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Bioorganic & Medicinal Chemistry Letters Aug 2024We report the use of trimethylsilyl azide and Selectfluor to implement a standard protocol targeted at the prenylated nucleic acid known as iA-RNA. After optimizing the...
We report the use of trimethylsilyl azide and Selectfluor to implement a standard protocol targeted at the prenylated nucleic acid known as iA-RNA. After optimizing the conditions, we applied this method to regulate a wide range of iA-RNA species using synthetic imidazole-based probes (I-IV). We observed that prenylated nucleic acid plays a crucial role in the cell hemostasis in A549 cell lines.
Topics: Humans; Imidazoles; Click Chemistry; Halogenation; Azides; A549 Cells; RNA; Molecular Structure; RNA Stability
PubMed: 38795737
DOI: 10.1016/j.bmcl.2024.129815 -
International Journal of Molecular... May 2024Protein farnesylation is a post-translational modification where a 15-carbon farnesyl isoprenoid is appended to the C-terminal end of a protein by farnesyltransferase...
Protein farnesylation is a post-translational modification where a 15-carbon farnesyl isoprenoid is appended to the C-terminal end of a protein by farnesyltransferase (FTase). This process often causes proteins to associate with the membrane and participate in signal transduction pathways. The most common substrates of FTase are proteins that have C-terminal tetrapeptide CaaX box sequences where the cysteine is the site of modification. However, recent work has shown that five amino acid sequences can also be recognized, including the pentapeptides CMIIM and CSLMQ. In this work, peptide libraries were initially used to systematically vary the residues in those two parental sequences using an assay based on Matrix Assisted Laser Desorption Ionization-Mass Spectrometry (MALDI-MS). In addition, 192 pentapeptide sequences from the human proteome were screened using that assay to discover additional extended CaaaX-box motifs. Selected hits from that screening effort were rescreened using an in vivo yeast reporter protein assay. The X-ray crystal structure of CMIIM bound to FTase was also solved, showing that the C-terminal tripeptide of that sequence interacted with the enzyme in a similar manner as the C-terminal tripeptide of CVVM, suggesting that the tripeptide comprises a common structural element for substrate recognition in both tetrapeptide and pentapeptide sequences. Molecular dynamics simulation of CMIIM bound to FTase further shed light on the molecular interactions involved, showing that a putative catalytically competent Zn(II)-thiolate species was able to form. Bioinformatic predictions of tetrapeptide (CaaX-box) reactivity correlated well with the reactivity of pentapeptides obtained from in vivo analysis, reinforcing the importance of the C-terminal tripeptide motif. This analysis provides a structural framework for understanding the reactivity of extended CaaaX-box motifs and a method that may be useful for predicting the reactivity of additional FTase substrates bearing CaaaX-box sequences.
Topics: Humans; Computational Biology; Peptide Library; Substrate Specificity; Farnesyltranstransferase; Oligopeptides; Amino Acid Sequence; Crystallography, X-Ray; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Protein Binding
PubMed: 38791363
DOI: 10.3390/ijms25105324 -
Foods (Basel, Switzerland) May 2024In this study, we investigated the anti-hypertensive properties of mulberry products by modulating the renin-angiotensin system (RAS). Comparative analysis showed that...
In this study, we investigated the anti-hypertensive properties of mulberry products by modulating the renin-angiotensin system (RAS). Comparative analysis showed that the ethyl acetate fractions, particularly from the Cheongil and Daeshim cultivars, contained the highest levels of polyphenols and flavonoids, with concentrations reaching 110 mg gallic acid equivalent (GE)/g and 471 mg catechin equivalent (CE)/g of extract, respectively. The ethyl acetate fraction showed superior angiotensin-converting enzyme (ACE) inhibitory activity, mainly because of the presence of the prenylated flavonoids kuwanon G and H. UPLC/Q-TOF-MS analysis identified kuwanon G and H as the primary active components, which significantly contributed to the pharmacological efficacy of the extract. In vivo testing of mice fed a high-salt diet showed that the ethyl acetate fraction substantially reduced the heart weight and lowered the serum renin and angiotensinogen levels by 34% and 25%, respectively, highlighting its potential to modulate the RAS. These results suggested that the ethyl acetate fraction of mulberry root bark is a promising candidate for the development of natural ACE inhibitors. This finding has significant implications for the management of hypertension through RAS regulation and the promotion of cardiovascular health in the functional food industry.
