Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “ALKYLATION”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,315 records · Page 73Linked to original sources

Size-controlled synthesis of monodispersed silver nanoparticles capped by long-chain alkyl carboxylates from silver carboxylate and tertiary amine.

Monodispersed silver nanoparticles capped by long-chain alkyl carboxylates were prepared by the reaction of silver carboxylate with tertiary amine at 80 degrees C for 2 h. This approach is a unique, size-controlled synthetic method for the large-scale preparation of silver nanoparticles. Long-chain alkyl carboxylate derived from a precursor acts as a stabilizer to avoid the aggregation of silver nanoparticles and to control particle size. In addition, amine plays an important role both as a reagent to form a thermally unstable, amine-coordinated intermediate, bis(amine)silver(I) carboxylate, and as a mild reducing agent for the intermediate to produce nanoparticles at a low temperature. The silver core and carboxylate-capping ligand of silver nanoparticles were characterized by various techniques such as transmission electron microscopy, optical absorption spectroscopy, powder X-ray diffraction, X-ray photoelectron spectroscopy, gas chromatograph mass spectroscopy, and thermogravimetric and differential thermal analysis. The diameter of the nanoparticles can be strongly influenced by the alkyl chain length and the structure of the carboxylate. The average diameters of the silver nanoparticles were controlled to less than 5 nm in the case of silver carboxylate with a single alkyl chain length of 13 or 17 carbon atoms. On the contrary, the average diameters of silver nanoparticles became large and polydisperse in the case of silver carboxylate with a chain length of 7 carbon atoms or a branched chain. In comparing triethylamine with trioctylamine, there was no obvious effect to regulate the size distribution of the nanoparticles because they could not function as a capping ligand of the nanoparticles due to their weak coordination to silver. In addition, the heat treatment of silver nanoparticles in solution rather than in the solid state was effective for the growth of particles while maintaining narrow size distributions.

Journal Article↗

N-alkyl-4-boronopyridinium salts as thermally stable and reusable amide condensation catalysts.

[reaction: see text] N-Alkyl-4-boronopyridinium salts are highly effective and reusable catalysts for the dehydrative amide condensation reaction between equimolar mixtures of carboxylic acids and amines. N-Alkylboronopyridinium salts are thermally stabilized in the order N-alkyl-2-boronopyridinium salt << N-alkyl-3-boronopyridinium salt < N-alkyl-4-boronopyridinium salt. Homogeneous catalysts, such as 4-borono-N-methylpyridinium iodide, are more effective in the presence of ionic liquid and can be recovered by extraction with ionic liquid. In contrast, heterogeneous catalysts, such as polystyrene-bound 4-boronopyridinium salts, are effective even in the absence of ionic liquid and can be recovered by filtration.

Journal Article↗

Interference of S-alkyl derivatives of glutathione with brain ionotropic glutamate receptors.

The effects of glutathione, glutathione sulfonate and S-alkyl derivatives of glutathione on the binding of glutamate and selective ligands of ionotropic N-methyl-D-aspartate (NMDA) and non-NMDA receptors were studied with mouse synaptic membranes. The effects of glutathione and its analogues on 45Ca2+ influx were also estimated in cultured rat cerebellar granule cells. Reduced and oxidized glutathione, glutathione sulfonate, S-methyl-, -ethyl-, -propyl-, -butyl- and -pentylglutathione inhibited the Na+-independent binding of L-[3H]glutamate. They strongly inhibited also the binding of (S)-2-amino-3-hydroxy-5-[3H]methyl-4-isoxazolepropionate [3H]AMPA (IC50 values: 0.8-15.9 microM). S-Alkylation of glutathione rendered the derivatives unable to inhibit [3H]kainate binding. The NMDA-sensitive binding of L-[3H]glutamate and the binding of 3-[(R)-2-carboxypiperazin-4-yl][1,2-(3)H]propyl-1-phosphonate ([3H]CPP, a competitive antagonist at NMDA sites) were inhibited by the peptides at micromolar concentrations. The strychnine-insensitive binding of the NMDA coagonist [3H]glycine was attenuated only by oxidized glutathione and glutathione sulfonate. All peptides slightly enhanced the use-dependent binding of [3H]dizocilpine (MK-801) to the NMDA-gated ionophores. This effect was additive with the effect of glycine but not with that of saturating concentrations of glutamate or glutamate plus glycine. The glutamate- and NMDA-evoked influx of 45Ca2+ into cerebellar granule cells was inhibited by the S-alkyl derivatives of glutathione. We conclude that besides glutathione the endogenous S-methylglutathione and glutathione sulfonate and the synthetic S-alkyl derivatives of glutathione act as ligands of the AMPA and NMDA receptors. In the NMDA receptor-ionophore these glutathione analogues bind preferably to the glutamate recognition site via their gamma-glutamyl moieties.

