Enantioselective Syntheses and Cytotoxicity of N,O-Nucleosides
04 Jul 2003-Journal of Medicinal Chemistry (American Chemical Society)-Vol. 46, Iss: 17, pp 3696-3702
TL;DR: (5'S)-5-Fluoro-1-isoxazolidin-5-yl-1H-pyrimidine-2,4-dione [(-)-AdFU], while showing low level of cytotoxicity, is a good inductor of apoptosis on lymphoid and monocytoid cells, acting as a strong potentiator of Fas-induced cell death.
Abstract: Enantiomers of 4‘-aza-2‘,3‘-dideoxynucleosides have been prepared by two different synthetic approaches, on the basis of 1,3-dipolar cycloaddition of a chiral nitrone. Cytotoxicity and apoptotic activity have been investigated. (5‘S)-5-Fluoro-1-isoxazolidin-5-yl-1H-pyrimidine-2,4-dione [(−)-AdFU], while showing low level of cytotoxicity, is a good inductor of apoptosis on lymphoid and monocytoid cells, acting as a strong potentiator of Fas-induced cell death.
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TL;DR: In this article, a review of asymmetric 1,3-dipolar cycloaddition reactions involving a variety of heteroylides (or ylide equivalents) and dipolarophiles is presented.
543 citations
TL;DR: This review aims to be a comprehensive and general summary of the different isoxazolidine syntheses, their use as starting building blocks for the preparation of natural compounds, and their main biological activities.
Abstract: The isoxazolidine ring represents one of the privileged structures in medicinal chemistry, and there have been an increasing number of studies on isoxazolidine and isoxazolidine-containing compounds. Optimization of the 1,3-dipolar cycloaddition (1,3-DC), original methods including electrophilic or palladium-mediated cyclization of unsaturated hydroxylamine, has been developed to obtain isoxazolidines. Novel reactions involving the isoxazolidine ring have been highlighted to accomplish total synthesis or to obtain bioactive compounds, one of the most significant examples being probably the thermic ring contraction applied to the total synthesis of (±)-Gelsemoxonine. The unique isoxazolidine scaffold also exhibits an impressive potential as a mimic of nucleosides, carbohydrates, PNA, amino acids, and steroid analogs. This review aims to be a comprehensive and general summary of the different isoxazolidine syntheses, their use as starting building blocks for the preparation of natural compounds, and their m...
176 citations
TL;DR: Azides, nitrones, and azomethine ylides are the most appropriate 1,3-dipoles for the synthesis of privileged structures with the highest biological responses against viruses.
Abstract: In the present perspective the advances and real possibilities of 1,3-dipolar cycloadditions as key steps in the total synthesis of virus inhibitors are described. Azides, nitrones, and azomethine ylides are the most appropriate 1,3-dipoles for the synthesis of privileged structures with the highest biological responses against viruses.
124 citations
TL;DR: Phosphonated carbocyclic 2'-oxa-3'-aza-nucleosides, while showing low levels of cytotoxicity, exert a specific inhibitor activity on two different reverse transcriptases, which is comparable with that of AZT, opening new perspectives on their possible use as therapeutic agents, in anti-retroviral and anti-HBV chemotherapy.
Abstract: Phosphonated carbocyclic 2'-oxa-3'-aza-nucleosides have been synthesized in good yields by 1,3-dipolar cycloaddition methodology. The cytotoxicity and the reverse transcriptase inhibitory activity of the obtained compounds have been investigated. Phosphonated carbocyclic 2'-oxa-3'-aza-nucleosides, while showing low levels of cytotoxicity, exert a specific inhibitor activity on two different reverse transcriptases, which is comparable with that of AZT, opening new perspectives on their possible use as therapeutic agents, in anti-retroviral and anti-HBV chemotherapy.
71 citations
TL;DR: In particular, compounds 7c and 7e show high levels of cytotoxicity on MOLT-3 leukemia cells; 7e exerts a remarkable enhancing activity on apoptosis caused by anti-fas antibody addition.
Abstract: Isoxazolidinyl polycyclic aromatic hydrocarbons (isoxazolidinyl-PAHs) have been synthesized in good yields by 1,3-dipolar cycloaddition methodology promoted by microwave irradiation. The structures of the obtained cycloadducts have been determined by NOE experiments and supported by computational studies at the AM1 level. The cytotoxicity and antiviral activity of the synthesized compounds have been investigated. In particular, compounds 7c and 7e show high levels of cytotoxicity on MOLT-3 leukemia cells; 7e exerts a remarkable enhancing activity on apoptosis caused by anti-fas antibody addition. Furthermore, compounds 7b and 8b exhibit specific antiviral effects against the Punta Toro virus.