PubMed: 38790847
DOI: 10.3390/foods13101547 -
Scientific Reports May 2024Auraptene (AUR) and umbelliprenin (UMB) are naturally occurring prenylated coumarins that have demonstrated promising anticancer effects across various human cancer cell... (Meta-Analysis)
Meta-Analysis
Auraptene (AUR) and umbelliprenin (UMB) are naturally occurring prenylated coumarins that have demonstrated promising anticancer effects across various human cancer cell lines. This meta-analysis aimed to systematically assess, compare, and quantify the anticancer efficacy of AUR and UMB by synthesizing evidence from in vitro studies. A comprehensive literature search identified 27 eligible studies investigating AUR or UMB against cancer cells. Mixed-effects models revealed significant negative associations between coumarin dose and viability for AUR (est. = - 2.27) and UMB (est. = - 3.990), underscoring their dose-dependent cytotoxicity. Meta-regression indicated slightly higher potency for UMB over AUR, potentially due to increased lipophilicity imparted by additional isoprenyl units. Machine learning approaches identified coumarin dose and cancer type as the most influential determinants of toxicity, while treatment duration and the specific coumarin displayed weaker effects. Moderate (AUR) to substantial (UMB) between-study heterogeneity was detected, although the findings proved robust. In summary, this meta-analysis establishes AUR and UMB as promising natural anticancer candidates with clear dose-toxicity relationships across diverse malignancies. The structural insights and quantifications of anticancer efficacy can inform forthcoming efforts assessing therapeutic potential in pre-clinical models and human trials.
Topics: Humans; Coumarins; Umbelliferones; Antineoplastic Agents; Cell Line, Tumor; Neoplasms; Cell Survival
PubMed: 38783034
DOI: 10.1038/s41598-024-62747-z -
Phytochemistry Aug 2024Farnesylated chalcones were favored by researchers due to their different biological activities. However, only five naturally occurring farnesylated chalcones were...
Farnesylated chalcones were favored by researchers due to their different biological activities. However, only five naturally occurring farnesylated chalcones were described in the literature until now. Here, the farnesylation of six chalcones by the Aspergillus terreus aromatic prenyltransferase AtaPT was reported. Fourteen monofarnesylated chalcones (1F1-1F5, 2F1-2F3, 3F1, 3F2, 4F1, 4F2, 5F1, 6F1, and 6F2) and a difarnesylated product (2F3) were obtained, enriching the diversity of natural farnesylated chalcones significantly. Ten of them are C-farnesylated products, which complement O-farnesylated chalcones by chemical synthesis. Fourteen products have not been reported prior to this study. Nine of the produced compounds (1F2-1F5, 2F1-2F3, 5F1, and 6F1) exhibited inhibitory effect on α-glucosidase with IC values ranging from 24.08 ± 1.44 to 190.0 ± 0.28 μM. Among them, compounds 2F3 with IC value at 24.08 ± 1.44 μM and 1F4 with IC value at 30.09 ± 0.59 μM showed about 20 times stronger than the positive control acarbose with an IC at 536.87 ± 24.25 μM in α-glucosidase inhibitory assays.
Topics: Dimethylallyltranstransferase; Chalcones; Aspergillus; Molecular Structure; Prenylation; Structure-Activity Relationship; Glycoside Hydrolase Inhibitors; alpha-Glucosidases; Dose-Response Relationship, Drug
PubMed: 38763314
DOI: 10.1016/j.phytochem.2024.114149 -
Journal of Medicinal Chemistry Jun 2024The trafficking chaperone PDE6D (or PDEδ) was proposed as a surrogate target for K-Ras, leading to the development of a series of inhibitors that block its prenyl...
