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PubMed1999

Structure, interaction, dynamics and solvent effects on the DNA-EcoRI complex in aqueous solution from molecular dynamics simulation.

A 0.7-ns molecular dynamics simulation of the DNA-EcoRI complex in a 7.0-A solvent shell indicated a stable behavior of the system. No significant evaporation or smearing of the solvent's outer boundary occurred. The structure and the intermolecular interactions were found to be well maintained during the simulation. The interaction pattern in the simulation was found to be very similar to that in the crystal structure. Most of the specific interactions between the DNA and the protein were found to be enhanced in the simulation compared to that in the crystal structure as a result of improved interaction geometry. The nonspecific interactions were found to be stronger than the specific ones. The specific interactions between the N7 atoms of Gua(4) or Ade(5) or Ade(6) and the protein were found to be present over almost the entire time of the simulation, whereas hydrogen bonds involving the amino groups of the Ade(5) and Ade(6) with the protein were found to be relatively weaker, with lower probability and shorter lifetime. The time evolution of the root mean square deviations of the DNA and the protein were highly correlated even at the later part of the simulation, showing the tight binding between them. Several long-lived water bridges were found between the DNA backbone atoms and the protein and also between the two protein monomers, which increased the overall stability of the complex. The two protein monomers were found to interact strongly with each other. The energy of the DNA kink deformation was estimated as approximately 31 kcal/mol.

Binding Sites↗

PubMed2000

Antibody-dependent enhancement of HSV-1 infection by anti-gK sera.

We previously reported that vaccination of BALB/c mice with the baculovirus expressed HSV-1 glycoprotein K (gK) or passive transfer of gK purified IgG to naive BALB/c mice causes severe exacerbation of HSV-1 induced corneal scarring following ocular challenge. In addition, a productive chronic infection, rather than a latent infection, is found in most trigeminal ganglia. These phenomena are accompanied by a very high T(H)1+T(H)2 response in the eye (Ghiasi, H., Cai, S., Nesburn, A.B., Wechsler, S.L., 1996. Vaccination with herpes simplex virus type 1 glycoprotein K impairs clearance of virus from the trigeminal ganglia resulting in chronic infection. Virology 224, 330-333; Ghiasi, H., Cai, S., Slanina, S., Nesburn, A. B., Wechsler, S.L., 1997. Nonneutralizing antibody against the glycoprotein K of herpes simplex virus type-1 exacerbates herpes simplex virus type-1-induced corneal scarring in various virus-mouse strain combinations. Invest. Ophthalmol. Vis. Sci. 38, 1213-1221; Ghiasi, H., Hofman, F.M., Cai, S., Perng, G.C., Nesburn, A.B., Wechsler, S.L., 1999. Vaccination with different HSV-1 glycoproteins induces different patterns of ocular cytokine responses following HSV-1 challenge of vaccinated mice. Vaccine 17, 2576-2582). In the studies reported here, we investigated the hypothesis that anti-gK serum produces antibody-dependent enhancement (ADE) of ocular HSV-1 infection. We found that gK vaccinated mice had significantly higher HSV-1 titers in their eyes than gD or mock-vaccinated mice and that anti-gK sera enhanced HSV-1 infection in the macrophage cell line U937. In addition, passive transfer of anti-gK sera to naive mice 24 h prior to ocular HSV-1 challenge also increased viral replication. These results were consistent with ADE of HSV-1 by sera to gK. This suggests that the severely exacerbated corneal disease seen following HSV-1 ocular challenge of gK vaccinated mice is a result of ADE. The ability of gK sera to cause harmful ADE may impact HSV-1 vaccine development.

Animals↗

PubMed1996

Site-specific substitution of inosine at the terminal positions of a pre-mRNA intron: implications for the configuration of the terminal base interaction.

Genetic evidence in yeast has revealed that a non-Watson-Crick base-pairing interaction between terminal guanosine residues of the intron is required for the second step of pre-mRNA splicing. To explore the likely configuration of the interaction between the terminal guanosines of the intron, inosine was uniformly incorporated into an adenovirus pre-mRNA substrate (Ade) to replace guanosine residues. Splicing of the inosine-containing Ade pre-mRNA was completely inhibited. Psoralen cross-linking reveals that the association of U1 and U2 snRNPs with the intron was impaired. To eliminate the deleterious effects caused by complete inosine replacement, guanosine residues at the splice site(s) of the Ade pre-mRNA were substituted by inosine. Such pre-mRNA substrates were obtained by ligation of two or three RNA fragments; the 3' piece was primed with inosine or mono-phosphate inosine. Splicing of the Ade pre-mRNA containing an inosine residue at the 5' or the 3' splice site, or at both sites proceeds normally. Thus, the functions of the terminal guanosine residues of the intron in splicing can be replaced by inosine. This result supports the previous notion that an N1-carbonyl symmetric interaction likely occurs between the intron terminal residues during pre-mRNA splicing.

