5-halogenated Derivatives Research Articles

Factors Governing the Chemical Stability and NMR Parameters of Uracil Tautomers and Its 5-Halogen Derivatives.

We report on the density functional theory (DFT) modelling of structural, energetic and NMR parameters of uracil and its derivatives (5-halogenouracil (5XU), X = F, Cl, Br and I) in vacuum and in water using the polarizable continuum model (PCM) and the solvent model density (SMD) approach. On the basis of the obtained results, we conclude that the intramolecular electrostatic interactions are the main factors governing the stability of the six tautomeric forms of uracil and 5XU. Two indices of aromaticity, the harmonic oscillator model of aromaticity (HOMA), satisfying the geometric criterion, and the nuclear independent chemical shift (NICS), were applied to evaluate the aromaticity of uracil and its derivatives in the gas phase and water. The values of these parameters showed that the most stable tautomer is the least aromatic. A good performance of newly designed xOPBE density functional in combination with both large aug-cc-pVQZ and small STO(1M)−3G basis sets for predicting chemical shifts of uracil and 5-fluorouracil in vacuum and water was observed. As a practical alternative for calculating the chemical shifts of challenging heterocyclic compounds, we also propose B3LYP calculations with small STO(1M)−3G basis set. The indirect spin–spin coupling constants predicted by B3LYP/aug-cc-pVQZ(mixed) method reproduce the experimental data for uracil and 5-fluorouracil well.

XszenFHal, a novel tryptophan 5-halogenase from Xenorhabdus szentirmaii

Flavin-dependent halogenases (FHals) catalyse the halogenation of electron-rich substrates, mainly aromatics. Halogenated compounds have many applications, as pharmaceutical, agrochemicals or as starting materials for the synthesis of complex molecules. By exploring the sequenced bacterial diversity, we discovered and characterized XszenFHal, a novel FHal from Xenorhabdus szentirmaii, a symbiotic bacterium of entomopathogenic nematode. The substrate scope of XszenFHal was examined and revealed activities towards tryptophan, indole and indole derivatives, leading to the formation of the corresponding 5-chloro products. XszenFHal makes a valuable addition to the panel of flavin-dependent halogenases already discovered and enriches the potential for biotechnology applications by allowing access to 5-halogenated indole derivatives.

On the Cooperativity Effect in Watson and Crick and Wobble Pairs for a Halouracil Series and Its Potential Quantitative Application Studied through Surface-Enhanced Raman Spectroscopy.

The nature of the cooperativity effect of hydrogen bonds in Watson and Crick and wobble base pairs formed with thymine, uracil, and its 5-halogenated derivatives (5-fluoro, -chloro, and -bromouracil) has been studied through SERS and by using chemometric tools to process data and extract relevant information. Remarkable differences between the two kinds of pairs were clearly observed, and the behavior correlated to the withdrawing character of different substituents at the 5-position of uracil was verified. Multivariate analyses have also unveiled information about the pair's stability, and a stronger cooperativity effect seems to rule the Watson and Crick pairs when compared to wobble pairs. Defined patterns in the behavior of Watson and Crick pairs allowed the design of an indirect methodology for quantifying 5-bromouracil using a partial least squares (PLS) method with variable selection. Limit of detection (LOD) values of 0.037 and 0.112 mmol L-1 in the absence and presence of structurally similar interferences were reached, while its direct surface-enhanced Raman spectroscopy (SERS) quantification is only possible at ∼45 mmol L-1.

Role of Weak Hydrogen Bonds and Halogen Bonds in 5-Halo-1,3-dimethyluracils and Their Cocrystals—A Combined Experimental and Computational Study

Seven single crystals containing either N,N-dimethyluracil (DMHU) or one of its 5-halogenated derivatives (DMXU; X = F, Cl, Br, I) were prepared using N,N-dimethylformamide as the crystallization solvent. Single crystal X-ray diffraction and quantum chemical calculations carried out at the spin component scaled local MP2 level of theory were then used to study the intramolecular halogen and nonconventional hydrogen bonds present in the structures. The results were compared to and contrasted with the previously reported data for uracil and its halogenated derivatives. In particular, the intermolecular interactions in DMIU were compared to the halogen and hydrogen bonds in 5-iodouracil that, in contrast to DMHU and its derivatives, displays conventional hydrogen bonds involving its strong N–H donor sites. The crystallographic and computational analyses showed that, while nonconventional hydrogen bonds are present in both DMHU and DMXU, halogen bonds could only be identified in DMBrU and DMIU, in which case ...

