- 6-Isobutyrylaminopurine: A convenient building block for the synthesis of carbocyclic adenosine analogs
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Readily available 6-isobutyrylaminopurine can replace either a primary or secondary OH group under Mitsunobu conditions and provide an efficient synthesis of carbocyclic analogs of adenosine. X-ray data indicates that only the desired N9-substituted derivatives of adenine are formed.
- Zhou, Jingian,Bouhadir, Kamal,Webb, Thomas R.,Shevlin, Philip B.
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- Supramolecular copolymer micelles based on the complementary multiple hydrogen bonds of nucleobases for drug delivery
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Novel supramolecular copolymer micelles with stimuli-responsive abilities were successfully prepared through the complementary multiple hydrogen bonds of nucleobases and then applied for rapid intracellular release of drugs. First, both adenine-terminated poly(-caprolactone) (PCL-A) and uracil-terminated poly(ethylene glycol) (PEG-U) were synthesized. The supramolecular amphiphilic block copolymers (PCL-A:U-PEG) were formed based on multiple hydrogen bonding interactions between PCL-A and PEG-U. The micelles self-assembled from PCL-A:U-PEG were sufficiently stable in water but prone to fast aggregation in acidic condition due to the dynamic and sensitive nature of noncovalent interactions. The low cytotoxicity of supramolecular copolymer micelles was confirmed by MTT assay against NIH/3T3 normal cells. As a hydrophobic anticancer model drug, doxorubicin (DOX) was encapsulated into these supramolecular copolymer micelles. In vitro release studies demonstrated that the release of DOX from micelles was significantly faster at mildly acid pH of 5.0 compared to physiological pH. MTT assay against HeLa cancer cells showed DOX-loaded micelles had high anticancer efficacy. Hence, these supramolecular copolymer micelles based on the complementary multiple hydrogen bonds of nucleobases are very promising candidates for rapid controlled release of drugs.
- Wang, Dali,Su, Yue,Jin, Chengyu,Zhu, Bangshang,Pang, Yan,Zhu, Lijuan,Liu, Jinyao,Tu, Chunlai,Yan, Deyue,Zhu, Xinyuan
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- Synthesis and assembly behavior of heteronucleobase-functionalized poly(ε-caprolactone)
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The heteronucleobase (adenine and uracil)-functionalized poly(ε-caprolactone) (A-PCL-U) possessing supramolecular structure has been successfully synthesized through the combination of ringopening polymerization and Michael addition reaction. Attachment of multiple hydrogen-bonding units to chain ends of PCL results in phase separation and substantial increase in the viscosity. The association constant (Ka) between adenine and uracil groups of A-PCL-U calculated from NMR measurement is 18.9 M-1. XRD and DSC analyses indicate that the crystalline structure of the A-PCL-U is changed to some extent due to phase segregation as compared to the PCL homopolymer. The AFM micrograph demonstrates that phase segregation is formed from the hard nucleobase chain ends and the soft poly(ε-caprolactone) chains of the supramolecular complex.
- Lin, I.-Hong,Cheng, Chih-Chia,Yen, Ying-Chieh,Chang, Feng-Chih
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Read Online
- An improved synthesis of adefovir and related analogues
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An improved synthesis of the antiviral drug adefovir is presented. Problems associated with current routes to adefovir include capricious yields and a reliance on problematic reagents and solvents, such as magnesium tert-butoxide and DMF, to achieve high conversions to the target. A systematic study within our laboratory led to the identification of an iodide reagent which affords higher yields than previous approaches and allows for reactions to be conducted up to 10 g in scale under milder conditions. The use of a novel tetrabutylammonium salt of adenine facilitates alkylations in solvents other than DMF. Additionally, we have investigated how regioselectivity is affected by the substitution pattern of the nucleobase. Finally, this chemistry was successfully applied to the synthesis of several new adefovir analogues, highlighting the versatility of our approach.
- Jones, David J.,O’Leary, Eileen M.,O’Sullivan, Timothy P.
