- Benzimidazole derivative BI292 as well as preparation method and application thereof
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The invention discloses a benzimidazole derivative BI292 and a preparation method thereof, and the benzimidazole derivative BI292 is chemically named as 1-[(2R, 4S, 5R)-4-hydroxy-5-(hydroxymethyl) tetrahydrofuran-2-yl]-1H-benzo [d] imidazole-4-carboxylic acid methyl ester. The benzimidazole derivative and the pharmaceutically acceptable salt, the solvate and the hydrate of the benzimidazole derivative have excellent in-vivo and in-vitro anti-tumor activity on MCF-7, SK-BR-3, HCT 116, U-118 MG, U-87 MG and MDA-MB-468, and have a relatively good application prospect in preparation of anti-tumor drugs.
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Paragraph 0019; 0021-0024
(2021/06/09)
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- Benzimidazole derivative BI305 and preparation method and application thereof
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The invention discloses a benzimidazole derivative BI305 and a preparation method thereof, and the chemical name of the benzimidazole derivative BI305 is 1-[tetrahydro-4-hydroxy-5-(hydroxymethyl) furan-2-yl]-N, N-dimethyl-1H-benzo [d] imidazole-4-formamide. The benzimidazole derivative and the pharmaceutically acceptable salt, solvate and hydrate thereof have excellent anti-tumor in-vivo and in-vitro activity on MCF-7, SK-BR-3, HCT 116, U-118 MG, U-87 MG and MDA-MB-468, and have a good application prospect in preparation of anti-tumor drugs.
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Paragraph 0020; 0022-0024
(2021/02/13)
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- SOLID STATE FORMS OF 5-CHLORO-6-[(2-IMINOPYRROLIDIN-1-YL)METHYL]PYRIMIDINE-2,4-(1H,3H)-DIONE HYDROCHLORIDE AND THEIR PROCESSES FOR THE PREPARATION THEREOF
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The present invention relates to solid state forms of 5-chloro-6-[(2-iminopyrrolidin-1-yl)methyl]pyrimidine-2,4-(1H,3H)-dione hydrochloride compound of formula-1a and their processes for the preparation thereof and an improved process for the preparation of 5-chloro-6-[(2-iminopyrrolidin-1-yl)methyl]pyrimidine-2,4-(1H,3H)-dione hydrochloride. The present inventors also provides an amorphous polymorph of the combination drug consisting of 2'-deoxy-5-(trifluoromethyl) uridine and 5-chloro-6-[(2-iminopyrrolidin-1-yl)methyl]pyrimidine-2,4-(1H,3H)-dione monohydrochloride and its process for the preparation.
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- Synthesis method of desicitabine intermediate alpha-substituted deoxyribose
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The invention provides a synthesis method of desicitabine intermediate alpha-substituted deoxyribose. The synthesis route is as follows: R refers to p-methyl benzoyl and X refers to chlorine atomin according to the formula 3 and the formula I. The synthesis method includes the following steps: 1) methylation reaction: a compound of formula 1 is reacted with methyl alcohol under acid catalysis to obtain a compound of the formula 2; 2) acylation reaction: the compound of the formula 2 is dissolved in an organic solvent and reacted with p-methyl benzoyl chloride under alkali catalysis to obtain acompound of the formula 3; 3) chlorination reaction: acetyl chloride is used to adjust the pH value of the acylation reaction solution at low temperature, the acylation reaction solution is filtered,is added with a low polar solvent A, and then is added with acetic acid solution of hydrogen chloride to react to obtain a compound of formula I. The synthesis method uses p-methyl benzoyl as a protective group in the process of synthesizing dicitabine key intermediate to substitute for deoxyribose, and controls the chlorination reaction conditions to obtain high purity alpha-substituted deoxyribose, the high purity alpha-substituted deoxyribose is conducive to coupling with silylation-protected 5-azacytidine to obtain high proportion of beta / alpha, and the dicitabine yield rate is increased.
