Tunicamycin cyclitol analogues are established as a structurally distinct class of selective DPAGT1-targeted anticancer agents and it is demonstrated that stabilization of the glycosidic linkage is an effective strategy for enhancing pharmacological selectivity, improving in vivo performance, and simplifying the synthetic route.
Benzylisoquinoline alkaloids (BIAs) hold broad pharmaceutical potential, yet poor water solubility and low bioavailability limit their application. Glycosylation improves these properties, but glycosyltransferases (GTs) efficiently catalyzing diverse BIAs remain scarce. Here, we identify UGT74AN1 from Asclepias curassavica, capable of glycosylating various BIAs. Structure-guided semirational engineering yielded the double mutant UGT74AN1M2, exhibiting a 341-fold increase in catalytic efficiency. Molecular dynamics simulations revealed that these mutations widen the substrate channel and strengthen binding. To overcome UDP-glucose dependency, we designed the fusion enzyme AtSuSy-L12-UGT74AN1M2 via the iMARS platform, enabling in situ UDP-glucose generation coupled with highly efficient BIA glycosylation. Consequently, the synthesized dihydrojatrorrhizine-3-O-β-d-glucoside (1b) demonstrated superior antitumor activity compared to its aglycone through stronger proliferation inhibition and apoptosis induction. This work provides an efficient enzymatic toolkit for green BIA glycoside synthesis and identifies promising candidates for drug development.
Jun Song, Yu Qin, Lu Jin et al.· Journal of Agricultural and...· 0 citations
Simplification of the complex macrolide UK-2A delivers florylpicoxamid, while optimization of its synthetically challenging pyridinyl acid remained underdeveloped. Scaffold hopping with 14 structurally distinctive heterocyclic acids in the molecular evolution of florylpicoxamid led to thiazole amide as a novel antifungal chemotype. The concomitant antifungal optimization achieved a structurally unique candidate, LEX-K02 (9al, EC50 = 0.140 μM), exhibiting 49-fold higher activity against Gaeumannomyces graminis than florylpicoxamid (EC50 = 7.06 μM). It was demonstrated to possess a unique mechanism in view of both antifungal phenotypes and molecular docking simulation. This antifungal candidate can disrupt the cell membrane. Transcriptomics and metabolomics analysis suggested that compound LEX-K02 may affect the synthesis of N-glycans by targeting the map00510 pathway, and is safe for wheat. Pyridinyl acid optimization of UK-2A-related molecules was validated as a viable fungicide discovery strategy.
Wenlong Kong, Pengzhi Sun, Xian Ming et al.· Journal of Agricultural and...· 0 citations
Leucine-rich pentatricopeptide repeat containing (LRPPRC), a critical regulator of mitochondrial gene expression, is overexpressed in various malignancies and sustains oxidative phosphorylation (OXPHOS)-dependent adenosine triphosphate (ATP) production essential for tumor growth, chemoresistance, and stem cell survival, rendering it a promising therapeutic target. Herein, using an aptamer-assisted fluorescence polarization platform, we identified acylhydrazone-skeleton inhibitors targeting LRPPRC's RNA-binding domain, leading to the design and synthesis of over 60 derivatives. Lead compound 3o exhibited excellent LRPPRC inhibitory activity (92% at 6.25 μM vs 38% for gossypol acetate (GAA)) and induced robust LRPPRC degradation. Notably, 3o downregulated downstream OXPHOS subunits and ATP synthase, eliciting broad antiproliferative effects, particularly in refractory and drug-resistant A549, BXPC-3, and NCI-H1975 cells (IC50 = 0.54, 0.27, and 1.39 μM, respectively). In PC9 and HCT116 xenografts, 3o achieved tumor growth inhibition (TGI) rates of 73 and 49% with favorable safety profiles. Overall, we developed novel biphenyl-acylhydrazone LRPPRC inhibitors as potent antitumor agents acting via OXPHOS modulation, providing a valuable lead compound for cancer therapy.
