The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has prompted great interest in novel broad-spectrum antivirals, including perylene-related compounds. In the present study, we performed a structure-activity relationship analysis of a series of perylene derivatives, which comprised a large planar perylene residue, and structurally divergent polar groups connected to the perylene core by a rigid ethynyl or thiophene linker. Most of the tested compounds did not exhibit significant cytotoxicity towards multiple cell types susceptible to SARS-CoV-2 infection, and did not change the expressions of cellular stress-related genes under normal light conditions. These compounds showed nanomolar or sub-micromolar dose-dependent anti-SARS-CoV-2 activity, and also suppressed the in vitro replication of feline coronavirus (FCoV), also termed feline infectious peritonitis virus (FIPV). Perylene compounds exhibited high affinity for liposomal and cellular membranes, and efficiently intercalated into the envelopes of SARS-CoV-2 virions, thereby blocking the viral-cell fusion machinery. Furthermore, the studied compounds were demonstrated to be potent photosensitizers, generating reactive oxygen species (ROS), and their anti-SARS-CoV-2 activities were considerably enhanced after irradiation with blue light. Our results indicated that photosensitization is the major mechanism underlying the anti-SARS-CoV-2 activity of perylene derivatives, with these compounds completely losing their antiviral potency under red light. Overall, perylene-based compounds are broad-spectrum antivirals against multiple enveloped viruses, with antiviral action based on light-induced photochemical damage (ROS-mediated, likely singlet oxygen-mediated), causing impairment of viral membrane rheology.
- MeSH
- Antiviral Agents pharmacology chemistry MeSH
- COVID-19 * MeSH
- Cats MeSH
- Perylene * pharmacology MeSH
- Reactive Oxygen Species MeSH
- SARS-CoV-2 MeSH
- Singlet Oxygen MeSH
- Virion MeSH
- Viral Envelope MeSH
- Animals MeSH
- Check Tag
- Cats MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
A structure-activity relationship (SAR) study in terms of G-quadruplex binding ability and antiproliferative activity of six fluorescent perylenemonoimide (PMIs) derivatives is reported. A positive charge seems to be the key to target G4. This study also reveals the importance of the element substitution in the potential biological activity of PMIs, being the polyethylene glycol (PEG) chains in the peri position responsible for their antiproliferative activity. Among them, the cationic PMI6 with two PEG chains is the most promising compound since its fluorescence is enhanced in the presence of G-quadruplex structures. Moreover, PMI6 binds to the human telomeric G-quadruplex hTelo with high affinity and displays a high antiproliferative potential towards HeLa (cervical adenocarcinoma), A549 (lung adenocarcinoma) and A2780 (ovarian adenocarcinoma) cells. Its fate can be followed inside cells thanks to its fluorescent properties: the compound is found to accumulate in the mitochondria.
- MeSH
- G-Quadruplexes drug effects MeSH
- Imides chemical synthesis chemistry pharmacology MeSH
- Cells, Cultured MeSH
- Humans MeSH
- Mitochondria drug effects MeSH
- Molecular Structure MeSH
- Perylene analogs & derivatives chemical synthesis chemistry pharmacology MeSH
- Cell Proliferation drug effects MeSH
- Dose-Response Relationship, Drug MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Photosensitive compounds found in herbs have been reported in recent years as having a variety of interesting medicinal and biological activities. In this review, we focus on photosensitizers such as hypericin and its model compounds emodin, quinizarin, and danthron, which have antiviral, antifungal, antineoplastic, and antitumor effects. They can be utilized as potential agents in photodynamic therapy, especially in photodynamic therapy (PDT) for cancer. We aimed to give a comprehensive summary of the physical and chemical properties of these interesting molecules, emphasizing their mechanism of action in relation to their different interactions with biomacromolecules, specifically with DNA.