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- Preparation of pyridine-stretched 2′-deoxyhypoxanthosine phosphoramidite
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Pyridine-stretched 2-deoxyhypoxanthosine (strH) phosphoramidite was prepared in eight steps from Hoffer's sugar (2-deoxy-3,5-di-O-(p-toluoyl)-a-D-erythro-pentofuranosyl chloride). Improved synthesis of the Hoffer sugar was achieved without need for distillation or chromatographic separation of intermediates, or use of gaseous HCl. Conditions were optimised to provide a key nitrile intermediate for the preparation of strH whereby the cesium salt of 4(5)-nitroimidazole was glycosylated using Hoffer's sugar. The nitrile intermediate was also used to prepare pyridine-stretched 2-deoxyadenosine (strA) and pyridine-stretched 2-deoxy-2,6-diaminonebulamine (strD). Preliminary studies indicate that strH forms a stronger, size-expanded base pair with adenine compared with the Watson-Crick thymine-adenine base pair.
- Clayton, Russell,Davis, Michael L.,Li, Wei,Fraser, William,Ramsden, Christopher A.
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- Regioselective and stereoselective route to N2-β-tetrazolyl unnatural nucleosides via SN2 reaction at the anomeric center of Hoffer's chlorosugar
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We are reporting a regioselective and stereoselective route to N2-β-tetrazolyl aromatic donor/acceptor unnatural nucleosides as new class of possible DNA base analogs. The SN2 substitution reaction at the anomeric center of Hoffer's chlorosugar with various 5-substituted aromatic tetrazoles in THF in presence of K2CO3 proceeds with regioselectivity at N2-tetrazoles and stereoselectivity at α-chlorosugar with very good yield. The stereoelectronic and steric effects play a crucial role for the observed outcome which is also supported from a theoretical (DFT) study. The methodology is simple, eco-compatible and the tetrazolyl unnatural nucleosides might find applications in decorating DNA for various biotechnological and DNA based material science applications.
- Bag, Subhendu Sekhar,Talukdar, Sangita,Anjali
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p. 2044 - 2050
(2016/04/05)
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- 4'-SUBSTITUTED NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS
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Provided is 4'-substituted nucleoside derivatives of Formula I and their use in the inhibition of HIV reverse transcriptase, the prophylaxis of infection by HIV, the treatment of infection by HIV, and the prophylaxis, treatment, and delay in the onset or progression of AIDS and/or ARC.
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- Triazolyl donor/acceptor chromophore decorated unnatural nucleosides and oligonucleotides with duplex stability comparable to that of a natural adenine/thymine pair
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We report the design and synthesis of triazolyl donor/acceptor unnatural nucleosides via click chemistry and studies on the duplex stabilization of DNA containing two such new nucleosides. The observed duplex stabilization among the self-pair/heteropair has been found to be comparable to that of a natural A/T pair. Our observations on the comparable duplex stabilization has been explained on the basis of possible π-π stacking and/or charge transfer interactions between the pairing partners. The evidence of ground-state charge transfer complexation came from the UV-vis spectra and the static quenching of fluorescence in a heteropair. We have also exploited one of our unnatural DNAs in stabilizing abasic DNA.
