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1.
Sci Rep ; 11(1): 23243, 2021 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-34853392

RESUMO

Specific guanine rich nucleic acid sequences can form non-canonical structures, like the four stranded G-quadruplex (GQ). We studied the GQ-forming sequence (named HepB) found in the genome of the hepatitis B virus. Fluorescence-, infrared- and CD-spectroscopy were used. HepB shows a hybrid form in presence of K+, but Na+, Li+, and Rb+ induce parallel structure. Higher concentrations of metal ions increase the unfolding temperature, which was explained by a short thermodynamic calculation. Temperature stability of the GQ structure was determined for all these ions. Na+ has stronger stabilizing effect on HepB than K+, which is highly unusual. The transition temperatures were 56.6, 53.8, 58.5 and 54.4 °C for Na+, K+, Li+, and Rb+ respectively. Binding constants for Na+ and K+ were 10.2 mM and 7.1 mM respectively. Study of three ligands designed in cancer research for GQ targeting (TMPyP4, BRACO19 and PhenDC3) showed unequivocally their binding to HepB. Binding was proven by the increased stability of the bound form. The stabilization was higher than 20 °C for TMPyP4 and PhenDC3, while it was considerably lower for BRACO19. These results might have medical importance in the fight against the hepatitis B virus.


Assuntos
Acridinas/metabolismo , Compostos de Anéis Fundidos/metabolismo , Quadruplex G , Vírus da Hepatite B/genética , Porfirinas/metabolismo , Acridinas/química , DNA/química , Compostos de Anéis Fundidos/química , Genoma Viral , Vírus da Hepatite B/química , Vírus da Hepatite B/metabolismo , Ligantes , Porfirinas/química , Termodinâmica
2.
Viruses ; 13(11)2021 11 04.
Artigo em Inglês | MEDLINE | ID: mdl-34835025

RESUMO

Pseudorabies virus (PRV) is the causative agent of Aujeszky's disease, which still causes large economic losses for the swine industry. Therefore, it is urgent to find a new strategy to prevent and control PRV infection. Previous studies have proven that guanine (G)-rich DNA or RNA sequences in some other viruses' genomes have the potential to form G-quadruplex (G4), which serve as promising antivirus targets. In this study, we identified two novel G4-forming sequences, OriL-A and OriL-S, which are located at the upstream origin of replication (OriL) in the PRV genome and conserved across 32 PRV strains. Circular dichroism (CD) spectroscopy and a gel electrophoresis assay showed that the two G-rich sequences can fold into parallel G4 structures in vitro. Moreover, fluorescence resonance energy transfer (FRET) melting and a Taq polymerase stop assay indicated that the G4 ligand PhenDC3 has the capacity to bind and stabilize the G4. Notably, the treatment of PRV-infected cells with G4-stabilizer PhenDC3 significantly inhibited PRV DNA replication in host cells but did not affect PRV's attachment and entry. These results not only expand our knowledge about the G4 characteristics in the PRV genome but also suggest that G4 may serve as an innovative therapeutic target against PRV.


Assuntos
Antivirais/farmacologia , Quadruplex G , Herpesvirus Suídeo 1/genética , Origem de Replicação/genética , Animais , Antivirais/química , Linhagem Celular , Replicação do DNA/efeitos dos fármacos , DNA Viral/biossíntese , DNA Viral/química , DNA Viral/efeitos dos fármacos , Compostos de Anéis Fundidos/química , Compostos de Anéis Fundidos/farmacologia , Quadruplex G/efeitos dos fármacos , Genoma Viral/efeitos dos fármacos , Genoma Viral/genética , Herpesvirus Suídeo 1/efeitos dos fármacos , Herpesvirus Suídeo 1/fisiologia , Origem de Replicação/efeitos dos fármacos , Suínos , Replicação Viral/efeitos dos fármacos
3.
PLoS One ; 16(9): e0257808, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34582495