- MeSH
- Anthraquinones chemistry MeSH
- Photochemotherapy MeSH
- Photosensitizing Agents chemistry pharmacology MeSH
- Humans MeSH
- Neoplasms drug therapy MeSH
- Perylene analogs & derivatives chemistry pharmacology MeSH
- Antineoplastic Agents chemistry pharmacology MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
OBJECTIVE: Cancer stem-like cells (CSLCs) are considered a root of tumorigenicity and resistance. However, their identification remains challenging. The use of the side population (SP) assay as a credible marker of CSLCs remains controversial. The SP assay relies on the elevated activity of ABC transporters that, in turn, can be modulated by hypericin (HYP), a photosensitizer and bioactive compound of St. John's Wort (Hypericum perforatum), a popular over-the-counter antidepressant. Here we aimed to comprehensively characterize the SP phenotype of cancer cells and to determine the impact of HYP on these cells. METHODS: Flow cytometry and sorting-based assays were employed, including CD24-, CD44-, CD133-, and ALDH-positivity, clonogenicity, 3D-forming ability, ABC transporter expression and activity, and intracellular accumulation of HYP/Hoechst 33342. The tumorigenic ability of SP, nonSP, and HYP-treated cells was verified by xenotransplantation into immunodeficient mice. RESULTS: The SP phenotype was associated with elevated expression of several investigated transporters and more intensive growth in non-adherent conditions but not with higher clonogenicity, tumorigenicity or ALDH-positivity. Despite stimulated BCRP level and MRP1 activity, HYP reversibly decreased the SP proportion, presumably via competitive inhibition of BCRP. HYP-selected SP cells acquired additional traits of resistance and extensively eliminated HYP. CONCLUSIONS: Our results suggest that SP is not an unequivocal CSLC-marker. However, SP could play an important role in modulating HYP-treatment and serve as a negative predictive tool for HYP-based therapies. Moreover, the use of supplements containing HYP by cancer patients should be carefully considered, due to its proposed effect on drug efflux and complex impact on tumor cells, which have not yet been sufficiently characterized.
- MeSH
- ATP Binding Cassette Transporter, Subfamily G, Member 2 metabolism MeSH
- Aldehyde Dehydrogenase metabolism MeSH
- Survival Analysis MeSH
- Clone Cells MeSH
- Spheroids, Cellular drug effects metabolism pathology MeSH
- Phenotype MeSH
- Carcinogenesis drug effects metabolism pathology MeSH
- Humans MeSH
- Mice, SCID MeSH
- Biomarkers, Tumor metabolism MeSH
- Cell Line, Tumor MeSH
- Neoplastic Stem Cells drug effects metabolism pathology MeSH
- Neoplasm Proteins metabolism MeSH
- Neoplasms metabolism pathology MeSH
- ATP Binding Cassette Transporter, Subfamily B, Member 1 metabolism MeSH
- Perylene analogs & derivatives pharmacology MeSH
- Substrate Specificity drug effects MeSH
- Side-Population Cells drug effects pathology MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
BACKGROUND/AIM: We report the incorporation of prospective anticancer agent hypericin into DNA and bovine serum albumin (BSA), respectively, with emphasis on comparison of the differences in interaction mode between hypericin and its model compound emodin. MATERIALS AND METHODS: Spectrophotometric methods were used for determination of the binding constants of the drug complex with biomacromolecules. Differential scanning calorimetry was applied for evaluation of drug-macromolecule complex thermal stability. RESULTS: The strength of interaction expressed by binding constants was found to be 4.0×104 l/mol for hypericin-DNA and 8.1×104 l/mol for emodin-DNA complex. Both molecules stabilize bovine serum albumin macromolecule and bind into the hydrophobic cavity in IIA subunit but their localization within the molecule is different. CONCLUSION: Anticancer agent hypericin and its derivative emodin interact with DNA with medium strength and are probably incorporated into the groove of DNA by hydrogen bonds. Bovine serum albumin can serve as a transport protein for hypericin since the binding force between both molecules is adequate.