- Bag, Subhendu Sekhar,Talukdar, Sangita,Matsumoto, Katsuhiko,Kundu, Rajen
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p. 278 - 291
(2013/02/25)
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- Quadracyclic adenine: A non-perturbing fluorescent adenine analogue
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Fluorescent-base analogues (FBAs) comprise a group of increasingly important molecules for the investigation of nucleic acid structure and dynamics as well as of interactions between nucleic acids and other molecules. Here, we report on the synthesis, detailed spectroscopic characterisation and base-pairing properties of a new environment-sensitive fluorescent adenine analogue, quadracyclic adenine (qA). After developing an efficient route of synthesis for the phosphoramidite of qA it was incorporated into DNA in high yield by using standard solid-phase synthesis procedures. In DNA qA serves as an adenine analogue that preserves the B-form and, in contrast to most currently available FBAs, maintains or even increases the stability of the duplex. We demonstrate that, unlike fluorescent adenine analogues, such as the most commonly used one, 2-aminopurine, and the recently developed triazole adenine, qA shows highly specific base-pairing with thymine. Moreover, qA has an absorption band outside the absorption of the natural nucleobases (>300 nm) and can thus be selectively excited. Upon excitation the qA monomer displays a fluorescence quantum yield of 6.8 % with an emission maximum at 456 nm. More importantly, upon incorporation into DNA the fluorescence of qA is significantly less quenched than most FBAs. This results in quantum yields that in some sequences reach values that are up to fourfold higher than maximum values reported for 2-aminopurine. To facilitate future utilisation of qA in biochemical and biophysical studies we investigated its fluorescence properties in greater detail and resolved its absorption band outside the DNA absorption region into distinct transition dipole moments. In conclusion, the unique combination of properties of qA make it a promising alternative to current fluorescent adenine analogues for future detailed studies of nucleic acid-containing systems. Copyright
- Dierckx, Anke,Miannay, Francois-Alexandre,Ben Gaied, Nouha,Preus, Soren,Bjoerck, Markus,Brown, Tom,Wilhelmsson, L. Marcus
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supporting information; experimental part
p. 5987 - 5997
(2012/07/14)
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- A highly fluorescent DNA toolkit: Synthesis and properties of oligonucleotides containing new Cy3, Cy5 and Cy3B monomers
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Cy3B is an extremely bright and stable fluorescent dye, which is only available for coupling to nucleic acids post-synthetically. This severely limits its use in the fields of genomics, biology and nanotechnology. We have optimized the synthesis of Cy3B, and for the first time produced a diverse range of Cy3B monomers for use in solid-phase oligonucleotide synthesis. This molecular toolkit includes phosphoramidite monomers with Cy3B linked to deoxyribose, to the 5-position of thymine, and to a hexynyl linker, in addition to an oligonucleotide synthesis resin in which Cy3B is linked to deoxyribose. These monomers have been used to incorporate single and multiple Cy3B units into oligonucleotides internally and at both termini. Cy3B Taqman probes, Scorpions and HyBeacons have been synthesized and used successfully in mutation detection, and a dual Cy3B Molecular Beacon was synthesized and found to be superior to the corresponding Cy3B/DABCYL Beacon. Attachment of Cy3, Cy3B and Cy5 to the 5-position of thymidine by an ethynyl linker enabled the synthesis of an oligonucleotide FRET system. The rigid linker between the dye and nucleobase minimizes dye-dye and dye-DNA interactions and reduces fluorescence quenching. These reagents open up new future applications of Cy3B, including more sensitive single-molecule and cell-imaging studies. The Author(s) 2012.
- Hall, Lucy M.,Gerowska, Marta,Brown, Tom
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- Synthesis and evaluation of 6-Aza-2′-deoxyuridine monophosphate analogs as inhibitors of thymidylate synthases, and as substrates or inhibitors of thymidine monophosphate kinase in mycobacterium tuberculosis
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A series of 5-substituted analogs of 6-aza-2′-deoxyuridine 5′-monophosphate, 6-aza-dUMP, has been synthesized and evaluated as potential inhibitors of the two mycobacterial thymidylate synthases (i.e., a flavin-dependent thymidylate synthase, ThyX, and a classical thymidylate synthase, ThyA). Replacement of C(6) of the natural substrate dUMP by a N-atom in 6-aza-dUMP 1a led to a derivative with weak ThyX inhibitory activity (33% inhibition at 50 μM). Introduction of alkyl and aryl groups at C(5) of 1a resulted in complete loss of inhibitory activity, whereas the attachment of a 3-(octanamido)prop-1-ynyl side chain in derivative 3 retained the weak level of mycobacterial ThyX inhibition (40% inhibition at 50 μM). None of the synthesized derivatives displayed any significant inhibitory activity against mycobacterial ThyA. The compounds have also been evaluated as potential inhibitors of mycobacterial thymidine monophosphate kinase (TMPKmt). None of the derivatives showed any significant TMPKmt inhibition. However, replacement of C(6) of the natural substrate (dTMP) by a N-atom furnished 6-aza-dTMP (1b), which still was recognized as a substrate by TMPKmt. Copyright
- Koegler, Martin,Busson, Roger,De Jonghe, Steven,Rozenski, Jef,Van Belle, Kristien,Louat, Thierry,Munier-Lehmann, Helne,Herdewijn, Piet
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p. 536 - 556
(2012/05/20)
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- Prodan-containing nucleotide and use thereof
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A compound represented by formula (1): wherein R1 is a substituent represented by formula (2): wherein R2 is ═O or —NH2, with the proviso that when R2 is ═O, H is attached to the 1-position N of the pyrimidine ring, and the bond between the 1-position N and the 6-position C is a single bond; or a substituent represented by formula (3): wherein R3 is —OH, ═O, or —NH2, with the proviso that when R3 is —OH or —NH2, R4 is H; when R3 is ═O, R4 is —NH2; and when R3 is ═O, H is attached to the 1-position N of the purine ring, and the bond between the 1-position N and the 6-position C is a single bond.