Animals↗

Field cryofocussing hydride generation applied to the simultaneous multi-elemental determination of alkyl-metal(loid) species in natural waters using ICP-MS detection.

Two hydride generation manifold systems, utilizing flow injection and cryotrapping techniques for alkyl-metal(loid) speciation analysis in natural waters, are described in this paper. They provide shipboard capacity for simultaneous derivatization of analytes with NaBH4 and cryotrapping of the generated products in a field packed column at -196 degrees C. The first system is a large-volume hydride generator, using a reagent-injection flow technique as a flow batch type, that has been fully optimized and applied to the simultaneous detection of alkylated species in estuarine waters. The technique permits the analysis of a large volume sample (0.5-11) at a sampling rate of 3 h-1. The second is an online continuous flow hydride generator. A sampling rate of 3-12 h-1 can be achieved with samples of 0.1-0.51. In addition, shipboard operation eliminates major problems related to sample pretreatment, transport and storage. Ultra-trace multi-element determination is finally performed in the laboratory by cryogenic GC hyphenated with ICP-MS. Routine detection limits of 0.5-10 pg (as metal) for 0.51 water samples were achieved for the selected alkyl-metal(loid) species of arsenic, germanium, mercury and tin. Concentrations of various species, obtained from water samples taken from the Rhine estuary, are also presented. These species include alkylated arsenic compounds, other than methyl derivatives, that have been tentatively identified and are reported here for the first time.

Chemistry Techniques, Analytical↗

Complete ozonolysis of alkyl substituted ethenes at -60 degrees C: distributions of ozonide and oligomeric products.

The distribution of ozonide and oligomeric structures formed on complete ozonolysis of alkenes in a non-participating solvent at -60 degrees C is governed by the alkyl substitution around the carbon-carbon double bond. The ozonolysis of a 1,1-alkyl substituted ethene generally favours the formation of an ozonide (a 1,2,4-trioxolane). Whereas the ozonolysis of a 1,1,2-alkyl substituted ethene also produces ozonide, a considerable amount of the ozonised products are oligomeric in nature. For example, the ozonolysis of 3-methylpent-2-ene in solution to high conversion in pentane yields oligomers with structural units derived from the fragmentation products of the primary ozonide (a 1,2,3-trioxolane) which are namely butanone carbonyl oxide and acetaldehyde; these can be characterised by electrospray ionisation mass spectroscopy (ESI-MS) under soft ionisation conditions. The predominant oligomers formed are rich in carbonyl oxide units (80 + mol%) and are cyclic in nature. A small proportion of the oligomers formed are open chain compounds with end groups that suggest that chain termination is brought about either by water or by hydrogen peroxide. Residual water in the solvent will react with the carbonyl oxides to produce 2-methoxybut-2-yl hydroperoxide, which we propose readily decomposes generating hydrogen peroxide. A significant yield of oligomers also is obtained from the ozonolysis of a 1,2-alkyl substituted ethene. The ozonolysis of trans-hex-2-ene in pentane yields oligomers containing up to four structural units and are predicted to be mainly cyclic.