Anticancer drug IUdR and other 5-halogen derivatives of 2′-deoxyuridine: conformers, hydrates, and structure–activity relationships

The effect of hydration on the molecular structure and energetics of the most stable conformers of the nucleoside analog 5-iodo-2′-deoxyuridine (IUdR) was carried out. To simulate the first hydration shell, two models were considered: the PCM model and the Discrete model (DM), including a variable number (1–20) of explicit water molecules surrounding the nucleoside. More than two hundred hydrated structures with water were analyzed by B3LYP and MP2 quantum chemical methods. Conformer B1 (syn-gg-gg) is the most stable by B3LYP and MP2, in the isolated state and in the first hydration shell. The CP-corrected formation and interaction energies for IUdR and water molecules were determined. The effect of the hydration on the total atomic charges and intermolecular distances were also discussed. 5-fluoro- (FUdR), 5-chloro- (ClUdR), and 5-bromo- (BrUdR) 2′-deoxyuridine derivatives were full optimized, and the effect of the halogen atom on the molecular structure was analyzed. In these, three derivatives was simulated the first hydration shell with 20 explicit water molecules within the DM. Several relationships/tendencies structure–activity were established that can help for the design of new drugs.

Simulation of a tetramer form of 5-chlorouracil: The vibrational spectra and molecular structure in the isolated and in the solid state by using DFT calculations

A Raman and FT-IR study of the biomolecule 5-chlorouracil in the solid state was carried out. The unit cell found in the crystal was simulated as a tetramer form by density functional calculations. They were performed to clarify the assignments of the experimentally observed bands in the spectra. Calculations in the monomer form and comparisons with the experimental data in Ar matrix were also carried out. The error in the calculated frequencies was analyzed and reduced by using scaling equations and scaling factors deduced from the uracil molecule. The calculations with the B3LYP method and with the 6-31G(d,p) and 6-311+G(2d,p) basis set, appear in general to be useful, when combining with a scaling equation procedure or with the specific scale factors, for interpretation of the general features of the IR and Raman spectra. The scaled values were used in the reassignment of the IR and Raman experimental bands. Comparison of the results with those determined in uracil and 5-halogenated derivatives were performed. The substitution at 5-position of the uracil ring by a chlorine atom has a little effect on the geometric parameters.

Trypanosoma cruziDHOD structure-based design of 5-halogen and 5-alkyl orotate derivatives

<i>Trypanosoma cruzi</i>DHOD structure-based design of 5-halogen and 5-alkyl orotate derivatives

Synthesis and antimicrobial activities of 1-(5-substituted-2-oxo indolin-3-ylidene)-4-(substituted pyridin-2-yl) thiosemicarbazide

A series of 1-(5-substituted-2-oxoindolin-3-ylidene)-4-(substituted-pyridin-2-yl)thio semicarbazide derivatives were synthesized by the reaction of 4-(substituted-pyridin-2-yl) thiosemicarbazide and 5-halogenated isatin derivatives. The newly synthesized compounds were characterized on the basis of spectral (FT-IR, H, C NMR and mass) analysis. Investigation of in vitro anti-bacterial and anti-fungal activity of synthesized compounds was done by disc diffusion method against B. subtilis, S. aureus, E. coli, P. aeruginosa, C. albicans, and A. niger. All the compounds exhibited moderate to good anti-bacterial and anti-fungal activity.

Anti-herpesvirus activities and cytotoxicities of 2-thiopyrimidine nucleoside analogues in vitro.