Base Composition↗

PubMed2001

Measurement of 8-hydroxy-2'-deoxyadenosine in DNA by liquid chromatography/mass spectrometry.

8-Hydroxyadenine (8-OH-Ade) is one of the major lesions, which is formed in DNA by hydroxyl radical attack on the C-8 position of adenine followed by oxidation. We describe the measurement of the nucleoside form of this compound, 8-hydroxy-2'-deoxyadenosine (8-OH-dAdo) in DNA by liquid chromatography/mass spectrometry (LC/MS). The developed methodology enabled the separation by LC of 8-OH-dAdo from intact and modified nucleosides in enzymic hydrolysates of DNA. Measurements by MS were performed using atmospheric pressure ionization-electrospray process. Isotope-dilution MS was applied for quantification using a stable isotope-labeled analog of 8-OH-dAdo. The level of sensitivity of LC/MS with selected-ion monitoring (SIM) for 8-OH-dAdo amounted to approximately 10 femtomol of this compound on the LC column. This level of sensitivity is similar to that previously reported using LC-tandem MS (LC/MS/MS) with multiple-reaction monitoring mode (MRM) (7.5 femtomol). This compound was quantified in DNA at a level of approximately one molecule/10(6) DNA bases using amounts of DNA as low as 5 microg. The results suggested that this lesion may be quantified in DNA at even lower levels, when more DNA is used for analysis. In addition, gas chromatography/isotope-dilution mass spectrometry with SIM (GC/IDMS-SIM) was applied to measure 8-OH-Ade in DNA following its removal from DNA by acidic hydrolysis. The background levels of 8-OH-dAdo and 8-OH-Ade measured by LC/IDMS-SIM and GC/IDMS-SIM, respectively, were nearly identical. In addition, DNA samples, which were exposed to ionizing radiation at different radiation doses, were analyzed by these techniques. Nearly identical results were obtained, indicating that both LC/IDMS-SIM and GC/IDMS-SIM can provide similar results. The level of sensitivity of GC/MS-SIM for 8-OH-Ade was also measured and found to be significantly greater than that of LC/MS-SIM and the reported sensitivity of LC/MS/MS-MRM for 8-OH-dAdo. The results show that the LC/MS technique is well suited for the measurement of 8-OH-dAdo in DNA.

Animals↗

PubMed2001

A computerized method for identifying incidents associated with adverse drug events in outpatients.

INTRODUCTION: In inpatients, computer monitors have been used to improve the detection of adverse drug events (ADEs). However, similar programs have not been available in outpatients. OBJECTIVE: To describe an approach for detecting incidents suggesting that an ADE may have occurred in outpatients by adapting methods from inpatient computer monitoring and developing terminology searches of electronic medical records. METHODS: One year of information from the outpatient electronic medical record (EMR) at one hospital and its clinics was reviewed. Altogether, 23064 patients and 88514 visits were identified. Patient demographics, medical problem lists, ICD-9 claims, patient allergies, medication history and all clinic visit notes were extracted and merged. We then searched for incidents suggesting that an ADE might be present using four methods: ICD-9 claims, new allergies, computer rules linking laboratory data to known medication exposures, and a medical terminology lexicon (M2D2). In this report, we describe how these search methods were developed to allow for ADE identification. CONCLUSION: The ability to carry out such quality-related work is an example of the benefits of the outpatient EMR that may not be apparent to those institutions considering adopting it.

Adverse Drug Reaction Reporting Systems↗

PubMed2005

Ambulatory care visits for treating adverse drug effects in the United States, 1995-2001.