67 citations
References
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TL;DR: The rationale behind current and future drug-based strategies for combating viral infections and the need for further refinement of antiviral drug design and development is described.
Abstract: A decade ago, just five drugs were licensed for the treatment of viral infections. Since then, greater understanding of viral life cycles, prompted in particular by the need to combat human immunodeficiency virus, has resulted in the discovery and validation of several targets for therapeutic intervention. Consequently, the current antiviral repertoire now includes more than 30 drugs. But we still lack effective therapies for several viral infections, and established treatments are not always effective or well tolerated, highlighting the need for further refinement of antiviral drug design and development. Here, I describe the rationale behind current and future drug-based strategies for combating viral infections.
565 citations
TL;DR: A highly reproducible, inexpensive, rapid, and easily accessible method of analysis has been developed for simultaneously detecting apoptosis and necro sis.
Abstract: Background:
Methods widely used to detect apoptosis do not allow us to easily distinguish between nuclei from viable or necrotic cells. Even if apoptosis and necrosis seem to occur as alternatives at the single cell level, they could be present simultaneously in a cell population much more frequently than expected. For this reason, attention was focused on attempting to recognize, by multiparameter flow cytometry, the characteristics of viable cells and of apoptotic or necrotic dead cells.
Methods:
Apoptosis and necrosis were induced in vitro in murine thymocytes and lymphocytes from adult peripheral blood by using dexamethasone or prostaglandin E2 treatment and heat shock at 60°C or hydrogen peroxide, respectively. Traditional methods, such as DNA gel electrophoresis and propidium iodide staining followed by single-fluorescence analysis or annexin-V–fluorescein isothiocyanate plus propidium iodide staining by using flow cytometry, were compared with a new method. This method consisted of combined light-scatter and red fluorescence analysis by flow cytometry after isolation of nuclei by hypotonic solution as well as high-dose detergent treatment and DNA staining with propidium iodide.
Results:
Results showed that, although traditional methods such as DNA-gel electrophoresis and single-parameter fluorescence flow cytometry analysis were unable, as expected, to discriminate among viability, apoptosis, and necrosis, our new method has enabled us to easily identify nuclei from viable, apoptotic, and necrotic cells. Results obtained by using our method were comparable to those obtained by using two-color analysis of cells after propidium iodide/annexin V staining.
Conclusions:
A highly reproducible, inexpensive, rapid, and easily accessible method of analysis has been developed for simultaneously detecting apoptosis and necrosis. Cytometry 35:145–153, 1999. © 1999 Wiley-Liss, Inc.
64 citations
TL;DR: It is demonstrated, that infection of monocytoid cells by Herpes simplex virus 2 (HSV-2) resulted, in time- and dose-dependent induction of apoptosis as an exclusive cytopathic effect, the phenomenon was confirmed using four different techniques.
Abstract: Increasing evidence indicates that apoptosis can be associated with several viral infections. Here we demonstrate, that infection of monocytoid cells by Herpes simplex virus 2 (HSV-2) resulted, in time- and dose-dependent induction of apoptosis as an exclusive cytopathic effect. The phenomenon was confirmed using four different techniques. Conversely, apoptosis was not observed in the Vero cell line. Virus yield in monocytoid cells was delayed and reduced, although well detectable, in comparison with that observed in Vero cells. Nevertheless, released virions exhibited full infecting capability. Apoptosis induced by HSV-2 was not inhibited by cycloheximide and only partially by an UV-treatment which completely abrogated infectivity. Virus-induced apoptosis was partly inhibited by indomethacin and was associated with a down-regulation of Bcl-2. A similar, but less pronounced, apoptosis-inducing effect in monocytoid cells was also observed with HSV-1 infection. Depending on the target cells, therefore, HSV could complete a cycle of infection which is characterized by apoptosis of infected cells.
45 citations
TL;DR: In this article, the title compounds were obtained by 1,3-dipolar cycloadditions of methylene nitrones, prepared in situ from suitably protected hydroxylamines, to 1- N -vinyl-thymine.
43 citations
TL;DR: In this article, a flexible synthetic procedure to access a new and biologically interesting class of N, O -psiconucleosides by 1,3-dipolar cycloaddition of C -ethoxycarbonyl- N -methyl nitrone with ethyl 2-(acetyloxy)acrylate, followed by Vorbruggen nucleosidation and sodium borohydride reduction, is described.
33 citations