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Page/Page column 18; sheet 1
(2008/06/13)
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- Template-directed DNA photoligation via α-5-cyanovinyldeoxyuridine
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(Chemical Equation Presented) We describe an efficient template-directed photoligation of oligodeoxynucleotides (ODNs) using α-5- cyanovinyldeoxyuridine (αcU). An efficient photoligation was produced by photoirradiation of an ODN containing thymine at the 5′ end with an ODN containing thymine at the 5′ end in the presence of a template ODN. This photoligation method is a new and efficient way to synthesize branched ODNs.
- Ogino, Masayuki,Yoshimura, Yoshinaga,Nakazawa, Akio,Saito, Isao,Fujimoto, Kenzo
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p. 2853 - 2856
(2007/10/03)
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- Introduction of peptide functions into DNA by nucleic acid peptides, NAPs
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Nucleic acid peptides (NAPs) with a mimetic amino acid side residue at the base position of the nucleotide via an amide bond were synthesized from 3-deoxy-6-O-(4,4′-dimethoxytrityl)allonic acid methyl ester as the common precursor. Furthermore, an NAP with an octapeptide at the C1′ position was synthesized. The peptide-linked NAP exhibits both functions of the oligopeptide part and of the oligonucleotide part. Copyright
- Kawakami, Junji,Wang, Zhong-Ming,Fujiki, Hiroyoshi,Izumi, Satoshi,Sugimoto, Naoki
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p. 1554 - 1555
(2007/10/03)
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- Efficient Preparation of 2-Deoxy-3,5-di-O-p-toluoyl-α-D- ribofuranosyl Chloride
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An efficient method for the synthesis of 1-O-methyl-3,5-di-O-p-toluoyl-2- deoxy-α/β-D-ribose is described. Upon treatment with HCl, 2-deoxy-3,5-di-O-p-toluoyl-α-D-ribofuranosyl chloride, previously unstable, was produced as a white solid, stable in air indefinitely.
- Dhimitruka, Ilirian,SantaLucia Jr., John
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p. 335 - 337
(2007/10/03)
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- Synthesis of fluorophore and quencher monomers for use in Scorpion primers and nucleic acid structural probes
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The synthesis of monomers to incorporate fluorescein and methyl red within sequence and at the termini of modified oligonucleotides was reported. These monomers were used in the solid-phase synthesis of fluorogenic oligonucleotides for genetic analysis and the study of multi-stranded nucleic acid structures. Fluorescence quenching and energy transfer were also used to study the structural, thermodynamic and kinetic properties of higher order nucleic acid structures.
- McKeen, Catherine M.,Brown, Lynda J.,Nicol, Jamie T.G.,Mellor, John M.,Brown, Tom
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p. 2267 - 2275
(2007/10/03)
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- Synthesis and Characterization of π-Stacked Phenothiazine-Labeled Oligodeoxynucleotides
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(Matrix Presented) A facile procedure for the incorporation of N-methyl phenothiazine as the terminal nucleoside in oligodeoxynucleotides is reported. The phenothiazine nucleoside analogue is synthesized and then incorporated into DNA using an automated DNA solid-phase synthesizer. Phenothiazine-labeled oligodeoxynucleotides form stable B-form duplexes with higher melting temperatures compared to unlabeled DNA duplexes.