The trafficking chaperone PDE6D (or PDEδ) was proposed as a surrogate target for K-Ras, leading to the development of a series of inhibitors that block its prenyl binding pocket. These inhibitors suffered from low solubility and suspected off-target effects, preventing their clinical development. Here, we developed a highly soluble, low nanomolar PDE6D inhibitor (PDE6Di), Deltaflexin3, which has the lowest off-target activity as compared to three prominent reference compounds. Deltaflexin3 reduces Ras signaling and selectively decreases the growth of mutant and -dependent cancer cells. We further show that PKG2-mediated phosphorylation of Ser181 lowers K-Ras binding to PDE6D. Thus, Deltaflexin3 combines with the approved PKG2 activator Sildenafil to more potently inhibit PDE6D/K-Ras binding, cancer cell proliferation, and microtumor growth. As observed previously, inhibition of Ras trafficking, signaling, and cancer cell proliferation remained overall modest. Our results suggest reevaluating PDE6D as a K-Ras surrogate target in cancer.
Topics: Humans; Cyclic Nucleotide Phosphodiesterases, Type 6; Sildenafil Citrate; Proto-Oncogene Proteins p21(ras); Cell Proliferation; Cell Line, Tumor; Antineoplastic Agents; Mutation; Animals; Structure-Activity Relationship; Phosphodiesterase Inhibitors
PubMed: 38758695
DOI: 10.1021/acs.jmedchem.3c02129 -
The Journal of Antibiotics Jul 2024Two new cyclic dipeptides, paranazzamides A (1) and B (2) containing a C7-prenylated tryptophan, were isolated from a culture broth of snake fungal disease-isolate...
Two new cyclic dipeptides, paranazzamides A (1) and B (2) containing a C7-prenylated tryptophan, were isolated from a culture broth of snake fungal disease-isolate Paranannizziopsis sp. UH-21. This is the first report on the new secondary metabolites from Paranannizziopsis sp. The planar structures of 1 and 2 were elucidated using various spectroscopic techniques including MS and 1D/2D NMR. The absolute configuration of 1 was assigned by comparison with the synthesized compound. Compounds 1 and 2 exhibited no antifungal activity, no antibacterial activity, and no cytotoxic activity even at a concentration of 128 µg ml, whereas 1 and 2 exhibited amphotericin B potentiating activity against Candida auris in combination treatment.
Topics: Tryptophan; Dipeptides; Peptides, Cyclic; Animals; Antifungal Agents; Magnetic Resonance Spectroscopy; Microbial Sensitivity Tests; Anti-Bacterial Agents; Candida; Prenylation; Amphotericin B; Molecular Structure; Humans
PubMed: 38750250
DOI: 10.1038/s41429-024-00725-3 -
Planta Medica Jun 2024, which contains isoflavones and prenylated derivatives, has analgesic and anti-inflammatory properties and is an ingredient in traditional Thai medicine for...
, which contains isoflavones and prenylated derivatives, has analgesic and anti-inflammatory properties and is an ingredient in traditional Thai medicine for perimenopause and menopause. However, the estrogenic activity of has not yet been explored. Therefore, this study aimed to examine the estrogenic activity of the stem extract of and its isoflavone derivatives. In this study, we conducted a proliferation assay in MCF-7 cells, and used quantitative reverse transcription polymerase chain reaction to assess gene expression. We found that the relative cell proliferation of the compounds (1 µM) was ranked in the following order as compared to 0.1 nM 17-estradiol (100%): genistein (97.84%) > derrisisoflavone A (83.17%) > genistein-7--[-rhamnopyranosyl-(1 → 6)-glucopyranoside] (69.55%) > 6,8-diprenylgenistein (51.91%) > lupalbigenin (18.72%). Furthermore, cotreatment with 1 µM lupalbigenin and 0.1 nM 17-estradiol was performed, which decreased cell proliferation to 80.38%. results suggest that lupalbigenin has an estrogen-antagonistic effect. At a dose of 1 µM, genistein had the strongest efficacy in increasing the expression of human estrogen receptor by 4.0-fold compared to the control. Furthermore, genistein-7--[-rhamnopyranosyl-(1 → 6)]--glucopyranoside augmented the gene expression of human estrogen receptor and human estrogen receptor by 1.5- and 3.4-fold, respectively. Prenylated derivatives of genistein (derrisisoflavone A, 6,8-diprenylgenistein, and lupalbigenin) significantly suppressed the gene expression of the human androgen receptor. The administration of the crude extract at 10 µg/mL significantly suppressed human androgen receptor (0.6-fold) and transmembrane protease serine 2 (0.1-fold) expression but did not significantly affect human estrogen receptor and human estrogen receptor gene expression. This herbal medicine may be safe for estrogen-exposed breast cancer patients.
