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1.
J Org Chem ; 89(14): 10021-10026, 2024 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-38955329

RESUMO

Herein, we report a mild and general protocol for chemoselective deacetylation of mixed acetyl- and benzoyl-protected carbohydrates under mild acidic conditions. The protocol allows quick access to partially protected carbohydrates, which serve as versatile synthetic intermediates during the total synthesis of various mono- and oligosaccharide targets. The applicability of the developed protocol was successfully demonstrated on a range of carbohydrate substrates of various configurations and substitution patterns featuring functionalized aliphatic and aromatic aglycones. The protocol has shown excellent compatibility with the widely used O-anomeric protecting groups, prespacer aglycones, and thioglycoside glycosyl donors.

2.
ChemMedChem ; 18(11): e202300026, 2023 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-36998118

RESUMO

The development of novel photo-dynamic therapy (PDT) agents enabling to treat the oxygen-deficient tumors is the emerging tasks for the modern medicinal chemistry. Herein, we describe the design and preparation of water-soluble agents for PDT which generate active radical species upon light irradiation. Two conjugates of carbohydrates with 1,2,4,6-substituted-1,4-dihydro-1,2,4,5-tetrazin-3(2H)-ones (AlkVZs) demonstrated high oxygen-independent cytotoxicity on PC-3 and Jurkat cancer cells under light irradiation combining with low toxicity in the dark. The efficacy of prepared compounds was estimated using MTT and Alamar Blue tests as well as microscopic dead/live colored images and flow cytometry. The analysis of obtained results reveals the influence of sugar moiety on the activity of AlkVZs. We believe that obtained compounds have high potency as platform for design of new agents for photo-dynamic therapy.


Assuntos
Neoplasias , Fotoquimioterapia , Oxigênio , Fármacos Fotossensibilizantes/química , Luz , Neoplasias/tratamento farmacológico
3.
Sci Rep ; 9(1): 4872, 2019 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-30890744

RESUMO

Severe hypoxia leads to decline in cardiac contractility and induces arrhythmic events in part due to oxidative damage to cardiomyocyte proteins including ion transporters. This results in compromised handling of Ca2+ ions that trigger heart contractile machinery. Here, we demonstrate that thiol-containing compounds such as N-acetylcysteine (NAC), glutathione ethyl ester (et-GSH), oxidized tetraethylglutathione (tet-GSSG), oxidized glutathione (GSSG) and S-nitrosoglutathione (GSNO) are capable of reducing negative effects of hypoxia on isolated rat cardiomyocytes. Preincubation of cardiomyocytes with 0.1 mM GSNO, 0.5 mM et-GSH, GSSG, tet-GSSG or with 10 mM NAC allows cells 5-times longer tolerate the hypoxic conditions and elicit regular Ca2+ transients in response to electric pacing. The shape of Ca2+ transients generated in the presence of GSNO, et-GSH and NAC was similar to that observed in normoxic control cardiomyocytes. The leader compound, GSNO, accelerated by 34% the recovery of normal contractile function of isolated rat heart subjected to ischemia-reperfusion. GSNO increased glutathionylation of Na,K-ATPase alpha-2 subunit, the principal ion-transporter of cardiac myocyte sarcolemma, which prevents irreversible oxidation of Na,K-ATPase and regulates its function to support normal Ca2+ ion handling in hypoxic cardiomyocytes. Altogether, GSNO appears effective cardioprotector in hypoxic conditions worth further studies toward its cardiovascular application.


Assuntos
Arritmias Cardíacas/tratamento farmacológico , Hipóxia Celular/efeitos dos fármacos , Contração Miocárdica/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Animais , Arritmias Cardíacas/patologia , Sinalização do Cálcio/efeitos dos fármacos , Estimulação Elétrica , Glutationa/análogos & derivados , Glutationa/farmacologia , Dissulfeto de Glutationa/farmacologia , Coração/efeitos dos fármacos , Coração/fisiopatologia , Humanos , Contração Muscular/efeitos dos fármacos , Contração Miocárdica/fisiologia , Técnicas de Cultura de Órgãos , Oxigênio/metabolismo , Ratos , S-Nitrosoglutationa/farmacologia , Compostos de Sulfidrila/farmacologia
4.
Oxid Med Cell Longev ; 2017: 9456163, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28421129