Twenty 2-thiopyrimidine nucleoside analogues were synthesized and examined for inhibitory activity against herpes simplex virus (HSV) type 1 and 2, varicella-zoster virus (VZV), human cytomegalovirus (HCMV) and thymidine kinase-deficient HSV (HSV-TK-) replication in vitro. 2-thiouracil (thymine) arabinoside, 2'-deoxy-2-thiouridine (or 2-thiothymidine) and their 5-halogenated derivatives showed anti-HSV activity in both RPM18226 (human B-lymphoblastoid cells) and MRC-5 (human embryo lung cells). 2'-deoxy-5-halogenated-2-thiocytidines were also inhibitory against HSV, whereas 2-thiocytosine arabinoside and its derivatives were not inhibitory against HSV replication, except 5-bromo and 5-iodo congeners (TN-31, TN-32). Substitution of the halogen atom at the 5-position of the pyrimidine rings to an atom with a higher molecular weight increased anti-HSV and VZV activities, except for the anti-HSV activity of 2-thiouracil arabinosides. 2'-deoxy-5-methyl-, and 2'-deoxy-5-iodo-2-thiouridines (TN-17, TN-44) showed the most potent anti-HSV activity, and 2'-deoxy-5-chloro- and 2'-deoxy-5-bromo-2-thiocytidines were potent inhibitors of VZV replication. However, none of the compounds inhibited HCMV and HSV-TK- replication. TN-31 and TN-32 were shown to inhibited HCMV and HSV-TK- as well as HSV and VZV replication. The cytotoxicity of the 2-thio-pyrimidine nucleoside analogues was less than that of the 2-oxy-congeners of the compounds (5-iodo-2'-deoxyuridine, 5-iodo-2'-deoxycytidine, thymine arabinoside and cytosine arabinoside). The selectivity index of 2'-deoxy-5-iodo-2-thiouridine (TN-44) was higher than that of 5-iodo-deoxyuridine. TN-17 and TN-44 were not cytotoxic to resting or stimulated human peripheral blood mononuclear cells at 400 microM, although TN-32 was cytotoxic at a concentration of 20 microM.

A Study of the Hydration of Deoxydinucleoside Monophosphates Containing Thymine, Uracil and Its 5-Halogen Derivatives: Monte Carlo Simulation

An extensive Monte Carlo simulation of hydration of various conformations of the dinucleoside monophosphates (DNP), containing thymine, uracil and its 5-halogen derivatives has been performed. An anti-anti conformation is the most energetically stable one for each of the DNPs. In the majority of cases the energy preference is determined by water-water interaction. For other dimers conformational energy is the most important factor, or both the factors are of nearly equal importance. The introduction of the methyl group into the 5-position of uracil ring most noticeably influences the conformational energy and leads to the decrease of its stabilizing contribution to the total interaction energy. The introduction of halogen atoms increases the relative content of anti-syn and syn-anti conformations of DNPs as compared to the parent ones due to the formation of an energetically more favorable water structure around these conformations. A correlation is observed between the Monte Carlo results for the halogenated DNPs and their experimental photoproduct distribution. The data obtained demonstrates a sequence dependence in the photochemistry of the halogenated dinucleoside monophosphates.

THEORETICAL INVESTIGATION OF EXCIMER AND EXCIPLEX STATES OF URACIL AND HALOGEN DERIVATIVES: EFFECT OF NONPARALLELISM OF BASES

Theoretical modeling of initial steps of the photodimerization mechanism of uracil, 5-methyl-and 5-halogen derivatives was performed. The interaction energy of bases in stacked dimers in the ground and lowest excited states was calculated as a function of the distance between the base planes and of the rotation angles within the perturbation theory for the extended Hückel treatment. The existence of excimer and exciplex region on the potential surface of the excited state was revealed. The excimer (exciplex) geometry has the planes nonparallel with more close contact of the C5-C6 bonds as compared to the ground state of dimers. The results provide new information useful for understanding the photodimerization mechanism of bases and testifies that the singlet excimer state can be a precursor of the photodimerization reaction.

3'-Fluoro-2',3'-dideoxy-5-chlorouridine: most selective anti-HIV-1 agent among a series of new 2'- and 3'-fluorinated 2',3'-dideoxynucleoside analogues.

A series of 2'- and 3'-fluorinated 2',3'-dideoxynucleosides and 3'-azido-2',3'-dideoxynucleosides were synthesized and evaluated for their inhibitory activity against human immunodeficiency virus-1 (HIV-1) replication in MT-4 cells. Neither conversion of 3'-fluoro- or 3'-azido-2',3'-dideoxyadenosine to the corresponding inosine derivatives nor 8-bromination of 2',3'-dideoxyadenosine resulted in increased anti-HIV-1 activity. Nor did introduction of a 2'-fluorine in the erythro or threo configuration lead to improved anti-HIV-1 activity of the parent 2',3'-dideoxynucleosides. 1-(2-Fluoro-2,3-dideoxy-beta-D-threo-pentofuranosyl)cytosine and 1-(2-fluoro-2,3-dideoxy-beta-D-erythropentofuranosyl)thymine were only marginally active. However, 3'-fluoro-2',3'-dideoxyuridine (FddUrd) proved to be potent and a relatively nontoxic inhibitor of HIV-1. 5-Halogenated derivatives of FddUrd were prepared in attempts to further increase its anti-HIV potency and selectivity. Of these 5-halogenated derivatives, 3'-fluoro-2',3'-dideoxy-5-chlorouridine emerged as the most selective inhibitor of HIV-1 replication. Its selectivity index was comparable to that of azidothymidine when evaluated under the same conditions.