PubMed: 38749481
DOI: 10.1055/a-2328-2750 -
BioRxiv : the Preprint Server For... May 2024Cancer cells must maintain lipid supplies for their proliferation and do so by upregulating lipogenic gene programs. The sterol regulatory element-binding proteins...
Cancer cells must maintain lipid supplies for their proliferation and do so by upregulating lipogenic gene programs. The sterol regulatory element-binding proteins (SREBPs) act as modulators of lipid homeostasis by acting as transcriptional activators of genes required for fatty acid and cholesterol synthesis and uptake. SREBPs have been recognized as chemotherapeutic targets in multiple cancers, however it is not well understood which SREBP target genes are essential for tumorigenesis. Using parallel in vitro and in vivo CRISPR knockout screens, we identified terpenoid backbone biosynthesis genes as essential for pancreatic ductal adenocarcinoma (PDAC) tumor development. Specifically, we identified the non-sterol isoprenoid product of the mevalonate pathway, geranylgeranyl diphosphate (GGPP), as an essential lipid for tumor growth. Mechanistically, we observed that restricting mevalonate pathway activity using statins and SREBP inhibitors synergistically induced apoptosis and caused disruptions in small G protein prenylation that have pleiotropic effects on cellular signaling pathways. Finally, we demonstrated that ( ) knockdown significantly reduces tumor burden in an orthotopic xenograft mouse model. These findings indicate that PDAC tumors selectively require GGPP over other lipids such as cholesterol and fatty acids and that this is a targetable vulnerability of pancreatic cancer cells.
PubMed: 38746286
DOI: 10.1101/2024.05.03.592368 -
Frontiers in Chemistry 2024A series of 16 novel prenylated chalcones () was synthesized by microwave-assisted green synthesis using 5-prenyloxy-2-hydroxyacetophenone and different benzaldehydes....
A series of 16 novel prenylated chalcones () was synthesized by microwave-assisted green synthesis using 5-prenyloxy-2-hydroxyacetophenone and different benzaldehydes. Comparisons were also performed between the microwave and conventional methods in terms of the reaction times and yields of all compounds, where the reaction times in the microwave and conventional methods were 1-4 min and 12-48 h, respectively. The synthesized compounds were characterized using different spectroscopic techniques, including IR, H-NMR, C-NMR, and LC-HRMS. The antifungal activities of all compounds were evaluated against and under conditions and were additionally supported by structure-activity relationship (SAR) and molecular docking studies. Out of the 16 compounds screened, 2'-hydroxy-4-benzyloxy-5'--prenylchalcone () showed the highest activity against both and , with ED of 25.02 and 31.87 mg/L, respectively. The molecular docking studies of the prenylated chalcones within the active sites of the EF1 and RPB2 gene sequences and FoCut5a sequence as the respective receptors for and revealed the importance of the compounds, where the binding energies of the docked molecules ranged from -38.3538 to -26.6837 kcal/mol for and -43.400 to -23.839 kcal/mol for . Additional docking parameters showed that these compounds formed stable complexes with the protein molecules.
PubMed: 38746019
DOI: 10.3389/fchem.2024.1389848