Journal Article↗

Nucleophilic identity substitution reactions. The reaction between hydrogen fluoride and protonated alkyl fluorides.

The gas phase reactions between HF and the protonated alkyl fluorides MeFH+, EtFH+, Pr(i)FH+, and Bu(t)FH+ have been studied using ab initio methods. The potential energy profiles for both nucleophilic substitution (S(N)2) and elimination (E2) pathways have been investigated. Both backside Walden inversion and frontside nucleophilic substitution reaction profiles have been generated. Backside substitution is very favourable, but shows relatively little variation with the alkyl group. Frontside substitution reaction barriers are only slightly higher than the barrier for backside substitution for HF + MeFH+, and the difference in barrier heights for frontside and backside displacement seems negligible for the larger alkyl groups. Reaction barrier trends have been analysed and compared with the results of similar studies of the H2O/ROH2+ and NH3/RNH3+ systems (R = Me, Et, Pr(i), and Bu(t)). Compared to the two other classes, protonated fluorides have extreme structures which, with the exception of the Me substrate, are weakly bound complexes between an alkyl cation and HF. The results nourish the idea that nucleophilic substitution reactions are better understood in view of competition between frontside and backside substitution than from the traditional S(N)1/S(N)2 perspective.

Chemistry, Organic↗

Evaluation of anti-herpetic and antioxidant activities, and cytotoxic and genotoxic effects of synthetic alkyl-esters of gallic acid.

The n-alkyl esters of gallic acid (CAS 13857-8) have a diverse range of uses as antioxidants in food, cosmetics and pharmaceutical industries. Pharmaceutical studies performed with these compounds have found that they have many therapeutic potentialities including anti-cancer, antiviral and antimicrobial properties. However, more interest has been devoted to their antioxidant activity due to the ability to scavenge and reduce reactive oxygen species (ROS) formation. In this study, gallic acid and 14 different alkyl gallates were tested. The cytotoxicity and anti-herpetic (HSV-1, KOS and 29-R strains) activity were studied by using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) colorimetric assay and the cell viability by using the Trypan blue dye exclusion method. The genotoxicity was studied by the Comet assay and the antioxidant activity by using the DPPH (1,1-diphenyl-2-picrylhydrazyl) radical scavenging and microsomal lipid peroxidation-inhibiting activities. The results showed that all the tested compounds have anti-herpetic activity at non cytotoxic concentrations with selectivity indices (SI = CC50/EC50) varying from 0.89 to 18.34, depending on the used HSV-1 strain. It was observed that all tested alkyl gallates showed some degree of genotoxicity, at the tested concentrations, except cetyl gallate, at 256.60 micromol/L (p <0.05, t-Student test), probably induced by ROS released by infected cells and/or by the alkyl gallates that were not antioxidants, at the tested concentrations, in which they demonstrated anti-herpetic activity. The hydroxyl groups can induce DNA damage due interactions with some metal ions, which are naturally present in the culture medium supplemented with fetal bovine serum, probably explaining the genotoxicity detected. However, the obtained results showed considerable antioxidant activity at smaller concentrations, when compared to quercetin which is considered as a reference drug due to its already described antioxidant potential: DPPH radical scavenging activity with IC50 values varying from 17 to 31 micromol/L; and microsomal lipid peroxidation-inhibiting activity with IC50 values varying from 21 to 59 micromol/L. It was observed that the presence of hydroxyl groups in these molecules is important for their pharmacological profile, but the length of the lateral carbonic chain does not have considerable influence.

Animals↗

Single particle dynamics in ionic liquids of 1-alkyl-3-methylimidazolium cations.