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supporting information
p. 801 - 810
(2019/04/17)
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- Preparation method of adefovir dipivoxil crystals
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The invention belongs to the technical field of drug preparation and in particular relates to a preparation method of adefovir dipivoxil crystals. The preparation method comprises the following steps: synthesizing diethyl phosphite; synthesizing diethyl (p-phenylsulfonyloxy)methylphosphonate; synthesizing 9-(2-hydroxyethyl) adenine; synthesizing 4,9-[2-(diethylphosphonomethoxy)ethyl]adenine; synthesizing adefovir; synthesizing adefovir dipivoxil. Compared with the prior art, the preparation method of the adefovir dipivoxil crystals, provided by the invention, takes acetonitrile as a water-soluble organic medium, and the difficulty that DMF (Dimethyl Formamide) is difficult to remove is overcome; ethyl acetate is used for replacing isopropyl acetate in a previous process, isopropyl ether is used for replacing ethyl ether and ethanol is used for replacing acetone; the preparation method is simple to operate; the obtained product has good purity and high yield; the industrialized production is easy to realize and the production cost is reduced.
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Paragraph 0020-0021
(2017/07/21)
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- Adefovir dipivoxil a hydrate and its preparation method (by machine translation)
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Adefovir dipivoxil this invention relates to a method for preparing a hydrate thereof, with an aqueous acetone as the solvent, can be obtained by the freeze-drying of a water composition of adefovir dipivoxil freeze-dried powder. The method is simple and convenient to operate, can selectively obtain a hydrate, high product yield, purity is good, is very suitable for large-scale production. (by machine translation)
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Paragraph 0026-0028
(2017/02/09)
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- Hg2+ detecting aggregation-induced emission type fluorescent sensor and production method and application thereof
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The invention discloses an Hg2+ detecting aggregation-induced emission type fluorescent sensor and a production method and application thereof. The structural formula of the fluorescent sensor is as shown in specification. The fluorescent sensor is of aggregation-induced emission property and is nonluminous in solution, and its fluorescent light is enhanced in an aggregation state, accordingly, the fluorescent sensor can be applied to recognition of highly specific selectivity and anti-interference performance of Hg2+. Besides, the fluorescent sensor has high biocompatibility and cellular permeability, can target mitochondria in cells and light the Hg2+ in mitochondria by fluorescent light, and accordingly can realize detection of Hg2+ in the mitochondria.
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Paragraph 0009; 0036
(2017/06/22)
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- 8-(2-Furyl)adenine derivatives as A2A adenosine receptor ligands
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Selective adenosine receptor modulators are potential tools for numerous therapeutic applications, including cardiovascular, inflammatory, and neurodegenerative diseases. In this work, the synthesis and biological evaluation at the four human adenosine receptor subtypes of a series of 9-substituted 8-(2-furyl)adenine derivatives are reported. Results show that 8-(2-furyl)-9-methyladenine is endowed with high affinity at the A2A subtype. Further modification of this compound with introduction of arylacetyl or arylcarbamoyl groups in N6-position takes to different effects on the A2A affinity and in particular on the selectivity versus the other three adenosine receptor subtypes. A molecular modelling analysis at three different A2A receptor crystal structures provides an interpretation of the obtained biological results.
- Dal Ben, Diego,Buccioni, Michela,Lambertucci, Catia,Thomas, Ajiroghene,Klotz, Karl-Norbert,Federico, Stephanie,Cacciari, Barbara,Spalluto, Giampiero,Volpini, Rosaria
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p. 525 - 535
(2013/11/19)
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- Ester prodrugs of acyclic nucleoside thiophosphonates compared to phosphonates: Synthesis, antiviral activity and decomposition study
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9-[2-(Thiophosphonomethoxy)ethyl]adenine [S-PMEA, 8] and (R)-9-[2-(Thiophosphonomethoxy)propyl]adenine [S-PMPA, 9] are acyclic nucleoside thiophosphonates we described recently that display the same antiviral spectrum (DNA viruses) as approved and potent phosphonates PMEA and (R)-PMPA. Here, we describe the synthesis, antiviral activities in infected cell cultures and decomposition study of bis(pivaloyloxymethoxy)-S-PMEA [Bis-POM-S-PMEA, 13] and bis(isopropyloxymethylcarbonyl)-S-PMPA [Bis-POC-S-PMPA, 14] as orally bioavailable prodrugs of the S-PMEA 8 and S-PMPA 9, in comparison to the equivalent "non-thio" derivatives [Bis-POM-PMEA, 11] and [Bis-POC-PMPA, 12]. Compounds 11, 12, 13 and 14 were evaluated for their in vitro antiviral activity against HIV-1-, HIV-2-, HBV- and a broad panel of DNA viruses, and found to exhibit moderate to potent antiviral activity. In order to determine the decomposition pathway of the prodrugs 11, 12, 13 and 14 into parent compounds PMEA, PMPA, 8 and 9, kinetic data and decomposition pathways in several media are presented. As expected, bis-POM-S-PMEA 13 and bis-POC-S-PMPA 14 behaved as prodrugs of S-PMEA 8 and S-PMPA 9. However, thiophosphonates 8 and 9 were released very smoothly in cell extracts, in contrast to the release of PMEA and PMPA from "non-thio" prodrugs 11 and 12.