RESUMO

The Ultraviolet-visible (UV-Vis) spectra indicate that anthracenyl chalcones (ACs) have high maximum wavelengths and good transparency windows for optical applications and are suitable for optoelectronic applications owing to their HOMO-LUMO energy gaps (2.93 and 2.76 eV). Different donor substituents on the AC affect their dipole moments and nonlinear optical (NLO) responses. The positive, negative, and neutral electrostatic potential regions of the molecules were identified using molecular electrostatic potential (MEP). The stability of the molecule on account of hyperconjugative interactions and accompanying charge delocalization was analyzed using natural bond orbital (NBO) analysis. Open and closed aperture Z-scans were performed using a continuous-wave frequency-doubled diode-pumped solid-state (DPSS) laser to measure the nonlinear absorption and nonlinear refractive index coefficients, respectively. The valley-to-peak profile of AC indicated a negative nonlinear refractive index coefficient. The obtained single crystals possess reverse saturation absorption due to excited-state absorption. The structural and nonlinear optical properties of the molecules have been discussed, along with the role of anthracene substitution for enhancing the nonlinear optical properties. The calculated third-order susceptibility value was 1.10 x10-4 esu at an intensity of 4.1 kW/cm2, higher than the reported values for related chalcone derivatives. The NLO response for both ACs offers excellent potential in optical switching and limiting applications.


Assuntos
Antracenos/química , Chalconas/química , Compostos de Anéis Fundidos/química , Cristalografia por Raios X , Teoria da Densidade Funcional , Estrutura Molecular , Teoria Quântica
4.
Biopolymers ; 112(4): e23415, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33368198

RESUMO

G-quadruplexes (G4) play crucial roles in biology, analytical chemistry and nanotechnology. The stability of G4 structures is impacted by the number of G-quartets, the length and positions of loops, flanking motifs, as well as additional structural elements such as bulges, capping base pairs, or triads. Algorithms such as G4Hunter or Quadparser may predict if a given sequence is G4-prone by calculating a quadruplex propensity score; however, experimental validation is still required. We previously demonstrated that this validation is not always straightforward, and that a combination of techniques is often required to unambiguously establish whether a sequence forms a G-quadruplex or not. In this article, we adapted the well-known FRET-melting assay to characterize G4 in batch, where the sequence to be tested is added, as an unlabeled competitor, to a system composed of a dual-labeled probe (F21T) and a specific quadruplex ligand. PhenDC3 was preferred over TMPyP4 because of its better selectivity for G-quadruplexes. In this so-called FRET-MC (melting competition) assay, G4-forming competitors lead to a marked decrease of the ligand-induced stabilization effect (∆Tm ), while non-specific competitors (e.g., single- or double-stranded sequences) have little effect. Sixty-five known sequences with different typical secondary structures were used to validate the assay, which was subsequently employed to assess eight novel sequences that were not previously characterized.


Assuntos
Compostos de Anéis Fundidos/química , Quadruplex G , Oligonucleotídeos/química , Bioensaio/métodos , Fluorescência , Transferência Ressonante de Energia de Fluorescência , Humanos , Técnicas In Vitro , Desnaturação de Ácido Nucleico
5.
Bioorg Chem ; 105: 104450, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33189994

RESUMO

In this study, various N-heterocyclic nitro prodrugs (NHN1-16) containing pyrimidine, triazine and piperazine rings were designed and synthesized. The final compounds were identified using FT-IR, 1H NMR, 13C NMR as well as elemental analyses. Enzymatic activities of compounds were conducted by using HPLC analysis to investigate the interaction of substrates with Ssap-NtrB nitroreductase enzyme. MTT assay was performed to evaluate the toxic effect of compounds against Hep3B and PC3 cancer cell lines and healthy HUVEC cell. It was observed that synthesized compounds NHN1-16 exhibited different cytotoxic profiles. Pyrimidine derivative NHN3 and triazine derivative NHN5 can be good drug candidates for prostate cancer with IC50 values of 54.75 µM and 48.9 µM, respectively. Compounds NHN6, NHN10, NHN12, NHN14 and NHN16 were selected as prodrug candidates because of non-toxic properties against three different cell models. The NHN prodrugs and Ssap-NtrB combinations were applied to SRB assay to reveal the prodrug capabilities of these selected compounds. SRB screening results showed that the metabolites of all selected non-toxic compounds showed remarkable cytotoxicity with IC50 values in the range of 1.71-4.72 nM on prostate cancer. Among the tested compounds, especially piperazine derivatives NHN12 and NHN14 showed significant toxic effect with IC50 values of 1.75 nM and 1.79 nM against PC3 cell compared with standart prodrug CB1954 (IC50: 1.71 nM). Novel compounds NHN12 and NHN14 can be considered as promising prodrug candidates for nitroreductase-prodrug based prostate cancer therapy.