- MeSH
- DNA chemistry metabolism MeSH
- Emodin chemistry pharmacology MeSH
- Molecular Structure MeSH
- Perylene analogs & derivatives chemistry pharmacology MeSH
- Antineoplastic Agents chemistry pharmacology MeSH
- Serum Albumin, Bovine chemistry metabolism MeSH
- Spectrum Analysis MeSH
- Thermodynamics MeSH
- Protein Binding MeSH
- Structure-Activity Relationship MeSH
- Animals MeSH
- Check Tag
- Animals MeSH
- Publication type
- Journal Article MeSH
This article is directed to determining concentrations of polycyclic aromatic hydrocarbons (PAHs), which are sorbed to solid particles in the air. Pollution sources were identified on the basis of the ratio of benzo[ghi]perylene (BghiPe) to benzo[a]pyrene (BaP). Because various important information is lost by determining the simple ratio of concentrations, least squares linear regression (classic ordinary least squares regression), reduced major axis, orthogonal regression, and Kendall-Theil robust diagnostics were utilized for identification. Statistical evaluation using all aforementioned methods demonstrated different ratios of the monitored PAHs in the intervals examined during warmer and colder periods. Analogous outputs were provided by comparing gradients of the emission factors acquired from the measured concentrations of BghiPe and BaP in motor vehicle exhaust gases. Based on these outputs, it was possible plausibly to state that the influence of burning organic fuels in heating stoves is prevalent in colder periods whereas in warmer periods transport was the exclusive source because other sources of PAH emissions were not found in the examined locations.
- MeSH
- Benzo(a)pyrene analysis MeSH
- Risk Assessment MeSH
- Air Pollutants analysis MeSH
- Linear Models MeSH
- Least-Squares Analysis MeSH
- Environmental Monitoring methods statistics & numerical data MeSH
- Perylene analogs & derivatives analysis MeSH
- Particulate Matter analysis MeSH
- Polycyclic Aromatic Hydrocarbons analysis MeSH
- Seasons MeSH
- Urbanization MeSH
- Vehicle Emissions analysis MeSH
- Publication type
- Journal Article MeSH
- Geographicals
- Czech Republic MeSH
By means of fluorescence microscopy the intracellular distribution of fluorescent drugs with different hydrophobicity (quinizarin, emodin and hypericin) was studied. Selective photoactivation of these drugs in precisely defined position (nuclear envelope) allowed moderately hydrophobic emodin enter the nucleus. Highly hydrophobic hypericin was predominantly kept in the membranes with no fluorescence observed in the nucleus. The redistribution of quinizarin, emodin and hypericin between lipids, proteins and DNA was studied in solutions and cells. Based on these results was proposed theoretical model of hydrophobic drugs' nuclear internalization after photo-activation. Molecular docking models showed that hypericin has the strongest affinity to P-glycoprotein involved in the cell detoxification. Presence of 10 μM quinizarin, emodin or hypericin increased P-glycoprotein function in U87 MG cells. Moreover, emodin pretreatment allowed quinizarin nuclear internalization without photo-activation, which was not the case for hypericin. The synergy of such pretreatment and photo-activation should lessen the drug doses with simultaneous increase of drug efficacy triggering cell apoptosis/necrosis.
- MeSH
- Anthraquinones chemistry pharmacology radiation effects MeSH
- Cell Nucleus metabolism radiation effects MeSH
- DNA chemistry MeSH
- Emodin chemistry pharmacology radiation effects MeSH
- Glioma metabolism MeSH
- Hydrophobic and Hydrophilic Interactions MeSH
- Cholesterol, LDL chemistry MeSH
- Humans MeSH
- Cell Line, Tumor MeSH
- ATP Binding Cassette Transporter, Subfamily B, Member 1 metabolism MeSH
- Perylene analogs & derivatives chemistry pharmacology radiation effects MeSH
- Serum Albumin chemistry MeSH
- Molecular Docking Simulation MeSH
- Light MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
By means of fluorescence spectroscopy we have studied the kinetics of interaction of a photosensitizer hypericin (Hyp) with high-density lipoproteins (HDL). Hyp is incorporated into HDL molecules as monomer till ratio Hyp/HDL ∼8:1 and above this ratio forms non-fluorescent aggregates. This number is different from that found in the case of Hyp incorporation into low-density lipoprotein (LDL) molecules (8:1 vs 30:1). The difference is mainly attributed to the smaller size of HDL in comparison with LDL molecule. Biphasic kinetics of Hyp association with HDL was observed. The rapid phase of incorporation is completed within seconds, while the slow one lasts several minutes. The kinetics of the association of Hyp molecules with free HDL, Hyp/HDL=10:1 complex and the redistribution of Hyp from Hyp/HDL=70:1 complex to free HDL molecules reveal a qualitative similar characteristics of these processes with those observed for the interaction of Hyp with LDL. However, the incorporation of Hyp into HDL in the "slow" phase is more rapid than to LDL and extend of Hyp penetration into lipoproteins in the fast phase is also much higher in the case of HDL. The lower concentration of cholesterol molecules in outer shell of HDL particles is probably the determining factor for the more rapid kinetics of Hyp incorporation to and redistribution from these molecules when comparing with LDL particles.