Ionic dynamics in room temperature molten salts (ionic liquids) containing 1-alkyl-3-methylimidazolium cations is investigated by molecular-dynamics simulations. Calculations were performed with united atom models, which were used in a previous detailed study of the equilibrium structure of ionic liquids [S. M. Urahata and M. C. C. Ribeiro, J. Chem. Phys. 120, 1855 (2004)]. The models were used in a systematic study of the dependency of several single particle time correlation functions on anion size (F-, Cl-, Br-, and PF6-) and alkyl chain length (1-methyl-, 1-ethyl-, 1-butyl-, and 1-octyl-). Despite of large mass and size of imidazolium cations, they exhibit larger mean-square displacement than anions. A further detailed picture of ionic motions is obtained by using appropriate projections of displacements along the plane or perpendicular to the plane of the imidazolium ring. A clear anisotropy in ionic displacement is revealed, the motion on the ring plane and almost perpendicular to the 1-alkyl chain being the less hindered one. Similar projections were performed on velocity correlation functions, whose spectra were used to relate short time ionic rattling with the corresponding long time diffusive regime. Time correlation functions of cation reorientation and dihedral angles of the alkyl chains are discussed, the latter decaying much faster than the former. A comparative physical picture of time scales for distinct dynamical processes in ionic liquids is provided.

Journal Article↗

Effect of alkyl chain length and size of the headgroups of the surfactant on solvent and rotational relaxation of Coumarin 480 in micelles and mixed micelles.

The effect of alkyl chain length and size of the headgroups of the surfactant on the solvation dynamics and rotational relaxation of Coumarin 480 (C-480) has been investigated using dynamic Stokes' shift of C-480 in different types of alkyltrimethylammonium bromide micelles and mixed micelles. The rotational relaxation time increases with increase in alkyl chain length of the surfactant. The increase in the number of alkyl chains of the surfactant leads to the more close packed micelles, hence the microviscosity of the micelles increases and consequently rotational relaxation time increases. Solvation time also increases due to the increase in number of alkyl chains of the surfactant. The change in solvation and rotational relaxation time is more prominent in micelles compared to mixed micelles. The solvation and rotational relaxation time also increase with the increase in size of the headgroup of the surfactant.

Journal Article↗

Hydrophobicity of Long Chain n-Alkyl Carboxylic Acids, as Measured by Their Distribution Between Heptane and Aqueous Solutions.

Previous data for the distribution of the n-alkyl carboxylic acids between aqueous buffers and heptane have suggested that the free energy of transfer between the two solvents does not increase with the length of the alkyl chain beyond palmitic acid, indicating a limit to the hydrophobicity of the alkyl chain at a length of about 15 carbon atoms. It is shown in this paper that previous measurements were influenced by unexpectedly strong pH-dependent association of the long-chain acids in the aqueous phase. Under conditions where such association becomes negligible, the free energy of transfer becomes a strictly linear function of alkyl chain length for all acids up to behenic acid (C(21)H(43)COOH).

Journal Article↗

HeLa cell variants that differ in sensitivity to monofunctional alkylating agents, with independence of cytotoxic and mutagenic responses.

Different strains of the established human cell line HeLa differ substantially in sensitivity to ethyl methanesulfonate (EtMes). The EtMes doses effective for either cytotoxicity or mutation induction in a line of HeLa S3 cells are about 1/10th those required in the CCL2 HeLa line of the American Type Culture Collection. By plating the sensitive HeLa S3 line in the presence of highly cytotoxic doses of EtMes, we obtained a clone (designated A6) that displays about 7-fold greater resistance to EtMes toxicity. This A6 isolate is also cross resistant to other simple monofunctional alkylating agents-exhibiting about 4-fold increased resistance to methyl methanesulfonate and 10- to 15-fold increased resistance to N-methyl-N'-nitro-N-nitrosoguanidine but is similar to the S3 parent in sensitivity to mitomycin C, UV radiation, and gamma-rays. In contrast to the results for cytotoxicity, the A6 variant and the S3 parent showed the same high susceptibility to EtMes induction of ouabain-resistant mutations. This is direct biological evidence that different alkylation lesions are normally responsible for mutagenic and cytotoxic effects. The S3 and A6 cell lines may differ in DNA repair capability specific to certain potentially lethal alkylation products. The comparative sensitivity of the A6 cells to alkylation mutagenesis may also prove useful in cell genetic studies by facilitating the generation of multiple mutants for recessive alleles and permitting exceptionally sensitive detection of specific mutagenic effects.