BACKGROUND: Adverse d[rug events (ADEs) are a well-recognized patient safety 4concern, but their magnitude is unknown. Ambulatory viisits for treating adverse drug effects (VADEs) as recordeed in national surveys offer an alternative way to estimatte the national prevalence of ADEs because each VA]DE indicates that an ADE occurred and was seriousenough to require care. METHODS: A nationallyrepresentative sample of visits to physician offices, hospital outpatient departments, and emergency departments was analyzed. VADEs were identified as tthe first-listed cause of injury. RESULTS: In 2001, there Awere 4.3 million VADEs in the United States, averaging 15 visits per 1,000 population. VADE rates at physicianoffices, hospital outpatient departments, and hospittal emergency departments were at 3.7, 3.4, and 7.3 lper 1,000 visits, respectively. There was an upward tr'end in the total number of VADEs from 1995 to 2001 ((p < .05), but the increases in VADEs per 1000 visits an.d per 1,000 population were not statistically significant. VADEs were lower in children younger than 15 and higher in the elderly aged 65-74 than in adults aged 225-44 (p < .01) and were more frequent in females than irn males (p < .05). DISCUSSION: Although methodologically conservative, the study suggests that ADEs are a significant threat to patient safety in the United States.

Adolescent↗

PubMed1998

Structural and enzymatic studies of a new analogue of coenzyme B12 with an alpha-adenosyl upper axial ligand.

A new analogue of coenzyme B12 (5'-deoxyadenosylcobalamin, AdoCbl), in which the configuration of the N-glycosidic bond in the Ado ligand is inverted [(alpha-ribo)AdoCbl], has been synthesized and its crystal structure determined by X-ray diffraction [MoKalpha, lambda = 0.71073 A, monoclinic P212121, a = 16.132(12) A, b = 21. 684(15) A, c = 27.30(3) A, 9611 independent reflections, R1 = 0. 0708]. As suggested by molecular mechanics modeling before the structure was known, the Ado ligand lies over the southern quadrant of the molecule, as is the case for AdoCbl. The most striking feature of the structure is disorder in the orientation of the adenine (Ade) moiety relative to the ribose of the Ado ligand. This was resolved with a two-state model in which in the major (0.57 occupancy) conformer the A16(O)-A11-A9(N)-A8 dihedral angle is 1.9 degrees and the Ade is virtually perpendicular to the corrin ring; in the minor conformer, the Ade is tilted down, and this dihedral is -48.7 degrees. The Co-C and axial Co-N bond lengths and the Co-C-C bond angle are quite similar to those in AdoCbl. The corrin ring is considerably flatter than that of AdoCbl, with a fold angle of 11.7 degrees. The molecule was successfully modeled by molecular mechanics (MM), and rotation of the Ado ligand relative to the corrin gave rise to four locally minimum structures with the Ado in the southern, eastern, northern, or western quadrant, with the southern conformation as the global minimum, as is the case with AdoCbl itself. Nuclear Overhauser effects (nOe's) observed by two-dimensional (2D) NMR were incorporated as restraints in molecular dynamics (MD) and simulated annealing (SA) calculations. A MD simulation at 300 K showed that only the southern conformation is populated with the Ado ligand confined to an arc from over C15 to over C12, while the Ade ring oscillates from perpendicular to parallel to the corrin ring. Twenty-seven structures were collected by MD-SA. Most of these annealed into the southern conformation, but examples of the other conformations were also found. The new analogue is a partially active coenzyme for the ribonucleotide reductase from Lactobacillus leichmanii with maximal activity that is 9.7% of that of AdoCbl itself, and a very high Km value (245 microM compared to 0.54 microM for AdoCbl). In addition, the rate constant for enzyme-induced carbon-cobalt bond cleavage of (alpha-ribo)AdoCbl is 160-fold smaller than that for AdoCbl, and only 1/3 as much cob(II)alamin is produced at the active site.

Adenosine↗

PubMed2004

One-dimensional oxalato-bridged Cu(II), Co(II), and Zn(II) complexes with purine and adenine as terminal ligands.