- MeSH
- Cell Line MeSH
- Chemistry, Pharmaceutical MeSH
- Spectrometry, Fluorescence MeSH
- Photosensitizing Agents chemistry MeSH
- Lipoproteins, HDL chemistry MeSH
- Lipoproteins, LDL chemistry MeSH
- Perylene analogs & derivatives chemistry MeSH
- Drug Liberation MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Some endophyte isolates were isolated in a bamboo pole sample parasitized the fungus Shiraia bambusicola from Zhejiang Province. After screening through hypocrellin bacteriostatic effect and fermentation test, we got the isolate TX4 of bacterial elicitor and GZUIFR-TT1 of fungal elicitor which had certain effect to promote S. bambusicola to produce hypocrellin. The Plackett-Burman design was introduced to evaluate the effects of nine factors based on single-factor test. Yeast extract, glucose, and isolate GZUIFR-TT1 elicitor were found to be the critical activity factors for increasing the total hypocrellin production. So we identified the isolate GZUIFR-TT1 as Trametes sp. Through response surface methodology, we obtained the optimum production conditions as follows: yeast extract, 2.99 g/L; glucose, 32.45 g/L; and Trametes sp. elicitor, 81.40 μg/mL. Under the above conditions, the experimental value of hypocrellin production was 102.60 mg/L, compared with the control it increased about 7.90 times.
- MeSH
- Anti-Infective Agents metabolism MeSH
- Ascomycota metabolism MeSH
- Biotechnology methods MeSH
- Quinones metabolism MeSH
- DNA, Fungal chemistry genetics MeSH
- Fermentation MeSH
- Culture Media chemistry MeSH
- DNA, Ribosomal Spacer chemistry genetics MeSH
- Molecular Sequence Data MeSH
- Perylene analogs & derivatives metabolism MeSH
- Sequence Analysis, DNA MeSH
- Trametes classification genetics growth & development isolation & purification MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Even though superresolution microscopy indicates that size of plasma membrane rafts is <20 nm, those structures have never been observed. Förster resonance energy transfer (FRET) is therefore still the most powerful optical method for characterization of such domains. In this letter we investigate relation between nanodomain affinity of a donor-acceptor (D/A) pair and the detectable nanodomain size/area. We show that probes with high affinity to the liquid-ordered (L(o)) phase are required for detecting domain sizes of a few nanometers, and/or domains that occupy a few percent of the bilayer area. A combination of donors and acceptors that prefer different phases is the more favorable approach. For instance, a D/A pair with the distribution constant of donors K(D) = 5 and acceptors K(A) = 0.01 can resolve a broad spectrum of nanodomain sizes. On the other hand, currently available donors and acceptors that prefer the same phase, either the liquid-disordered (L(d)) or L(o) phase, are not so convenient for determining domain sizes <20 nm. Here the detection limits of FRET experiments employing several commonly used D/A pairs have been investigated.
- MeSH
- Time Factors MeSH
- Cholera Toxin chemistry MeSH
- Electrons MeSH
- Phycoerythrin chemistry MeSH
- Carbocyanines chemistry MeSH
- Lipid Bilayers chemistry MeSH
- Membrane Microdomains chemistry MeSH
- Monte Carlo Method MeSH
- Nanoparticles chemistry MeSH
- Perylene chemistry MeSH
- Reproducibility of Results MeSH
- Fluorescence Resonance Energy Transfer methods MeSH
- Rhodamines chemistry MeSH
- Boron Compounds chemistry MeSH
- Particle Size MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