- Roux, Lo?c,Priet, Stéphane,Payrot, Nadine,Weck, Clément,Fournier, Ma?lenn,Zoulim, Fabien,Balzarini, Jan,Canard, Bruno,Alvarez, Karine
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p. 869 - 881
(2013/07/27)
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- Synthesis, cyclopolymerization and cyclo-copolymerization of 9-(2-Diallylaminoethyl)adenine and Its Hydrochloride Salt
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We report herein the synthesis and characterization of 9-(2- diallylaminoethyl) adenine. We evaluated two different synthetic routes starting with adenine where the optimal route was achieved through coupling of 9-(2-chloroethyl)adenine with diallylamine.
- Bouhadir, Kamal H.,Abramian, Lara,Ezzeddine, Alaa,Usher, Karyn,Vladimirov, Nikolay
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p. 13290 - 13306
(2013/02/22)
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- Synthesis of branched 9-[2-(2-phosphonoethoxy)ethyl]purines as a new class of acyclic nucleoside phosphonates which inhibit Plasmodium falciparum hypoxanthine-guanine-xanthine phosphoribosyltransferase
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The malarial parasite Plasmodium falciparum (Pf) lacks the de novo pathway and relies on the salvage enzyme, hypoxanthine-guanine-xanthine phosphoribosyltransferase (HGXPRT), for the synthesis of the 6-oxopurine nucleoside monophosphates. Specific acyclic
- Hockova, Dana,Holy, Antonin,Masojidkova, Milena,Keough, Dianne T.,Jersey, John de,Guddat, Luke W.
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body text
p. 6218 - 6232
(2011/02/26)
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- 8-Bromo-9-alkyl adenine derivatives as tools for developing new adenosine A2A and A2B receptors ligands
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Importance of making available selective adenosine receptor antagonists is boosted by recent findings of adenosine involvement in many CNS dysfunctions. In the present work a series of 8-bromo-9-alkyl adenines are prepared and fully characterized in radio
- Lambertucci, Catia,Antonini, Ippolito,Buccioni, Michela,Dal Ben, Diego,Kachare, Dhuldeo D.,Volpini, Rosaria,Klotz, Karl-Norbert,Cristalli, Gloria
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experimental part
p. 2812 - 2822
(2009/09/08)
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- NOVEL NUCLEOTIDE ANALOGUES AS PERCURSOR MOLECULES FOR ANTIVIRALS
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This invention relates to a purine or pyrimidine phosphonate compound of formula (I) or pharmaceutically acceptable salt thereof; wherein B, X, and R1-R3 are as defined in classes and subclasses herein. These compounds may be used as antiviral precursors. The invention also relates to therapeutic compositions of these compounds and their use for the preparation of a medication for treating and/or preventing a viral infection in a patient. The invention also provides methods for making these compounds. In particular, the invention provides an H- phosphinate precursor intermediate of formula (II) wherein B is a purine or pyrimidine base as defined herein and R1 is selected from the group comprising a hydrogen atom, and a methyl, ethyl, hydroxymethyl, hydroxyethyl and C1-6haloalkyl group.
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Page/Page column 69; 71
(2008/12/05)
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- Two simple protocols for the preparation of diallylaminoethyl-substituted nucleic bases: A comparison
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The syntheses of pyrimidine and purine nucleic bases substituted with diallylaminoethyl groups are reported following two different protocols. A comparison is made between the yield, expense, and difficulty of each route.
- Shatila, Rania S.,Bouhadir, Kamal H.