The reaction of nucleobases (adenine or purine) with a metallic salt in the presence of potassium oxalate in an aqueous solution yields one-dimensional complexes of formulas [M(mu-ox)(H(2)O)(pur)](n) (pur = purine, ox = oxalato ligand (2-); M = Cu(II) [1], Co(II) [2], and Zn(II) [3]), [Co(mu-ox)(H(2)O)(pur)(0.76)(ade)(0.24)](n)(4) and ([M(mu-ox)(H(2)O)(ade)].2(ade).(H(2)O))(n) (ade = adenine; M = Co(II) [5] and Zn(II) [6]). Their X-ray single-crystal structures, variable-temperature magnetic measurements, thermal behavior, and FT-IR spectroscopy are reported. The complexes 1-4 crystallize in the monoclinic space group P2(1)/a (No. 14) with similar crystallographic parameters. The compounds 5 and 6 are also isomorphous but crystallize in the triclinic space group P (No. 2). All compounds contain one-dimensional chains in which cis-[M(H(2)O)(L)](2+) units are bridged by bis-bidentate oxalato ligands with M(.)M intrachain distances in the range 5.23-5.57 A. In all cases, the metal atoms are six-coordinated by four oxalato oxygen atoms, one water molecule, and one nitrogen atom from a terminal nucleobase, building distorted octahedral MO(4)O(w)N surroundings. The purine ligand is bound to the metal atom through the most basic imidazole N9 atom in 1-4, whereas in 5 and 6 the minor groove site N3 of the adenine nucleobase is the donor atom. The crystal packing of compounds 5 and 6 shows the presence of uncoordinated adenine and water crystallization molecules. The cohesiveness of the supramolecular 3D structure of the compounds is achieved by means of an extensive network of noncovalent interactions (hydrogen bonds and pi-pi stacking interactions). Variable-temperature magnetic susceptibility measurements of the Cu(II) and Co(II) complexes in the range 2-300 K show the occurrence of antiferromagnetic intrachain interactions.

Adenine↗

PubMed2006

A windmill-shaped hexacopper(II) molecule built up by template core-controlled expansion of diaquatetrakis(mu2-adeninato-N3,N9)dicopper(II) with aqua(oxydiacetato)copper(II).

The windmill-shaped hexanuclear copper(II) cluster {(H(2)O)(2)Cu(2)(mu(3)-(Ade)(4)[Cu(oda)(H(2)O)](4)}.6H(2)O (1-o) has been synthesized in aqueous medium by in situ core-controlled expansion of the neutral building block Cu(2)(mu(2)-N3,N9-Ade)(4)(H(2)O)(2) (2) with Cu(oda)(H(2)O) (3-o) (Ade = adeninato(1-) and oda = oxydiacetato(2-) ligands). Crystal data for 2-b (2.5H(2)O): triclinic, space group P(-)1; a = 9.374(1), b = 9.440(1), c = 10.326(1) A; alpha = 78.72(1), beta = 76.77(1), gamma = 63.51(1) degrees ; final R(1) = 0.059; T = 100(2) K. Crystal data for 1-o: monoclinic, space group P2(1)/n; a = 15.203(2), b = 10.245(1), c = 19.094(2) A; beta = 101.61(1) degrees ; final R(1) = 0.049; T = 293(2) K. The X-shaped hexanuclear molecule consists of a central core (2) and four terminal arms (3-o) linked together by bridging mu(3)-N3,N7,N9-Ade ligands. There are three crystallographic independent metal atoms (two terminals, one central). All Cu(II) atoms exhibit a 4 + 1 coordination, of which one is an aqua apical ligand. The basal coordination sets complete the CuN(4) + O or CuO(3)N + O chromophores for the central or terminal metal atoms, respectively. Thermal stability and spectral and magnetic properties were also studied. Analogous compounds to 1-o with tridentate or tripodal tetradentate ligands L(2-), instead of oda, have also been synthesized.

Copper↗

PubMed1998

Quantitative and qualitative analysis of DNA methylation at N3-adenine by N-methyl-N-nitrosourea.

The sequence-specific alkylation of DNA by N-methyl-N-nitrosourea (MNU) has been demonstrated for the minor groove N3-methyladenine (N3-MeAde) adduct using neutral thermal hydrolysis and polyacrylamide sequencing gels. The ratio of relative yields of N7- and N3-MeAde and N7-methylguanine (N7-MeGua) is approximately 0.03:0. 15:1.00, respectively, on the basis of the gel data, and these values are comparable to relative yields determined by bulk digestion of MNU-methylated DNA when HPLC was used to analyze the individual adducts. In contrast to the methylation at N7-guanine (N7-Gua) by MNU, alkylation at Ade shows minimal sequence selectivity. Similar to the methylation at N7-Gua, formation of N3-MeAde by MNU is inhibited by 50-200 mM concentrations of NaCl and DNA binding cations, including distamycin and spermine. However, N3-MeAde formation at Ade residues within methidiumpropyl-EDTA-Fe(II) footprinted distamycin DNA affinity binding regions is selectively inhibited at low concentrations of distamycin relative to Ade sites outside of ligand binding regions, and N7-Gua within or outside the distamycin binding regions. HPLC analysis shows that distamycin also quantitatively inhibits the production of N3-methylguanine when calf thymus DNA is treated with MNU or methyl methanesulfonate. The specific inhibitory effect of distamycin, which binds in the minor groove at Ade/Thy-rich sequences, provides additional evidence that the predominant DNA lesion detected at Ade by sequencing gel analysis involves minor groove N3-MeAde modifications.