- Hashmi, S. A. Nadeem,Hu, Xi,Immoos, Chad E.,Lee, Stephen J.,Grinstaff, Mark W.
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p. 4571 - 4574
(2007/10/03)
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- Convenient preparation of 2-deoxy-3,5-di-O-p-toluoyl-α-D-erythro-pentofuranosyl chloride
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By using acetyl chloride as HCl generator, the procedure for the Hoffer preparation of the α-chloro sugar 4a was significantly improved. The α-configuration of the chloro atom was confirmed by using NOE measurement. Sequential transformation of 4a to the β-anomer and to the furfuryl derivative 6 was studied.
- Rolland, Valerie,Kotera, Mitsuharu,Lhomme, Jean
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p. 3505 - 3511
(2007/10/03)
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- Improved Syntheses of Halofuranose Derivatives with the Desired α-Configuration
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Chlorination of ribofuranose or 2-deoxyribofuranose derivatives was carried out in a 1,4-dioxane solution of hydrogen chloride. This improved procedure allowed the syntheses of 1-chloro-α-D-ribofuranose and 1-chloro-2-deoxy-α-D-ribofuranose derivatives and offered ease of handling, high yield, and the stereo-controlled α-configuration at C-1.
- Chin, Tsung-Mei,Huang, Liang-Kuen,Kan, Lou-Sing
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p. 413 - 416
(2007/10/03)
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- Synthesis of (2-deoxy-α- and -β-D-erythro-pentofuranosyl)(thymin-1-yl)alkanes and their incorporation into oligodeoxyribonucleotides. Effect of nucleobase-sugar linker flexibility on the formation of DNA-DNA and DNA-RNA hybrids
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On the basis of modeling studies, the (2-deoxy-α- and β-D-erythro-pentofuranosyl) (thymin-1-yl) alkanes 1a,b and 2a,b were selected as potential conformational probes for altDNA oligonucleotides. A straightforward approach to the synthesis of 1a,b and 2a,b from commercial 2-deoxy-D-ribose (3) and 1-O-methyl-2-deoxy-3,5-di-0-p-toluoyl-D-erythro-pentofuranose (13), respectively, was developed. These nucleoside analogues were converted to the phosphoramidite derivatives 27a,b-30a,b and incorporated into oligonucleotide 31 at predetermined sites and defined internucleotidic motifs. The insertion of 1a,b according to either a (3′ → 5′)- or a (3′ → 3′)-internucleotidic polarity produced oligonucleotides exhibiting a slightly higher affinity for their complementary unmodified DNA sequence than for the corresponding RNA sequence (Table 3). Conversely, the incorporation of 2a into 31 according to a (3′ → 3′)-orientation generated, for the first time, an altDNA oligonucleotide displaying a greater affinity for its complementary unmodified RNA sequence (ΔTm = 6°C) than for the corresponding DNA sequence (ΔTm = 10°C). This hybrid was, however, thermodynamically less stable than the duplex having unmodified α-2′-deoxythymidine similarly incorporated into 31 (ΔΔTm = 3°C).
- Boal, Jila H.,Wilk, Andrzej,Scremin, Carlo L.,Gray, Glenn N.,Phillips, Lawrence R.,Beaucage, Serge L.
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p. 8617 - 8626
(2007/10/03)
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- [(2-deoxy-α- and β-D-erythro-pentofuranosyl)thymin-1-yl] methane derivatives as potential conformational probes for altDNA oligonucleotides
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The previously unknown deoxyribonucleoside analogues 2a,b have been efficiently synthesized from commercial 1-O-methyl-2-deoxy-3,5-di-O-p-toluoyl-D-erythro-pentofuranose. The conversion of these nucleosides to the phosphoramidite derivatives 13a,b and 14a,b for subsequent incorporation into oligodeoxyribonucleotide analogues is also described.
- Scremin,Boal,Wilk,Phillips,Beaucage
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p. 207 - 212
(2007/10/03)
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- How do the gauche and anomeric effects drive the pseudorotational equilibrium of the pentofuranose moiety of nucleosides?
