PubMed · 13774655
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I SZORADY, G B PINTER, A PINTER. 1960-11-13. [Alizarin test].. https://pubmed.ncbi.nlm.nih.gov/13774655/
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Cancer is a disease characterized by genomic instability and aberrant DNA repair. Poly (ADP-ribose) polymerase-1 (PARP-1) represents a well-established therapeutic target, particularly in ovarian and prostate cancer. However, the currently approved PARP inhibitors face challenges such as resistance, toxicity, and reduced efficacy. The search for alternative scaffolds has therefore become increasingly urgent. In this study, we used an integrated approach combining computer-aided methods to search for potential lead compounds among emodin-based anthraquinone derivatives as PARP-1 inhibitors. Using a PASS-based QSAR approach, drug-likeness prediction, and in silico ADMET assessment, we pre-screened a large set of anthraquinones and identified several potential hits for interaction with PARP-1. These hits were studied using molecular docking with the PARP-1 catalytic domain (PDB ID: 7KK4). The most stable and compact complexes were further explored by 500 ns molecular dynamics (MD) simulations and various dynamic properties (RMSD, RMSF, Rg, SASA, MolSA, hydrogen bonds, PCA, DCCM). The key finding of this study is that several emodin-derived anthraquinones exhibited binding behavior and ADMET profiles comparable to, or better than, the reference PARP-1 inhibitor. Among them, CID-10425624 emerged as the most promising candidate, exhibiting stable binding, reduced conformational fluctuation, compact complex formation, persistent hydrogen-bond interactions, and enhanced dynamic residue correlations within the PARP-1 catalytic domain. These findings suggest that the anthraquinone scaffold can provide a valuable starting point for developing structurally distinct PARP-1 inhibitors. In summary, this study identified several emodin-derived anthraquinones, particularly CID-10425624, as computationally prioritized lead candidates for PARP-1 inhibition, providing a novel anthraquinone-based scaffold for further experimental validation and optimization.
A newly designed Gemini-shaped hexabenzocoronene amphiphile (1), carrying an isothiouronium ion-appended side chain, self-assembles in CH2Cl2 to form a nanotubular object, whose graphitic wall is densely covered by a positively charged molecular layer of isothiouronium ion pendants. The graphitic nanotube can be dispersed uniformly in aqueous media owing to effective hydration as well as electrostatic repulsion. Post-supramolecular functionalization of the nanotube surface is possible, without disruption of the tubular morphology, by taking advantage of a specific interaction of the isothiouronium ion pendants with oxoanion guests. Mixing with sodium poly(4-styrenesulfonate) results in wrapping of the nanotube, while complexation with an electron-accepting oxoanion such as anthraquinone carboxylate allows photoinduced electron transfer from the graphitic wall to the bound guest molecules.
The actinorhodin biosynthetic gene (act) cluster in Streptomyces coelicolor carries a functionally unknown gene, actVI-ORFA. We have characterized an ActVI-ORFA disruptant by functional complementation and reverse transcriptase polymerase chain reaction analysis of the expression profiles of the act genes. Introduction of the functional actVI-ORFA gene into the disruptant restored actinorhodin production to an extent similar to that seen in the wild-type cells and abolished the accumulation of actinorhodin biosynthetic intermediates and shunt products specific for actVI mutants. Thus, unique phenotypes observed in the mutant are solely dependent on the function of actVI-ORFA. The disruptant was shown to yield significantly lower levels of the transcripts for certain act genes, especially for the actVI-ORF1-VA-ORF2 transcription unit, leading to the accumulation of the intermediates and shunt products. The functional actVI-ORFA gene restored expression of actVI-ORF1, which encodes a key reductase in the actinorhodin tailoring step, in the mutant cells, indicating a possible regulatory role of ActVI-ORFA.