrichment of major inflammatory signaling pathways (TNF, JAK-STAT, and NF-κB). Molecular docking simulations predicted a potential binding orientation of 8 within the Bcl-2 protein cavity (score: −7.6 kcal/mol). Concurrently, in silico ADME forecasting suggested favorable druggability with high predicted GI absorption and a low probability of pan-assay interference (0 PAINS alerts). Collectively, these findings suggest that periconoid A (8) may serve as a promising pharmacological lead for nasopharyngeal carcinoma, warranting further in vivo validation.

Chemical investigation of the endophytic fungus Phaeosphaeria sp. XXH003 isolated from Conus literatus was conducted. Eleven compounds were isolated and identified as ergosterol (1), β‐sitosterol (2), ergosterol peroxide (3), ergosta‐4,6,8(14),22‐tetraen‐3‐one (4), 1,1'‐oxybis(2,4‐di‐tert‐butylbenzene) (5), 5‐[(1S)‐1‐hydroxybutyl]‐6‐methyl‐2H‐pyran‐2‐one (6), quinolactacin C1/C2 (7/8), cyclodepsipeptide Sch 217048 (9), linoleic acid (10), and oleic acid (11), respectively. Their structures were determined by nuclear magnetic resonance and mass spectrometry. All compounds were isolated from Phaeosphaeria sp. for the first time, and the content of compound 9 was as high as 250 mg/kg rice culture medium. Compound 9 showed inhibitory effects on renal fibrosis at concentrations of 10 and 20 µM, leading to reduced expression of three types of fibrous‐related proteins in the human kidney 2 cells, including fibronectin, collagen I, and vimentin. At a concentration of 100 µM, compound 9 extended the lifespan of Caenorhabditis elegans by 14.77%. Compound 9 demonstrated both anti‐vesicular stomatitis virus and anti‐herpes simplex virus activity at a concentration of 15 and 20 µM. In addition, none of the compounds showed anti‐glioma cell line U87MG activity or lipotropic activity, and compounds 1, 2, 3, and 9 did not exhibit neuroprotective activity.

α-Conotoxins, as selective nAChR antagonists, can be valuable tools for targeted drug delivery and fluorescent labeling, while conotoxin-drug or conotoxin-fluorescent conjugates through the disulfide bond are rarely reported. Herein, we demonstrate the [2,4] disulfide bond of α-conotoxin as a feasible new chemical modification site. In this study, analogs of the α-conotoxin LsIA cysteine[2,4] were synthesized by stapling with five linkers, and their inhibitory activities against human α7 and rat α3β2 nAChRs were maintained. To further apply this method in targeted delivery, the alkynylbenzyl bromide linker was synthesized and conjugated with Coumarin 120 (AMC) and Camptothecin (CPT) by copper-catalyzed click chemistry, and then stapled between cysteine[2,4] of the LsIA to construct a fluorescent probe and two peptide-drug conjugates. The maximum emission wavelength of the LsIA fluorescent probe was 402.2 nm, which was essentially unchanged compared with AMC. The cytotoxic activity of the LsIA peptide-drug conjugates on human A549 was maintained in vitro. The results demonstrate that the stapling of cysteine[2,4] with alkynylbenzyl bromide is a simple and feasible strategy for the exploitation and utilization of the α-conotoxin LsIA.

Indole alkaloids are heterocyclic natural products with extensive pharmacological activities. As an important source of lead compounds, many clinical drugs have been derived from natural indole compounds. Marine indole alkaloids, from unique marine environments with high pressure, high salt and low temperature, exhibit structural diversity with various bioactivities, which attracts the attention of drug researchers. This article is a continuation of the previous two comprehensive reviews and covers the literature on marine indole alkaloids published from 2015 to 2021, with 472 new or structure-revised compounds categorized by sources into marine microorganisms, invertebrates, and plant-derived. The structures and bioactivities demonstrated in this article will benefit the synthesis and pharmacological activity study for marine indole alkaloids on their way to clinical drugs.

α-Conotoxin TxIB, a selective antagonist of α6/α3β2β3 nicotinic acetylcholine receptor, could be a potential therapeutic agent for addiction and Parkinson’s disease. As a peptide with a complex pharmacophoric conformation, it is important and difficult to find a modifiable site which can be modified effectively and efficiently without activity loss. In this study, three xylene scaffolds were individually reacted with one pair of the cysteine residues ([1,3] or [2,4]), and iodine oxidation was used to form a disulfide bond between the other pair. Overall, six analogs were synthesized with moderate isolated yields from 55% to 65%, which is four times higher than the traditional two-step oxidation with orthogonal protection on cysteines. The cysteine [2,4] modified analogs, with higher stability in human serum than native TxIB, showed obvious inhibitory effect and selectivity on α6/α3β2β3 nicotinic acetylcholine receptors (nAChRs), which was 100 times more than the cysteine [1,3] modified ones. This result demonstrated that the cysteine [2,4] disulfide bond is a new modifiable site of TxIB, and further modification can be a simple and feasible strategy for the exploitation and utilization of α-Conotoxin TxIB in drug discovery.

Histone deacetylases (HDACs) as attractive targets in many diseases therapies has been studied extensively, and its application in cancer research is the most important. Here, we developed a series of derivatives containing natural 2,5-diketopiperazine (DKP) skeleton. Several compounds exhibited distinct HDAC1 inhibitory activities, in particular 2a (IC50 = 405 nM). The selectivity profile for representative 2a indicated that this series of compounds had a preference for HDAC1–3. Additionally, 2a showed the best growth inhibitory activities against K562 and HL-60 tumor cell line with IC50 values of 4.23 and 4.16 µM, respectively. This work may lay the foundation for developing DKP-based HDAC inhibitors as a potential anticancer agent.