Assuntos
Antineoplásicos/química , Colletotrichum/química , Compostos de Anéis Fundidos/química , Compostos Heterocíclicos/química , Nitrocompostos/química , Nitrorredutases/antagonistas & inibidores , Pró-Fármacos/química , Neoplasias da Próstata/tratamento farmacológico , Antineoplásicos/farmacologia , Aziridinas/farmacologia , Aziridinas/normas , Misturas Complexas/química , Misturas Complexas/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Fermentação , Compostos de Anéis Fundidos/farmacologia , Compostos Heterocíclicos/farmacologia , Humanos , Masculino , Policetídeos/química , Pró-Fármacos/farmacologia , Relação Estrutura-Atividade
6.
Bioorg Chem ; 105: 104449, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33189995

RESUMO

Three unusual polyketides with a 5/6/10-fused ring system, named colletotrichalactones A-Ca (1-3a), were isolated from cultures of the endophytic fungus, Colletotrichum sp. JS-0361, which was isolated from a leaf of Morus alba. Their structures, including their absolute stereochemistries, were completely established using extensive spectroscopic methods together with a chemical reaction utilizing competing enantioselective acylation coupled with LC/MS. Compounds possessing this ring skeleton were previously reported in three studies. Our rigorous chemical investigation revealed the complete configuration of this skeleton, which agreed with the results for glabramycin B with this ring skeleton established by computational chemistry and enantioselective synthesis in previous reports. 1 and 2 had unstable aldehyde groups that were easily converted to acetal groups in the presence of solvents. Meanwhile, compound 3a, with terminal acetal functionality, was deduced to be an artefact originating from compound 3 with a terminal aldehyde group. Compounds 1 and 3a displayed moderate-to-potent cytotoxic activities against MCF7 cells with IC50s of 35.06 and 25.20 µM, respectively.


Assuntos
Antineoplásicos/isolamento & purificação , Colletotrichum/química , Misturas Complexas/isolamento & purificação , Compostos de Anéis Fundidos/química , Policetídeos/química , Acilação , Antineoplásicos/farmacologia , Caprilatos/farmacologia , Misturas Complexas/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Lactonas/farmacologia , Células MCF-7 , Modelos Moleculares , Estrutura Molecular , Policetídeos/farmacologia , Estereoisomerismo
7.
Cell Chem Biol ; 26(12): 1716-1724.e9, 2019 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-31631010

RESUMO

Lethal small molecules are useful probes to discover and characterize novel cell death pathways and biochemical mechanisms. Here we report that the synthetic oxime-containing small molecule caspase-independent lethal 56 (CIL56) induces an unconventional form of nonapoptotic cell death distinct from necroptosis, ferroptosis, and other pathways. CIL56-induced cell death requires a catalytically active protein S-acyltransferase complex comprising the enzyme ZDHHC5 and an accessory subunit GOLGA7. The ZDHHC5-GOLGA7 complex is mutually stabilizing and localizes to the plasma membrane. CIL56 inhibits anterograde protein transport from the Golgi apparatus, which may be lethal in the context of ongoing ZDHHC5-GOLGA7 complex-dependent retrograde protein trafficking from the plasma membrane to internal sites. Other oxime-containing small molecules, structurally distinct from CIL56, may trigger cell death through the same pathway. These results define an unconventional form of nonapoptotic cell death regulated by protein S-acylation.


Assuntos
Aciltransferases/metabolismo , Morte Celular , Proteínas da Matriz do Complexo de Golgi/metabolismo , Acilação , Aciltransferases/química , Aciltransferases/genética , Animais , Morte Celular/efeitos dos fármacos , Linhagem Celular , Membrana Celular/metabolismo , Compostos de Anéis Fundidos/química , Compostos de Anéis Fundidos/farmacologia , Complexo de Golgi/efeitos dos fármacos , Complexo de Golgi/metabolismo , Complexo de Golgi/ultraestrutura , Proteínas da Matriz do Complexo de Golgi/química , Proteínas da Matriz do Complexo de Golgi/genética , Humanos , Camundongos , Oximas/química , Oximas/farmacologia , Proteína S/metabolismo , Transporte Proteico/efeitos dos fármacos
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