RESUMEN
Fifteen betulonic/betulinic acid conjugated with nucleoside derivatives were synthesized to enhance antitumor potency and water solubility. Among these, the methylated betulonic acid-azidothymidine compound (8c) exhibited a broad-spectrum of antitumor activity against three tested tumor cell lines, including SMMC-7721 (IC50 = 5.02 µM), KYSE-150 (IC50 = 5.68 µM), and SW620 (IC50 = 4.61 µM) and along with lower toxicity (TC50 > 100 µM) estimated by zebrafish embryos assay. Compared to betulinic acid (<0.05 µg/mL), compound 8c showed approximately 40-fold higher water solubility (1.98 µg/mL). In SMMC-7721 cells, compound 8c induced autophagy and apoptosis as its concentration increased. Transcriptomic sequencing analysis was used to understand the potential impacts of the underlying mechanism of 8c on SMMC-7721 cells. Transcriptomic studies indicated that compound 8c could activate autophagy by inhibiting the PI3K/AKT pathway in SMMC-7721 cells. Furthermore, in the xenograft mice study, compound 8c significantly slowed down the tumor growth, as potent as paclitaxel treated group. In conclusion, methylated betulonic acid-azidothymidine compound (8c) not only increases water solubility, but also enhances the potency against hepatocellular carcinoma cells by inducing autophagy and apoptosis, and suppressing the PI3K/Akt/mTOR signaling pathway.
RESUMEN
Polysaccharide from Asarum sieboldii Miq (ASP) was extracted and five phosphorylation polysaccharides with different degree of substitution were obtained, namely ASPP1, ASPP2, ASPP3, ASPP4, and ASPP5 (ASPPs). The physical and chemical structure and biological activities were studied. The results suggested that the carbohydrate and protein content were reduced while uronic acid was increased after phosphorylation modification. The molecular weight of ASPPs was significantly lower than that of ASP. ASPPs were acidic heteropolysaccharides mainly composed of galacturonic acid, galactose, glucose, fructose, and arabinose. The UV-vis spectrum indicated that the polysaccharides did not contain nucleic acid or protein after modification. The Fourier transform infrared spectrum demonstrated that ASPPs contained characteristic absorption peaks of P=O and P-O-C near 1270 and 980â cm-1 . ASPPs presented a triple helix conformation, but it was not presented in ASP. The scanning electron microscopy analysis showed that the surface topography and particle structure of ASP were different after modification. Compared with ASP, ASPPs enhanced the activity to scavenge DPPH and ABTS free radicals and possessed more protective ability to DNA oxidation caused by OHâ , GSâ , and AAPH free radicals. These results suggest that chemical modification is beneficial for the exploitation and utilization of natural polysaccharides.
Asunto(s)
Antioxidantes , Asarum , Antioxidantes/farmacología , Antioxidantes/química , Fosforilación , Polisacáridos/farmacología , Polisacáridos/química , Radicales Libres , Espectroscopía Infrarroja por Transformada de FourierRESUMEN
Based on hA2AAR structures, a hydrophobic C8-heteroaromatic ring in 5'-truncated adenosine analogues occupies the subpocket tightly, converting hA2AAR agonists into antagonists while maintaining affinity toward hA3AR. The final compounds of 2,8-disubstituted-N6-substituted 4'-thionucleosides, or 4'-oxo, were synthesized from d-mannose and d-erythrono-1,4-lactone, respectively, using a Pd-catalyst-controlled regioselective cross-coupling reaction. All tested compounds completely antagonized hA2AAR, including 5d with the highest affinity (Ki,A2A = 7.7 ± 0.5 nM). The hA2AAR-5d X-ray structure revealed that C8-heteroaromatic rings prevented receptor activation-associated conformational changes. However, the C8-substituted compounds still antagonized hA3AR. Structural SAR features and docking studies supported different binding modes at A2AAR and A3AR, elucidating pharmacophores for receptor activation and selectivity. Favorable pharmacokinetics were demonstrated, in which 5d displayed high oral absorption, moderate half-life, and bioavailability. Also, 5d significantly improved the antitumor effect of anti-PD-L1 in vivo. Overall, this study suggests that the novel dual A2AAR/A3AR nucleoside antagonists would be promising drug candidates for immune-oncology.