RESUMO

Background. Nitric oxide can successfully compete with oxygen for sites of electron-transport chain in conditions of myocardial hypoxia. These features may prevent excessive oxidative stress occurring in cardiomyocytes during sudden hypoxia-reoxygenation. Aim. To study the action of the potent stable NO donor dinitrosyl iron complex with glutathione (Oxacom®) on the recovery of myocardial contractile function and Ca2+ transients in cardiomyocytes during hypoxia-reoxygenation. Results. The isolated rat hearts were subjected to 30 min hypoxia followed by 30 min reoxygenation. The presence of 30 nM Oxacom in hypoxic perfusate reduced myocardial contracture and improved recovery of left ventricular developed pressure partly due to elimination of cardiac arrhythmias. The same Oxacom concentration limited reactive oxygen species generation in hypoxic cardiomyocytes and increased the viability of isolated cardiomyocytes during hypoxia from 12 to 52% and after reoxygenation from 0 to 40%. Oxacom prevented hypoxia-induced elevation of diastolic Ca2+ level and eliminated Ca2+ transport alterations manifested by slow Ca2+ removal from the sarcoplasm and delay in cardiomyocyte relaxation. Conclusion. The potent stable NO donor preserved cardiomyocyte integrity and improved functional recovery at hypoxia-reoxygenation both in the isolated heart and in cardiomyocytes mainly due to preservation of Ca2+ transport. Oxacom demonstrates potential for cardioprotection during hypoxia-reoxygenation.


Assuntos
Coração/efeitos dos fármacos , Ferro/farmacologia , Miocárdio/metabolismo , Óxidos de Nitrogênio/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Animais , Cálcio/metabolismo , Hipóxia Celular , Células Cultivadas , Glutationa/metabolismo , Masculino , Miocárdio/patologia , Miócitos Cardíacos/citologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo
5.
Nitric Oxide ; 26(3): 148-56, 2012 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-22326933

RESUMO

A comparative study of hypotensive effects of binuclear forms of dinitrosyl iron complexes (DNICs) with glutathione, S-nitrosoglutathione (GS-NO) and sodium nitrite (NaNO(2)) on rats has been carried out. The latter appeared to be the least efficient, viz., mean arterial pressure (MAP) decreased by 10 and 30 mmHg at 25 and 100 µmoles/kg of NaNO(2). In contrast, DNIC and GS-NO produced an appreciable hypotensive effect when used at much lower concentrations. GS-NO reduced MAP to the same extent, viz., to 90 mmHg, on a hundredfold dose scale (from 0.4 up to 50 µmoles/kg) with subsequent restoration of MAP within the next 6-15 min. A similar effect was observed for DNIC except that the amplitude of the MAP drop was lower and the duration of hypotension was essentially greater. DNIC with glutathione were selected as a basic material for pilot-scale production of a hypotensive drug (commercial name Oxacom®). Preliminary pharmacological testing of Oxacom did not establish any adverse or deleterious side effects. Clinical trials of Oxacom® were performed on 14 healthy male volunteers in whom single intravenous infusion of the drug (5mg/kg or 0.2 µmoles/kg of DNIC, respectively) evoked a characteristic response manifested as a 3-4 min drop by 24-27 mmHg of both diastolic and systolic AP with its subsequent slow restoration within the next 8-10h. The heart rate was quickly normalized after an initial increase. Cardiac output was unchanged despite reduced cardiac filling. A comprehensive analysis of clinical and biochemical data failed to establish any significant pathological changes in these parameters. The data obtained suggest that Oxacom® can be recommended for the second phase of clinical trials.


Assuntos
Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/toxicidade , Pressão Sanguínea/efeitos dos fármacos , Compostos Ferrosos/farmacologia , Glutationa/análogos & derivados , Adulto , Animais , Anti-Hipertensivos/efeitos adversos , Anti-Hipertensivos/sangue , Débito Cardíaco/efeitos dos fármacos , Embrião de Mamíferos/efeitos dos fármacos , Feminino , Compostos Ferrosos/efeitos adversos , Compostos Ferrosos/sangue , Compostos Ferrosos/toxicidade , Glutationa/efeitos adversos , Glutationa/sangue , Glutationa/farmacologia , Glutationa/toxicidade , Hemostasia/efeitos dos fármacos , Hormônios/sangue , Humanos , Masculino , Adesividade Plaquetária/efeitos dos fármacos , Gravidez , Ratos , Ratos Wistar , Testes de Toxicidade
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