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p. 1767 - 1770
(2007/10/03)
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- Synthesis, in vitro antiviral evaluation, and stability studies of novel α-borano-nucleotide analogues of 9-[2-(phosphonomethoxy)ethyl]adenine and (R)-9-[2-(phosphonomethoxy)propyl]adenine
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We describe here the synthesis of 9-[2-(Boranophosphonomethoxy)ethyl] adenine (6a) and (R)-9-[2-(Boranophosphonomethoxy)propyl]adenine (6b), the first α-boranophosphonate nucleosides in which a borane (BH3) group substitutes one nonbridging oxygen atom of the α-phosphonate moiety. H-phosphinates 5a and 5b and α-boranophosphonates 6a and 6b were evaluated for their in vitro activity against human immunodeficiency virus (HIV) infected cells and against a panel of DNA or RNA viruses. Compounds 5a, 5b, 6a, and 6b exhibited no significant antiviral activity in vitro and cytotoxicity. To measure the chemical and enzymatic stabilities of the target compounds 6a and 6b, kinetic data of decomposition for derivatives 5a, 5b, 6a, 6b, and standard compounds were studied at 37 °C in several media. The α- Boranophosphonates 6a and 6b were metabolized in culture medium into H-phosphinates 5a and 5b, with half-live values of 5.3 h for 6a and 1.3 h for 6b.
- Barral, Karine,Priet, Stéphane,Sire, Joséphine,Neyts, Johan,Balzarini, Jan,Canard, Bruno,Alvarez, Karine
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p. 7799 - 7806
(2008/02/02)
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- Prodrugs of phosphonate nucleotide analogues and methods for selecting and making same
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A novel method is provided for screening prodrugs of methoxyphosphonate nucleotide analogues to identify prodrugs selectively targeting desired tissues with antiviral or antitumor activity. This method has led to the identification of novel mixed ester-amidates of PMPA for retroviral or hepadnaviral therapy, including compounds of structure (5a) having substituent groups as defined herein. Compositions of these novel compounds in pharmaceutically acceptable excipients and their use in therapy and prophylaxis are provided. Also provided is an improved method for the use of magnesium alkoxide for the preparation of starting materials and compounds for use herein.
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- IMPROVED SYNTHESIS FOR HYDROXYALKYLATED HETEROCYCLIC BASES
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A hydroxyalkylated heterocyclic base is prepared by reacting a heterocyclic base with an alkylene carbonate in dimethylacetamide as a solvent, wherein the hydroxyalkylated heterocyclic base is isolated from the solvent using isopropanol or tert-butylmethylether.
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- Process for preparation of cyclic prodrugs of PMEA and PMPA
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The method of preparing compounds of Formula I is described: wherein: M and V are cis to one another and MPO3H2 is a phosphonic acid selected from the group consisting of 9-(2-phosphonylmethoxyethyl)adenine, and (R)-9-(2-phosphonylmethoxypropyl)adenine; wherein V is phenyl, optionally substituted with 1-2 substituents selected from a group consisting of fluoro, chloro, and bromo; comprising: coupling a chiral 1-phenylpropane-1,3-diol, wherein the phenyl may be optionally substituted, with MPOCl2 or an N-6 substituted analogue thereof. Additionally, methods and salt forms are described that enable isolation and purification of the desired isomer.
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- 9-(2-Aryloxyethyl) derivatives of adenine - A new class of non-nucleosidic antiviral agents
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New 9-(aryloxyalkyl) derivatives of adenine have been prepared by alkylation of adenine with tosylates, bromides, and α-chloro ethers containing terminal aromatic fragments in anhydrous DMF in the presence of potassium carbonate. The compounds of the 9-(2-phenoxyethyl)adenine series appear to be highly reactive against cytomegaloviruses of mankind in vitro, while derivatives of 9-(2-benzyloxyethyl)adenine demonstrate anti-HIV-1 activity. Compounds with shorter or longer chains, and also compounds which do not have aromatic fragments at the ends of the chains, do not possess antiviral activity.
- Petrov,Ozerov,Novikov,Pannecouque,Balzarini,De Clercq
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p. 1218 - 1226
(2007/10/03)
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- Synthesis and uptake of nitric oxide-releasing drugs by the P2 nucleoside transporter in trypanosoma equiperdum
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A series of S-nitrosothiols, structurally related to the NO-donor S-nitroso-N-acetylpenicillamine, and of organic nitrate esters that contain amidine groups which specify a recognition via the trypanosomal purine transporter P2, were synthesized and tested for their ability to inhibit the uptake of [2-3H]adenosine on Trypanosoma equiperdum. (C) 2000 Elsevier Science Ltd. All rights reserved.