Highly sensitive determination of 5-fluorouracil in human plasma by capillary gas chromatography and negative ion chemical ionization mass spectrometry

A sensitive method using gas chromatography and electron-capture negative ion mass spectrometry for the determination of 5-fluorouracil in plasma is described. 5-Chlorouracil was used as internal standard. Sample clean-up consisted of extraction of the 5-halogenated uracil derivatives with 2-propanol—diethyl ether (22:78, v/v) at pH 6, followed by a back-extraction into aqueous buffer at pH 10.5. Pentafluorobenzyl derivatives of 5-fluoro- and 5- chlorouracil were prepared by extractive alkylation with pentafluorobenzyl bromide with dichloromethane as solvent and tetrabutylammonium as counter-ion. The limit of sensitivity employing this technique was 50 fg on-column. Quantitation in human plasma was possible down to 3 · 10 -9 M (0.39 ng/ml). Mass fragmentographic analysis of 5-fluorouracil in plasma of patients after a bolus injection of 500 mg/m 2 is presented. Plasma concentrations could be determined for at least 8 h after administration.

Thymidylate synthetase-deficient mouse FM3A mammary carcinoma cell line as a tool for studying the thymidine salvage pathway and the incorporation of thymidine analogues into host cell DNA.

A thymidylate (dTMP) synthetase-deficient murine mammary carcinoma cell line (FM3A/TS-), auxotrophic for thymidine (dThd), proved extremely useful for studying the dependence of cell growth on the exogenous supply of dThd, the relation between cell growth and DNA synthesis, and the ability of a series of 25 5-substituted 2'-deoxyuridines (dUrd) to substitute for dThd in sustaining cell growth. FM3A/TS-cells did not proliferate unless dThd was supplied to the cell culture medium. The 5-halogenated dUrd derivatives 5-chloro-dUrd, 5-bromo-dUrd and 5-iodo-d Urd also sustained FM3A/TS- cell growth. The extents of incorporation of [methyl-3H]dThd and 5-iodo-[6-3H]dUrd into DNA were closely correlated with their stimulatory effects on FM3A/TS- cell growth. This suggests that the stimulatory effects of the dUrd analogues on the growth rate of FM3A/TS- cells may be considered as evidence for their incorporation into host cell DNA. Based on this premise it is postulated that, in addition to 5-chloro-dUrd, 5-bromo-dUrd, 5-iodo-dUrd and dThd itself, the following dThd analogues are also incorporated into FM3A/TS- cell DNA (in order of the extent to which they are incorporated): 5-hydroxy-dUrd greater than 5-propynyloxy-dUrd greater than 5-ethyl-dUrd greater than 5-ethynyl-dUrd approximately 5-vinyl-dUrd. Thus, the dTMP synthetase-deficient FM3A/TS- cell line represents a unique system to dissociate the de novo and salvage pathways of dTMP biosynthesis and to distinguish those dUrd analogues that are incorporated into DNA from those that are not.

Inhibitory effects of various 5-halogenated derivatives of 1-beta-D-arabinofuranosyluracil 5'-triphosphate on DNA polymerases from murine cells and oncornavirus: substituent effects on inhibitory action.

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTInhibitory effects of various 5-halogenated derivatives of 1-.beta.-D-arabinofuranosyluracil 5'-triphosphate on DNA polymerases from murine cells and oncornavirus: substituent effects on inhibitory actionKatsuhiko Ono, Masako Ogasawara, Atsuko Ohashi, Akio Matsukage, Taijo Takahashi, Chikao Nakayama, and Mineo SaneyoshiCite this: Biochemistry 1982, 21, 5, 1019–1024Publication Date (Print):March 2, 1982Publication History Published online1 May 2002Published inissue 2 March 1982https://doi.org/10.1021/bi00534a029RIGHTS & PERMISSIONSArticle Views30Altmetric-Citations8LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (754 KB) Get e-Alerts Get e-Alerts

E.S.R. of Spin-trapped Radicals in Gamma-irradiated Polycrystalline Nucleic Acid Constituents and Their Halogenated Derivatives