Cell Survival↗

Reaction of hydroxyl radicals with alkyl phosphates and the oxidation of phosphatoalkyl radicals by nitro compounds.

The rate constants for reactions of hydroxyl radicals with a number of alkyl phosphates have been determined by competition with KSCN. Hydroxyl radicals react with alkyl phosphates preferentially by H-abstraction at the alpha-position of the phosphate functions. The resulting alpha-phosphatoalkyl radicals are not very efficient one-electron reducing agents towards nitro compounds. They react with tetranitromethane (TNM) by addition to form adduct intermediates with absorption maxima at about 300 nm. The rate constants for decay of these TNM adducts to produce the nitroform anion (NF-) and the corresponding alpha-phosphato-alcohols have been determined by optical and/or conductance detection. The stability of these TNM adducts varies considerably with the chain length (methyl > ethyl > isopropyl) and number (trialkyl > dialkyl > monoalkyl) of the alkyl substituents. Additional formation of proton during or after the decay of the TNM adducts has been tentatively attributed to the hydrolysis of the alpha-phosphato-alcohols. Alpha-Phosphatoalkyl radicals derived from trimethyl, triethyl, triisopropyl, and diethyl phosphates react with p-nitroacetophenone (PNAP) very slowly (k < 5 x 10(7) dm3mol-1S-1) possibly forming adducts. One-electron reduction of PNAP by these radicals to PNAP.- was not observed under pulse radiolysis conditions. The rate constants for the reactions of .OH with glycerol 1-phosphate and glycerol 2-phosphate have been redetermined by competition with KSCN. Using the radical scavengers N,N,N',N'-tetramethyl-p-phenylenediamine (TMPD) and TNM, the percentage of .OH attack at each carbon atom was obtained. Contrary to the simple alkyl phosphates described above, the alpha-position to the phosphate function is the least favoured (10-15% in glycerol 1-phosphate and 6% in glycerol 2-phosphate). These so-formed alpha-phosphatoalkyl radicals react with TNM also by forming adducts. The beta-phosphatoalkyl radicals in both cases eliminate inorganic phosphate on formation (k > 10(6)S-1). The gamma-phosphatoalkyl radical from glycerol 1-phosphate undergoes base-catalysed water elimination (kobs = 1.8 x 10(5)S-1 at pH 10.6) to give an oxidizing radical. Products in the gamma-radiolysis of N2O-saturated solutions of glycerol 1-phosphate and glycerol 2-phosphate have been identified and their yields determined. The mechanisms for their formation are discussed.

Alkanes↗

The journey towards elucidating the anti-HCMV activity of alkylated bicyclic furano pyrimidines.

Bicyclic furanopyrimidines were recently discovered by us to be potent and selective inhibitors of VZV. Related studies to investigate the role of the sugar in this activity uncovered dideoxy furanopyrimidines as inhibitors of HCMV and this led to the preparation of highly modified long alkyl chain furanopyrimidines from the N- and O-alkylation of their parent bases. Herein we describe their synthesis and subsequent biological evaluation against HCMV. O-alkylated derivatives were almost invariably found to be at least equiactive with their N-alkylated counterparts. At this point, little change in activity has been found with large variation in N- and O-substituent.

Antiviral Agents↗

Mutagenicity of dibromodulcitol (DBD), an alkylating anticancer drug) and its mono- and bifunctional conversion products studied by the Salmonella/microsome assay.