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The conformational characteristics of abasic 1-deoxy sugars 1, 2, and 3 and pentofuranose moieties in 2′,3′-dideoxy-[ddA (6), ddG (7), ddC (8)], 2′-deoxy-[dA (9), dG (10), dC (11)], and ribo-β-D-nucleosides [Ade (12), Gua (13), Cyt (14)] were established through the analysis of vicinal proton-proton coupling constants extracted from their 500-MHz 1H-NMR spectra recorded at 20 K intervals in the temperature range from 278 to 358 K in D2O solution. Two novel deuterated analogues of (S)-tetrahydrofurfuryl alcohol (1), 2-(S)-(hydroxymethyl)-4-(R)-deuteriotetrahydrofuran (4) and 2-(S)-(hydroxymethyl)-3-(S)-deuteriotetrahydrofuran (5), have enabled unequivocal assignment of the complex nine-spin system in its 1H-NMR spectrum. The van't Hoff plots of (ln(XS/XN)] as a function of 1/T gave ΔH° and ΔS° values of pseudorotational equilibrium in pentofuranoses 1-3 and pentofuranose moieties in nucleosides 6-14. The values of ΔH° were dissected into various stereoelectronic effects (gauche versus anomeric effects) of exocyclic substituents on the pentofuranose moiety. Clearly, the gauche effect of the O4′-C4′-C3′-O3′ fragment drives the pseudorotational equilibrium to the S-type conformations, while the gauche effect of the O4′-C1′-C2′-O2′ fragment pushes the pseudorotational equilibrium to the N. These gauche effects are the strongest factors responsible for driving the N ? S pseudorotational equilibrium. The strength of the gauche effect of the O4′-C4′-C3′-O3′ fragment in abasic sugars 1-3 is further tuned by the presence of a heterocyclic base at C1′ in nucleosides 6-14. The relatively weaker anomeric effect of the heterocyclic base drives the N ? S equilibrium to the N. The assessment of the relative strengths of the anomeric effects in 2′,3′-dideoxy, 2′-deoxy-, and ribo-β-D-nucleosides has shown that the anomeric effect of the cytosine base is stronger than the anomeric effect of the adenine or guanine base. The experimental data suggest that the anomeric effect is considerably reduced as O4′ experiences the electron-withdrawing effect(s) of 2′(3′)-hydroxyls. The differences in the conformational preferences found in purine and pyrimidine ribonucleosides were additionally attributed to the distinct relative strength of the gauche effect of the N-C1′-C2′-O2′ fragment. The preference for the gauche orientation of the N-C1′-C2′-O2′ fragment and therefore S-type sugar conformation is affected by the nature of the purine or pyrimidine glycosyl nitrogen atom.
- Plavec, Janez,Tong, Weimin,Chattopadhyaya, Jyoti
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p. 9734 - 9746
(2007/10/02)
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- Novel DNA Analog for Potential Gene Regulating Agent. A Convenient Synthesis of α-Oligodeoxyribonucleotide Phosphorothioate Bearing 3'-Monophosphate
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α-2'-Deoxyoctathymydilic acid phosphorothioate analog bearing 3'-monophosphate was conveniently synthesized via phosphoramidite method using a riboadenosine attached Teflon-based solid support.The obtained oligomer exhibited enhanced stability toward the digestion by common nucleases.
- Shinozuka, Kazuo,Morita, Tsutomu,Hirota, Yoshiki,Sawai, Hiroaki
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p. 1941 - 1944
(2007/10/02)
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- Nucleoside Syntheses, XXII. Nucleoside Synthesis with Trimethylsilyl Triflate and Perchlorate as Catalysts
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The novel Lewis acids (CH3)3SiOSO2CF3 (5), (CH3)3SiOSO2C4F9 (6), and (CH3)3SiClO4 (4) are highly selective and efficient Friedel-Crafts catalysts for nucleoside formation from silylated heterocycles and peracylated sugars as well as for rearrangements of persilylated protected nucleosides.With basic silylated heterocycles these new catalysts give much higher yields of the natural N-1-nucleosides than with SnCl4.
- Vorbrueggen, Helmut,Krolikiewicz, Konrad,Bennua, Baerbel
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p. 1234 - 1255
(2007/10/02)
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