Adenine↗

PubMed2006

[Somnolence of unknown origin--illness or drug problem?].

A 64 year old female patient with previously known temporal lobe epilepsy (TLE) was admitted to the emergency department (ED) for further investigation of somnolence of unknown origin. Differential diagnosis remained puzzling after exclusion of an intracranial process and status epilepticus. Quantitative and qualitative fluctuations of consciousness are well known to take place in TLE as well as that these patients often are receiving several drugs for their illness. Drug history and measuring serum drug levels are helpful. Adverse Drug Events (ADE) are not rare in EDs: approximately 5% of ED patients are suffering an ADE and about 3% of patients admitted to hospitals are admitted because of an ADE. It is important to realize that three out of four ADEs are estimated to be preventable.

Anticonvulsants↗

PubMed1999

Towards system-wide strategies for reducing adverse drug events.

Despite the best efforts of committed health-care workers, there are many adverse drug events (ADE). A large proportion of ADE arise from system factors, either directly (e.g. poor equipment design) or indirectly (e.g. inappropriate rostering of staff). This paper represents the proceedings of a workshop focus group that deliberated on priority health-system issues identified as requiring action in order to minimise the risks of ADE. Major issues canvassed were the gathering of appropriate and useful data about ADE, the dissemination of information to professionals and consumers, and effective communication across groups of professionals, and between professionals and consumers. A number of recommendations were put forward as important first steps in addressing these issues.

Australia↗

PubMed1989

Assessment of adverse drug events during the clinical investigation of a new drug.

Identification and documentation of adverse drug events (ADEs) is an essential prerequisite for the evaluation of the therapeutic value of drug treatment. The present article focuses on the methods used to elicit ADEs during the early drug development phase. These methods vary in the sources of information (patient or physician) used to identify and document ADEs and in the areas (e.g., general scales or special motor performance scales) studied for ADEs.

Documentation↗

PubMed1981

On the molecular basis of transition mutations: frequencies of forming 2-aminopurine.cytosine and adenine.cytosine base mispairs in vitro.

We address the question of whether substituting 2-aminopurine (APur) in place of adenine (Ade) in DNA can increase the frequency of base mispairing with cytosine. Using DNA polymerase alpha to measure the rates of inserting deoxycytidine and thymidine nucleotides in direct competition with each other for APur or Ade sites on synthetic copolymer DNA templates, we observe that the ratio of dCMP to dTMP insertion is increased by a factor of at least 230 when APur replaces Ade on a poly(dA) template and by a factor of 35 when APur replaces Ade on a poly(dC,dA) template. These data support the idea that APur.C base mispairs are directly involved in APur induction of A.T leads to G.C transition mutations. The observed misinsertion frequency of cytosine substituting for thymine opposite template APur sites is about 5%. This value is in excellent agreement with earlier predictions and measurements for APur.C heteroduplex-heterozygote frequencies in T4 bacteriophage in vivo.

2-Aminopurine↗

PubMed1996

Characterization of the upstream sequence of the human CYP11A1 gene for cell type-specific expression.

The CYP11A1 gene encodes the cholesterol side-chain cleavage enzyme P450scc, which catalyzes the synthesis of steroids from cholesterol. This gene is expressed only in steroidogenic organs such as the adrenal, gonad, placenta, and brain. We have characterized an upstream regulatory element of the human CYP11A1 gene, termed AdE, which contributed to its cell type-specific expression. The AdE sequence contains two protein binding regions, AdE1 and AdE2, which bind many proteins including NF1- and Sp1-like proteins as shown by electrophoretic mobility shift assay, footprinting, competition, antibody supershift, and mutagenesis of the binding sites. When cloned in front of the CYP11A1 promoter or the heterologous thymidine kinase promoter, AdE sequences enhanced expression of the reporter gene in steroidogenic cell lines of the adrenal, gonad, and placental origin but not in nonsteroidogenic cell lines such as COS-1 and Rat-1. The function of AdE1 and AdE2 was lower when present individually than together. The combined action of multiple transcription factors binding to the AdE sequence brings about the final activation of the CYP11A1 gene in a tissue-specific manner.