Hairu Ren, Jie Liu, Dachi Wang et al.· Journal of Medicinal Chemist...· 0 citations
Actinomycins constitute a class of bioactive compounds known for their potent cytotoxic properties. Among them, actinomycin D, isolated in the 1940s from Streptomyces antibioticus, is the most extensively studied derivative. Structurally, actinomycins are characterized by a planar phenoxazinone chromophore flanked by two cyclic pentapeptides. They exert their biological effects primarily through DNA intercalation and transcription inhibition. Despite its remarkable bioactivity, the clinical application of actinomycin D is limited by significant adverse effects, including hepatotoxicity and restricted selectivity. These limitations underscore the need for structurally optimized analogs with improved therapeutic profiles and reduced toxicity. Over the decades, natural product discovery, precursor‐directed biosynthesis, and synthetic modification have yielded more than 70 structurally distinct derivatives, incorporating variations in both the peptide rings and the chromophore core. These structural modifications have resulted in diverse antibacterial, antiviral, and cytotoxic activities. Thus, this review critically examines the historical development, chemical diversity, and in vitro and preclinical bioactivity of actinomycin derivatives, highlighting key structural modifications over time and discussing their implications for future drug development.
In vivo efficacy evaluation demonstrated that 10d exhibited significantly superior tumor suppression in a subcutaneous xenograft model of H1975 tumors compared to celastrol, without causing notable systemic toxicity such as significant body weight loss.
Yu-Chi Zhao, Hanshuang Cai, Lijuan Zuo et al.· European journal of medicina...· 0 citations
Enzymatic browning mediated by polyphenol oxidase (PPO) remains a persistent challenge in food preservation. We report the rational design, synthesis, and evaluation of nine coumarin-sulfonamide hybrid inhibitors (DS1-9) featuring 6,7-dihydroxy-2-oxo-2H-chromen-4-yl cores linked to N-substituted benzenesulfonamide scaffolds, confirmed by FT-IR and 1H-NMR. Enzyme kinetics against Agaricus bisporus tyrosinase revealed competitive inhibition across the series, with Ki values spanning 46-775 uM. DFT calculations (B3LYP/def2-TZVP) characterized the electronic landscape, HOMO-LUMO energies (-5.716 to -6.455 eV; -1.716 to -2.278 eV), electrophilicity indices (3.5-4.2 eV), and dipole moments (4.98-11.24 Debye), while C-PCM solvation modeling, MEP mapping, and RDG analysis established that intramolecular hydrogen bonding (sign λ2ρ ≈ -0.025 to -0.035 a.u.) preorganizes binding-competent conformations. Molecular docking against PPO3 (PDB: 2Y9X) yielded binding affinities of -7.66 to -8.99 kcal/mol, substantially exceeding tropolone (-4.65 kcal/mol). DS-7 (N-3,4-dimethylisoxazol-5-yl) emerged as the lead compound (IC50 = 103 ± 5.64 µM; Ki = 46 uM), its potency driven by hydrogen bonding with Glu322, His85, and Asn260 alongside π-sigma/π-anion contacts. DS-1 (N-thiazol-2-yl; IC50 = 99.7 ± 0.91 µM; Ki = 57 uM) achieved comparable inhibition through a distinctive π-sulfur interaction with His85 and copper coordination. DS-6 (N-ethyl-N-phenyl; IC50 = 90.3 ± 4.86 µM; Ki = 129 uM) outperformed docking predictions via apparent induced-fit binding involving dual copper π-alkyl coordination. SAR analysis identified the 6,7-dihydroxycoumarin core, Val283 π-sigma anchoring, and lipophilic N-substitution as non-negotiable pharmacophoric elements, positioning DS-7, DS-1, and DS-6 for food preservation and biocatalytic applications.
Şeref Karadeniz, Ahmad Badreddin Musatat, Beste Karadeniz et al.· Biotechnology and applied bi...· 0 citations
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