Dibromodulcitol (DBD) and one of its most important bifunctional transformation products, dianhydrogalactitol (DAG) with similar cytostatic effect, were tested by the Salmonella/microsome assay on strains TA 1535, TA 1538, TA 98 and TA 100 using the plate incorporation technique. Both drugs were direct mutagens in strains TA 1535 and TA 100 and non-mutagenic in other strains. Their mutagenic effect was not influenced by S-9 mix from rat liver. Mutagenicity of DAG was very limited because of its marked toxicity. The other monofunctional alkylating derivatives, i.e., 1-bromo-3,6-anhydrodulcitol and 1,2-epoxy-3,6-anhydrodulcitol were highly mutagenic in strains TA 1535 and TA 100 with and without S-9 mix despite having no anticancer effect. Anticancer activity was exerted only by the bifunctional alkylating hexitols (DBD, DAG) which showed moderate mutagenic activity compared to the monofunctional derivatives. No correlation could be established between the mutagenic and anticancer effect of the four structurally related hexitols. Mutagenicity of urine and bile from rats after a single administration of the maximum tolerated (450 mg/kg) dose of DBD was also examined, and the hexitol components of the same urine sample were identified by t.l.c. DBD and its mutagenic transformation products were excreted in urine and not through the bile. The mutagenic effect of DBD observed cannot be attributed exclusively to DBD observed cannot be atributed exclusively to DBD itself, because the parent molecule, like other alkylating agents, easily undergoes spontaneous decomposition under in vitro and in vivo conditions to release both bi- and monofunctional alkylating solvolysis products and there highly reactive derivatives may play a role in this effect. No significant difference in the relative mutagenicity was detected between DBD and cyclophosphamide, used as a reference substance.

Animals↗

Rapid acquisition of multicellular drug resistance after a single exposure of mammary tumor cells to antitumor alkylating agents.

BACKGROUND: Clinical drug resistance is either intrinsic (de novo) or often acquired rapidly in conjunction with chemotherapy. By contrast, the selection of drug-resistant mutant cell lines in monolayer culture systems is usually a more protracted process. Sublines of mouse EMT-6 mammary tumor cells selected for resistance to various alkylating agents in vivo after serial passage into syngeneic mice manifest their resistance in vitro only when cultured as three-dimensional multicellular aggregates or spheroids. PURPOSE: We examined whether a single exposure of mouse EMT-6 or human MDA-MB-231 breast cancer cells to alkylating agents in vitro is sufficient for the induction of a resistance phenotype, which may be detected by re-applying the drugs to cells grown as three-dimensional aggregates. METHODS: Mouse EMT-6 and human MDA-MB-231 breast cancer cells cultured as three-dimensional aggregates were exposed to a single dose of alkylating agent for 1-5 days. Aggregates were dispersed, and cells were plated as monolayer cultures for up to 8 weeks to allow for recovery. Colony-forming ability was assessed after a subsequent alkylating-agent exposure of cells cultured as monolayers or three-dimensional aggregates. RESULTS: A single in vitro exposure to 12.5-microM cisplatin (CDDP) for 5 days or 25 microM 4-hydroperoxycyclophosphamide (4-O2H CTX) for 1 or 3 days without changing the medium was sufficient to induce transient but substantial resistance in EMT-6 cells as determined by clonogenic assays. Such resistance was not detected when monolayer cell cultures were used. The concentration of 4-O2H-CTX and the length of time the cells remained in three-dimensional culture after initial exposure to this drug was associated with the degree of subsequent drug resistance of cells grown as three-dimensional cultures. Furthermore, this acquired resistance after a single drug exposure was accompanied by changes in the three-dimensional architecture of the cell aggregates, which now formed much more compact multicellular spheroids. Similarly, a single exposure to 4-O2H-CTX was enough to bring about resistance in MDA-MB-231 cells detectable only in three-dimensional cultures, as well as the change in three-dimensional architecture. CONCLUSIONS: Rapid acquisition of resistance likely represents a physiologic mechanism of adaptation operative at the multicellular level rather than a stable genetic change and may be one of the reasons for the rapid development of drug resistance acquired by tumors in vivo. IMPLICATIONS: In vivo drug exposure may result in transient and low levels of drug resistance that may nevertheless be clinically relevant.