Free radicals in gamma-irradiated polycrystalline nucleic acid constituents and their 5-halogenated derivatives have been studied by e.s.r. and spin-trapping. After gamma-irradiation at room temperature, the polycrystalline samples were dissolved in aqueous solutions of t-nitrosobutane (tNB) in the absence or presence of oxygen. For many of the nucleic acid constituents, two types of radicals, -C(5)RH-C(6)H- and -C(5)R-C(6)H2-, formed by H-addition to the double bond [-C(5)R=C(6)H-] of the base, were observed, where R is -CH3 or -H. In addition, radicals formed on the sugar moiety were found for some nucleosides. When oxygen was present in the tNB solution, the relative stability of trapped radicals was changed, and thus the presence of more than one radical species could be established. For halogenated bases, the radical produced by H-abstraction from N(1) was observed, and an additional radical species formed by H-addition to the C(6) position was found for 5-fluorouracil. For halogenated nucleosides, the same spectrum was observed in all compounds except the 5-fluoroderivatives, and was assigned to the radicals produced on the sugar moiety. For 5-fluorodeoxyuridine and 5-fluorouridine, the radical formed by H-addition to the C(6) position of the base was observed. In general, the present results are in good agreement with those of previous single crystal studies, but in the case of halogenated compounds other than the 5-fluoroderivatives, it was not possible to spin-trap the alpha-halo radicals which were the most prominent radicals formed from gamma-irradiation of single crystals at room temperature.

Synthesis of some new halogenated N-thiazolyl substituted 2-mercapto benzoic acid amides and their use as possible fungicides.

One hundred and four acid amido compounds have been prepared by condensing 2-mercapto benzoic acid and its 5-bromo, 3, 5-dibromo and 3, 5-dichloro derivatives with 2-amino-4-substituted thiazoles and their 5-halogenated derivatives via the acid chloride. All these compounds have been tested against Helminthosporium. Four of the compounds were tested for their antibacterial, antihelminthic activities and also for their hypoglycemic activity.

Thymidylate synthetase catalyzed dehalogenation of 5-bromo-and 5-iodo-2′-deoxyuridylate

Thymidylate synthetase catalyzes a facile dehalogenation of 5-bromo-and 5-iodo-2′-deoxyuridylate in the presence of dithiothreitol. The chloro and fluoro nucleotides are not dehalogenated under similar conditions. A mechanism for this reaction is proposed which is in complete accord with previously ascertained features of the catalytic mechanism as well as model chemical reactions. This reaction is likely an important pathway in the biological dehalogenation of 5-halogenated uracil derivatives.

Relationship between the mutagenic and base-stacking properties of halogenated uracil derivatives: The crystal structures of 5-chloro- and 5-bromouracil

Three-dimensional X-ray diffraction data were used to determine the crystal structures of 5-chlorouracil and 5-bromouracil, two mutagenic pyrimidine analogs that can substitute for thymine in DNA. Crystals of the two compounds are nearly isostructural. The space group is P2 1 c , with a = 8.450(6), b = 6.842(3), c = 11.072(16) a ̊ , β = 123.53(19)° for 5-chlorouracil, and a = 8.598(3), b = 6.886(1), c = 11.417(5) a ̊ , β = 123.93(3)° for 5-bromouracil. Intensity data were collected with an automated diffractometer. The structures were refined by full-matrix least-squares to R = 0.058 for 5-chlorouracil and R = 0.027 for 5-bromouracil. The analogs form planar, hydrogen-bonded ribbons that are nearly identical to those found in the crystal structure of thymine monohydrate. As in many other structures of 5-halogenated uracil derivatives, the bases assume a stacking pattern that permits intimate contacts between the halogen substituents and the pyrimidine rings of adjacent bases. This stacking pattern involves halogen contacts that are significantly shorter than normal van der Waals interactions. The crystallographic results provide additional evidence that halogen substituents influence the stacking patterns of uracil derivatives, while exerting little direct effect on the hydrogen-bonding properties. The observed stacking patterns are consistent with the hypothesis that altered stacking interactions may account for the mis-pairing between 5-halogenated uracil bases and guanine residues within double-helical nucleic acids.

Halogen-substitution effect on the optical absorption bands of uracil.

Abstract The ultraviolet absorption spectra of uracil and its 5-halogenated derivatives have been in ­ vestigated in regard to the electron attracting properties of the substituents. It could be shown that the position of the two absorption bands is proportional to the inverse of the electronegativity; the extinction coefficients are a linear function of the electron affinities. In this way, the red shift obtained upon substitution with halogens can be explained. Also, the decrease in absorbance of the absorption bands at λ &gt; 250 nm, occuring concomitant­ ly, is understandable. The increase in absorbance with increasing electron affinity, as observed in the case of the absorption bands at λ &lt; 250 nm, might question the assumption that this band is due to a higher pi -pi* excitation