Asunto(s)
Adenosina , Neoplasias , Humanos , Adenosina/farmacología , Antagonistas de Receptores Androgénicos , Inmunoterapia , Antagonistas de Receptores Purinérgicos P1 , Relación Estructura-Actividad , Tionucleósidos/química , Tionucleósidos/farmacologíaRESUMEN
To overcome the metabolic instability of cordycepin (adenosine deaminase (ADA) metabolic deamination and plasma degradation) and obtain better bioactivity, three novel kinds of cordycepin derivatives 1a-1c containing unsaturated fatty acids including linoleic acid, arachidonic acid and α-linolenic acid, respectively, were designed and synthesized. In terms of antibacterial activity, the synthesized compounds 1a and 1c showed enhanced activity than cordycepin in the tested bacterial strains. 1a-1c also exhibited enhanced antitumor activity against four cancer cell lines (human cervical cancer cell line HeLa, human non-small cell lung cancer cell line A549, human breast cancer cell line MCF-7, and human hepatoma cell line SMMC-7721) compared with cordycepin. Notably, 1a and 1b showed better antitumor activity even compared with positive control 5-Fluorouracil (5-FU) in HeLa, MCF-7 and SMMC-7721. The cell cycle assay indicated that when compared with cordycepin, 1a and 1b could significantly inhibit the cell propagation trapped in S and G2/M phases and increase the percentage of cells trapped in G0/G1 in HeLa and A549, which might provide a synergistic antitumor mechanism evidence different from cordycepin. Last but not the least, 1a and 1b displayed improved stability both in ADA solution and mouse plasma compared with cordycepin and 1a owns a solubility of 130 µg/mL in PBS. These results offer a novel insight into the primary structure and activity relationship of how the unsaturated fatty acid chain could affect the bioactivity of cordycepin, which also represents a series of cordycepin analogs with obviously improved bioactivity and enhanced stability, therefore promoting its druggable enhancement.
Asunto(s)
Antineoplásicos , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Animales , Ratones , Línea Celular Tumoral , Fluorouracilo/farmacología , Antibacterianos/farmacología , Ácidos Grasos Insaturados/farmacología , Antineoplásicos/química , Proliferación Celular , Relación Estructura-Actividad , Ensayos de Selección de Medicamentos Antitumorales , ApoptosisRESUMEN
In this study, polysaccharide from Cortex periplocae (CPP) was modified and three carboxymethylation modification polysaccharides (CPPCs) were obtained, and their physicochemical characteristics and in vitro biological activities were investigated. Based on the ultraviolet-visible (UV-Vis) scan, CPPs (CPP and CPPCs) did not contain nucleic acids or proteins. However, the Fourier transform infrared (FTIR) spectrum showed a new absorption peak around 1731 cm-1. In addition, three absorption peaks near 1606, 1421, and 1326 cm-1 were enhanced after carboxymethylation modification. Based on UV-Vis scan, the maximum absorption wavelength of Congo Red + CPPs exhibited a red-shift compared to Congo Red meant CPPs had a triple helix conformation. Scanning electron microscopy (SEM) indicated that CPPCs exhibited more fragments and non-uniform-sized filiform than CPP. Thermal analysis showed that CPPCs degraded between the temperature 240 °C-350 °C and CPP in the 270 °C-350 °C. In addition, the antioxidant and DNA protecting activities of CPPCs were significantly enhanced compared to CPP. Overall, this study demonstrated the potential applications of CPPs in food and pharmaceutical industries.
Asunto(s)
Antioxidantes , Depuradores de Radicales Libres , Antioxidantes/farmacología , Antioxidantes/química , Depuradores de Radicales Libres/química , Rojo Congo , ADN , Polisacáridos/farmacología , Polisacáridos/química , Espectroscopía Infrarroja por Transformada de FourierRESUMEN
The 6'-fluorinated aristeromycins were designed as dual-target antiviral compounds aimed at inhibiting both the viral RNA-dependent RNA polymerase (RdRp) and the host cell S-adenosyl-l-homocysteine (SAH) hydrolase, which would indirectly target capping of viral RNA. The introduction of a fluorine at the 6'-position enhanced the inhibition of SAH hydrolase and the activity against RNA viruses. The adenosine and N6-methyladenosine analogues 2a-e showed potent inhibition against SAH hydrolase, while only the adenosine derivatives 2a-c exhibited potent antiviral activity against all tested RNA viruses such as Middle East respiratory syndrome-coronavirus (MERS-CoV), severe acute respiratory syndrome-coronavirus, chikungunya virus, and/or Zika virus. 6',6'-Difluoroaristeromycin (2c) showed the strongest antiviral effect for MERS-CoV, with a â¼2.5 log reduction in infectious progeny titer in viral load reduction assay. The phosphoramidate prodrug 3a also demonstrated potent broad-spectrum antiviral activity, possibly by inhibiting the viral RdRp. This study shows that 6'-fluorinated aristeromycins can serve as starting points for the development of broad-spectrum antiviral agents that target RNA viruses.