Animals↗

Cytogenetic effects induced by alkylated guanine in mammalian cells.

Cytogenetic effects of O6-ethylguanine (O6EtG) were investigated in V79 Chinese hamster cells and human lymphocytes. The frequency of micronuclei and of polyploid cells was increased in a dose-dependent manner in V79 cells. Micronuclei were larger than those induced by the alkylating agent diethylsulfate, suggesting that they originated from chromosome loss rather than from chromosome breakage. Chromosome displacement was also observed and further indicated damage to the spindle. In human lymphocytes, both aneuploidy and polyploidy were induced. O6EtG did not induce either micronuclei or polyploidy in a V79 derivative, deficient in hypoxanthine-guanine phosphoribosyl transferase, suggesting that conversion of the base to a nucleotide is necessary. Preliminary data indicated that 7-ethylguanine was also able to induce aneuploidy and polyploidy in lymphocytes, although it was barely active in V79 cells. The hypothesis proposed is that alkylated nucleotides may behave as spindle poisons. As a consequence, treatment of mammalian cells with alkylating agents may induce numerical chromosome aberrations via alkylation of guanine nucleotide pools, a pathway which has not so far been proposed.

Animals↗

Solution structure of a DNA duplex with a chiral alkyl phosphonate moiety.

The solution structures of two DNA decamers of sequence d(CCACCpxGGAAC).(GTTCCGGTGG) with a chiral alkyl phosphonate moiety (px) have been determined using NMR and restrained molecular dynamics simulations and compared with the solution structure of the unmodified duplex. The (1)H NMR spectra of two samples with pure stereochemistry in the modified phosphate have been assigned. The structures of both diastereoisomers, as well as the unmodified control duplex, have been determined from NMR-derived distance and torsion angle constraints. Accurate distance constraints were obtained from a complete relaxation matrix analysis of the NOE intensities. The structures have been refined with state of the art molecular dynamics methods, including explicit solvent and applying the particle mesh Ewald method to properly evaluate the long-range electrostatic interactions. In both cases, the calculations converge to well-defined structures, with RMSDs of approximately 1 A. The resulting structures belong to the general B family of DNA structures, even though the presence of the alkyl phosphonate moiety induces some slight displacement to the A-form in the neighborhood of the modified phosphate. Partial neutralization of this phosphate and the steric effect of the alkyl moiety provoke moderate bending in the DNA. This effect is more pronounced in the S diastereoisomer, where the alkyl group points inwards to the double helix.

Base Sequence↗

Reaction of diazoalkanes with 1-substituted 2, 4-dioxopyrimidines. Formation of O2, N-3 and O4-alkyl products.

In non-aqueous solution, diazomethane and diazoethane react with the O2, O4 and N-3 sites of uridine, thymidine, 1-methyluracil and 1-methylthymine. Diazoethane has a higher affinity for alkylating oxygens than does diazomethane. The relative ratio of O2:O4:N-3 methyl products is 1:2:16 and of ethyl products the ratio is 1:1:2. When the diazoethane reaction is performed in neutral buffered solution, the same proportion of O2:O4:N-3 ethyl products is found, but the extent of reaction is very low. O2-alkylation greatly labilizes the glycosidic bond of thymidine and uridine toward acid hydrolysis. All O2 and O4 alkyl 1-substituted 2,4-dioxopyrimidines are dealkylated in weak acid but the O2 alkyl group is the more stable.

Alkanes↗