- Soulere, Laurent,Hoffmann, Pascal,Bringaud, Frederic,Perie, Jacques
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p. 1347 - 1350
(2007/10/03)
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- Molecular Imprinting of Carboxylic Acids Employing Novel Functional Macroporous Polymers
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Imprinted network polymers incorporating basic functional groups were developed to assess the binding and specificity of carboxylic acids. The binding affinities were determined using t-BOC-phenylalanine and 2-phenylbutyric acid as templates and substrates. Chiral selectivity for the enantiomers of t-BOC-phenylalanine was found for polymers incorporating adenine or 2-aminopyridine functionality. Chiral selectivity in the case of (R)-(-)-2-phenylbutyric acid was found for the polymer utilizing N-(2-aminoethyl) methacrylamide as the functional monomer. Optimization of binding was achieved by changing polymerization conditions (thermal versus photochemical polymerization, monomer:template ratio) for t-BOC-phenylalanine imprinted polymers employing the N-(2-aminopyridine) methacrylamide monomer.
- Spivak, David,Shea, Kenneth J.
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p. 4627 - 4634
(2007/10/03)
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- N6,9-Disubstituted Adenines: Potent, Selective Antagonists at the A1 Adenosine Receptor
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N6-Substituted 9-methyladenines are potent antagonists of the activation of A1 adenosine receptors.The present study assessed the effect of N6 and N-9-substituents on the binding of adenines to the A1 and A2 receptors, respectively, of rat brain cortex and striatum and also on the antagonism of the A2 receptor mediated stimulation of the adenylate cyclase of PC12 cells by N-ethyladenosine-5'-uronamide.The potency ranking of 9-substituted adenines varied directly with the hydrophobicity of the substituent: cyclopentyl > phenyl > tetrahydrofuryl > ethyl > methyl > 2-hydroxyethyl.The 9-substituted adenines showed little selectivity for either receptor and the R enantiomer of N6-(1-phenyl-2-propyl)-9-methyladenine was only 4-fold more potent than the S enantiomer at the A1 receptor.An N6-cyclopentyl substituent increased potency at the A1 receptor and decreased potency at the A2 receptor, resulting in selectivity for the A1 receptor of up to 39-fold.The N6-cyclopentyl group completely overshadowed the effect of the hydrophobicity of the 9-substituent.A 2-chloro substituent did not alter the potency of an N6-substituted 9-methyladenine.
- Thompson, Robert D.,Secunda, Sherrie,Daly, John W.,Olsson, Ray A.
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p. 2877 - 2882
(2007/10/02)
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- Synthesis and biological evaluation of ATP analogues acting at putative purinergic P2X-receptors (on the guinea pig bladder)
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This paper describes studies carried out on a series of ATP analogues on the guinea pig bladder, a tissue reported to possess purinergic P2X-receptors.Optimisation of the pharmacological experimental technique enabled reproducible responses to ATP to be obtained in the 0.2-100 μM concentration range and the potencies of ATP analogues relative to ATP to be accurately determined.Alterations of the three main parts of the ATP molecule, i.e., the triphosphate, ribose and base, suggest that the triphosphate group is responsible for the efficacy of the agonist, whereas the ribose and adenine moieties are associated with affinity. quantitative analysis / ATP / purinergic / P2X-receptors / guinea pig bladder
- Howson, William,Taylor, Edwin Michael,Parsons, Michael Edward,Novelli, Riccardo,Wilczynska, Maria Aleksandra,Harris, Deborah Tracy
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p. 433 - 440
(2007/10/02)
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- 9-(AMINOALKYL)-8-HYDROXYADENINES: PREPARATION, MECHANISM OF FORMATION AND USE IN AFFINITY CHROMATOGRAPHY OF S-ADENOSYL-L-HOMOCYSTEINE HYDROLASE
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Bromine reacts with 9-(2-hydroxyethyl)- (Va), 9-(3-hydroxypropyl)- (Vb), 9-(2-hydroxypropyl)- (Vc), 9-(2,3-dihydroxypropyl)- (Vd), 9-(1,3-dihydroxy-2-propyl)- (Ve), 9-threo-(2,3-dihydroxybutyl)- (Vf) and 9-threo-(2,3,4-trihydroxybutyl)adenine (Vg) to give
- Holy, Antonin,Kohoutova, Jitka,Merta, Ales,Votruba, Ivan
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p. 459 - 477
(2007/10/02)
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