Asunto(s)
Adenosina/análogos & derivados , Antivirales/farmacología , Inhibidores Enzimáticos/farmacología , Virus ARN/efectos de los fármacos , Adenosina/síntesis química , Adenosina/farmacología , Adenosilhomocisteinasa/antagonistas & inhibidores , Animales , Antivirales/síntesis química , Chlorocebus aethiops , Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Halogenación , Humanos , Estructura Molecular , Profármacos/síntesis química , Profármacos/farmacología , ARN Polimerasa Dependiente del ARN/antagonistas & inhibidores , Células VeroRESUMEN
(-)-6'-ß-Fluoro-aristeromycin (2), a potent inhibitor of S-adenosylhomocysteine (AdoHcy) hydrolase, has been synthesized via stereoselective electrophilic fluorination followed by a purine base build-up approach. Interestingly, purine base condensation using a cyclic sulfate resulted in a synthesis of (+)-5'-ß-fluoro-isoaristeromycin (2a). Computational analysis indicates that the fluorine atom controlled the regioselectivity of the purine base substitution.
RESUMEN
A series of acyclic selenopurine nucleosides 3a-f and 4a-g were synthesized based on the bioisosteric rationale between oxygen and selenium, and then evaluated for antiviral activity. Among the compounds tested, seleno-acyclovir (4a) exhibited the most potent anti-herpes simplex virus (HSV)-1 (EC50 = 1.47 µM) and HSV-2 (EC50 = 6.34 µM) activities without cytotoxicity up to 100 µM, while 2,6-diaminopurine derivatives 4e-g exhibited significant anti-human cytomegalovirus (HCMV) activity, which is slightly more potent than the guanine derivative 4d, indicating that they might act as prodrugs of seleno-ganciclovir (4d).
Asunto(s)
Antivirales/síntesis química , Nucleósidos/síntesis química , Compuestos de Organoselenio/síntesis química , Purinas/síntesis química , 2-Aminopurina/análogos & derivados , 2-Aminopurina/síntesis química , 2-Aminopurina/farmacología , Aciclovir/análogos & derivados , Aciclovir/síntesis química , Aciclovir/farmacología , Antivirales/farmacología , Citomegalovirus/efectos de los fármacos , Guanina/análogos & derivados , Guanina/síntesis química , Guanina/farmacología , Herpesvirus Humano 1/efectos de los fármacos , Herpesvirus Humano 2/efectos de los fármacos , Humanos , Nucleósidos/farmacología , Compuestos de Organoselenio/farmacología , Profármacos/síntesis química , Profármacos/farmacología , Purinas/farmacología , Simplexvirus/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
A series of C8-substituted-4'-thioadenosine analogs 3a-3g, 15, and 17 and their truncated derivatives 4a-4j, 23-25, and 27 have been successfully synthesized from d-ribose and d-mannose, respectively, employing Pummerer type or Vorbrüggen condensation reactions and the functionalization at the C8-position of nucleobase via Stille coupling or nucleophilic aromatic substitution reactions as key steps. All the synthesized compounds were assayed for their HSP90 inhibitory activity, but they were found to be inactive up to 100µM. However, the 8-iodo derivatives 15, 17, and 27 exhibited potent anticancer activity, indicating that different mechanism of action might be involved in their biological activity.
Asunto(s)
Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Tionucleósidos/química , Tionucleósidos/farmacología , Espectroscopía de Resonancia Magnética con Carbono-13 , Línea Celular Tumoral , Diseño de Fármacos , Humanos , Espectroscopía de Protones por Resonancia Magnética , Espectrometría de Masa Bombardeada por Átomos Veloces , Tionucleósidos/síntesis químicaRESUMEN
Stereoselective synthesis of D-5-homo-4-selenoribose, serving as a versatile intermediate for the synthesis of 4'-selenonucleosides 12a-c, was accomplished using Sharpless asymmetric epoxidation, regioselective cleavage of the α,ß-epoxide, and stereoselective reduction of the ketone as the key steps.
Asunto(s)
Nucleósidos/síntesis química , Compuestos de Organoselenio/síntesis química , Compuestos Epoxi/química , Estructura Molecular , Nucleósidos/química , Compuestos de Organoselenio/química , EstereoisomerismoRESUMEN
BACKGROUND: 4'-seleno-homonucleosides were synthesized as next-generation nucleosides, and their cellular phosphorylation was studied to confirm the hypothesis that bulky selenium atom can sterically hinder the approach of cellular nucleoside kinase to the 5'-OH for phosphorylation. RESULTS: 4'-seleno-homonucleosides (n = 2), with one-carbon homologation, were synthesized through a tandem seleno-Michael addition-SN2 ring cyclization. LC-MS analysis demonstrated that they were phosphorylated by cellular nucleoside kinases, resulting in anticancer activity. CONCLUSION: The bulky selenium atom played a key role in deciding the phosphorylation by cellular nucleoside kinases. [Formula: see text].