- Synthesis and photophysical evaluation of new fluorescent 7-arylethynyl-7-deazaadenosine analogs
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Three new fluorescent 7-deaza-2′-deoxyadenosine analogs were synthesized via the Sonogashira cross-coupling reaction of 7-iodo-7-deaza-2′-deoxyadenosine with 1-ethynylpyrene, 2-ethynyl-6-methoxynaphthalene, and 9-ethynylphenanthrene. The spectral properties of these analogs were evaluated in dioxane, EtOH, and H2O to determine their potential for use as environmentally sensitive fluorescent probes. All three analogs displayed large solvatofluorochromicity in H2O, relative to their emission wavelengths in dioxane or EtOH. Moreover, all three analogs exhibited microenvironmental sensitivity of their fluorescence emission intensity, being moderate to high quantum yields in dioxane and EtOH and significantly lower in H2O. Various attempts to perform domino cross-coupling and annuation reactions on 7-deaza-7-alkynyladenine derivatives to form a new fused tricyclic adenine analog were unsuccessful.
- Matarazzo, Augusto,Brow, Justin,Hudson, Robert H.E.
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supporting information
p. 1093 - 1100
(2018/11/25)
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- Heterocyclic compound used as MNK inhibitor
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The invention relates to a heterocyclic compound, a pharmaceutical composition containing the heterocyclic compound, a preparation method thereof, and application thereof used as a mitogen activated protein kinase interacting kinase 1 and 2-MNK1/MNK2 inhibitor. The inhibitor is the heterocyclic compound as shown in the formula (I), or its pharmaceutically acceptable salt, prodrug, solvent compound, polycrystal, isomer, stable isotope derivative or a pharmaceutical composition containing the heterocyclic compound. The compound of the invention can be used for treating or preventing MNK-mediatedrelated diseases, such as cancers.
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Paragraph 0156; 0159
(2019/01/08)
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- Influence of the nucleobase and anchimeric assistance of the carboxyl acid groups in the hydrolysis of amino acid nucleoside phosphoramidates
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Nucleoside phosphoramidates (NPs) are a class of nucleotide analogues that has been developed as potential antiviral/antitumor prodrugs. Recently, we have shown that some amino acid nucleoside phosphoramidates (aaNPs) can act as substrates for viral polymerases like HIV-1 RT. Herein, we report the synthesis and hydrolysis of a series of new aaNPs, containing either natural or modified nucleobases to define the basis for their differential reactivity. Aqueous stability, kinetics, and hydrolysis pathways were studied by NMR spectroscopy at different solution pD values (5-7) and temperatures. It was observed that the kinetics and mechanism (P-N and/or P-O bond cleavage) of the hydrolysis reaction largely depend on the nature of the nucleobase and amino acid moieties. Aspartyl NPs were found to be more reactive than Gly or β-Ala NPs. For aspartyl NPs, the order of reactivity of the nucleobase was 1-deazaadenine>7- deazaadenine>adenine>thymine≥3-deazaadenine. Notably, neutral aqueous solutions of Asp-1-deaza-dAMP degraded spontaneously even at 4°C through exclusive P-O bond hydrolysis (a 50-fold reactivity difference for Asp-1-deaza-dAMP vs. Asp-3-deaza-dAMP at pD 5 and 70°C). Conformational studies by NMR spectroscopy and molecular modeling suggest the involvement of the protonated N3 atom in adenine and 1- and 7-deazaadenine in the intramolecular catalysis of the hydrolysis reaction through the rare syn conformation. Touching (nucleo)base: A dual intramolecular catalytic influence is demonstrated by the nucleobase and carboxyl groups in the chemical hydrolysis of amino acid nucleoside phosphoramidate prodrugs (see scheme). The replacement of the adenine N1 or N7 atoms instead of the N3 atom is shown to have a conformational role in which the protonated N3 is crucial in regulating the kinetics and mechanism of nucleotide (P-N pathway) versus nucleoside (P-O pathway) formation. Copyright
- Maiti, Munmun,Michielssens, Servaas,Dyubankova, Natalia,Maiti, Mohitosh,Lescrinier, Eveline,Ceulemans, Arnout,Herdewijn, Piet
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supporting information; experimental part
p. 857 - 868
(2012/03/26)
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- Synthesis and biological evaluation of 6,7-disubstituted 4-aminopyrido[2,3-d]pyrimidines as adenosine kinase inhibitors
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The synthesis and structure-activity relationship of a series of 6,7-disubstituted 4-aminopyrido[2,3-d]pyrimidines as novel non-nucleoside adenosine kinase inhibitors is described. A variety of substituents, primarily aryl, at the C6 and C7 positions of the pyridopyrimidine core were found to yield analogues that are potent inhibitors of adenosine kinase. In contrast to the 5,7-disubstituted and 5,6,7-trisubstituted pyridopyrimidine series, these analogues exhibited only modest potency to inhibit AK in intact cells.
- Perner, Richard J.,Lee, Chih-Hung,Jiang, Meiqun,Gu, Yu-Gui,DiDomenico, Stanley,Bayburt, Erol K.,Alexander, Karen M.,Kohlhaas, Kathy L.,Jarvis, Michael F.,Kowaluk, Elizabeth L.,Bhagwat, Shripad S.
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p. 2803 - 2807
(2007/10/03)
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- Discovery of 4-amino-5-(3-bromophenyl)-7-(6-morpholino-pyridin-3-yl)pyrido [2,3-d]pyrimidine, an orally active, non-nucleoside adenosine kinase inhibitor
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Adenosine (ADO) is an endogenous homeostatic inhibitory neuromodulator that reduces cellular excitability at sites of tissue injury and inflammation. Inhibition of adenosine kinase (AK), the primary metabolic enzyme for ADO, selectively increases ADO concentrations at sites of tissue trauma and enhances the analgesic and antiinflammatory actions of ADO. Optimization of the high-throughput screening lead, 4-amino-7-aryl-substituted pteridine (5) (AK IC50 = 440 nM), led to the identification of compound 21 (4-amino-5-(3-bromophenyl)-7-(6-morpholino-pyridin-3-yl)pyrido [2,3-d]pyrimidine, ABT-702), a novel, potent (AK IC50 = 1.7 nM) nonnucleoside AK inhibitor with oral activity in animal models of pain and inflammation.
- Lee,Jiang,Cowart,Gfesser,Perner,Ki Hwan Kim,Yu Gui Gu,Williams,Jarvis,Kowaluk,Stewart,Bhagwat
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p. 2133 - 2138
(2007/10/03)
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