Base Sequence↗

PubMed2004

ASHP national survey of pharmacy practice in hospital settings: monitoring and patient education--2003.

PURPOSE: Results of the 2003 ASHP national survey of pharmacy practice in hospital settings that pertain to monitoring and patient education are presented. METHODS: A stratified random sample of pharmacy directors at 1173 general and children's medical-surgical hospitals in the United States was surveyed by mail. SMG Marketing Group, Inc., supplied data on hospital characteristics; the survey sample was drawn from SMG's hospital database. RESULTS: The response rate was 47.1%. Virtually all hospitals (95.3%) had pharmacists regularly monitoring medication therapy in some capacity. Patient monitoring has improved since 2000; fewer respondents reported monitoring less than 25% of patients in the hospital, and most hospitals reported an increase in the amount of time pharmacists devoted to monitoring activities. Pharmacists were provided computer access to laboratory information in 78% of hospitals to facilitate this function. Detection and reporting of adverse drug events (ADEs) have substantially increased since 1999, with an increase of 42% in events reported internally. Strategies to improve ADE reporting were in place in 84% of hospitals, indicating that pharmacists are adopting the widely recommended philosophy of learning from errors. Errors were less widely reported externally, limiting the value of aggregated data for improving the medication-use process. Most hospitals (85.5%) had an interprofessional infrastructure in place to discuss and learn from voluntary reports of ADEs. Medication counseling continued to be relatively infrequent, with nearly three fourths of hospitals reporting fewer than 26% of inpatients received medication education. Pharmacist staffing in hospitals has risen significantly, from an average of 8.6 full-time equivalents (FTEs) in 2002 to 9.4 FTEs per hospital. Vacancy rates for pharmacists decreased from 7.3% in 2002 to 43%. It is now estimated that there are 1846 vacancies in hospital pharmacies. CONCLUSION: Notable improvements in hospital pharmacy practice have been made. The percentage of patients whose medication therapy is monitored by pharmacists has increased, and most hospitals reported that the amount of time pharmacists spent monitoring patients' medication therapy had increased. Internal and external reporting of ADEs has increased, and pharmacist vacancies have decreased from 2002. Staffing has also improved, suggesting an abatement of the critical shortage of pharmacists in the hospital setting.

Adverse Drug Reaction Reporting Systems↗

PubMed1992

Studies of antibody-dependent enhancement of human immunodeficiency virus (HIV) type 1 infection mediated by Fc receptors using sera from recipients of a recombinant gp160 experimental HIV-1 vaccine.

Subneutralizing concentrations of sera from human immunodeficiency virus (HIV)-1-infected patients augment HIV infection mediated by Fc receptor uptake by human monocytes and the monocytic cell line U937. Antibody-dependent enhancement (ADE) and neutralization activity were studied in the sera of HIV-1 antibody-negative volunteers who had been immunized with three 40-micrograms doses of a recombinant gp160 (rgp160) candidate HIV vaccine. Volunteers were vaccinated with rgp160 or a hepatitis B vaccine as a control on days 0, 30, and 180. Sera were obtained before and after three doses of vaccine and were tested for ADE and neutralization activity. Serum samples collected before vaccination showed neither neutralization nor ADE activity. Thirteen sera from volunteers who received gp160 and four from placebo recipients failed to show ADE. Three sera showed low levels of neutralization of strain IIIB of HIV. Vaccination with this dose of rgp160 produced neutralizing antibodies in some subjects but did not induce detectable enhancing antibodies.

AIDS Vaccines↗

PubMed1988

9-[(10-(aden-9-yl)-4,8-diazadecyl)amino]-6-chloro-2-methoxy-acridine incises DNA at apurinic sites.

The incision of DNA at apurinic/apyrimidinic sites (AP-sites) by chloro-6-methoxy-2 [(adenyl-9)-11)-4,8 diazadecyl]amino-9 acridine (Ade-Z-Acr), a 9-aminoacridine linked to an adenine, at nanomolar concentrations is described. Moreover, this drug, Ade-Z-Acr, is one of the most efficient drugs which cleaves DNA at AP-sites. The high activity is the result of the composition of the drug, since the individual components have no incising activity in the concentration range studied. The termini left by the Ade-Z-Acr molecule are a 3'deoxyribose and a 5'nucleotide. The termini and the inability of the Ade-Z-Acr to incise DNA with reduced AP-sites suggest that the mechanism of cleavage is beta-elimination.

Acridines↗