Acridine Molecule Research Articles

Influence of the out-of-plane distortions of nuclear configurations of molecules with then-AO of the heteroatom directed along theC 2 symmetry axis on spin-orbit coupling between thenπ*- and ππ*-states

This paper studies changes in the matrix elements (Ump) of spin-orbit coupling between the nπ*- and ππ*-states, which are induced by the (“chair,” “bath”) distortions of the nuclear configurations of molecules. The analysis is performed for acridine molecules in which the n-pz atomic orbital (AO) of the heteroatom is directed along the C2 symmetry axis. Earlier, for molecules with a planar nuclear configuration of C2v symmetry and with the heteroatom lying on the C2 axis, we established the dependence of Ump on the symmetry of ππ*-states [Γ(ππ*)=A1 or B2]. The values of Ump differ by more than one order of magnitude; this is in line with the difference between the interconversion rate constants (Kisc; two or three orders). In this work we have found that this contrast in Ump (and, accordingly, in Kisc) is retained when the nuclear configuration of the acridine molecule is distorted to the “chair” (AC-A) configuration, although the individuality of both molecular orbital types (nσ-MO and π-MO) and states nπ* and ππ* is annihilated to a certain extent. For the “bath” (AC-B) conformation the difference in Ump considerably diminishes. Reasons for the changes in the matrix elements of spin-orbit coupling and rate constants of the S-T conversion are analyzed. The available energy level diagram is critically analyzed, and a slightly different diagam as well as a scheme of nonradiating deactivation of acridine are suggested.

Intersystem crossing in molecules of aromatic compounds with their heteroatom on the C2 symmetry axis. Acridine

The electronic spectrum and matrix elements U mp of spin-orbit interactions, mixing electronic states of different types (nπ* and ππ*) in an acridine (AC) molecule, are calculated in an INDO/S approximation. In planar molecules, the np z AO being on the C 2=C z axis, the rate constant values K isc are found to differ by three orders of magnitude depending upon the symmetry of the states Γ(ππ*) = A 1 or B 2 (the elements U mp are 10 and 0.3 cm −1, respectively). The regularity of U mp variation, as the nuclear configuration of the molecule changes from planar to non-planar (in “butterfly” or “arm-chair” forms), is established. Scheme I of electron energy levels and deactivation of the S 1 (ππ*) state of the AC molecule is suggested instead of the Scheme K from previous studies. In Scheme I the main channel of deactivation results from the fast conversion S 1 ⇝ T 3( K isc = K 4 = 5 × 10 11s −1) from the state 1 A 1(ππ*) to 3 B 1(nπ*).

1:1 Molecular complex of acridine with 1,2,4,5-benzenetetracarbonitrile: refinement in space group P1

The crystal structure of C_(13)H_9N.C_(10)H_2N_4, which was originally described and refined in space group P1 [triclinic; a = 7.447 (4), b = 7.885 (5), c = 8.072 (9) A, α = 73.93 (9), β = 84.59 (9), γ = 85.85 (6) °, Z = 1; Toupet, Miniewicz & Ecolivet (1989). Acta Cryst. C45, 1044-1047], is better described in P1[bar]. The P1[bar] description entails disorder, with the N and CH groups of the central ring of the acridine molecule being indistinguishable. Revised coordinates are given.

Structure-activity investigation of the alteration of the physical state of the skeletal network of proteins in human erythrocyte membranes induced by 9-amino-1,2,3,4-tetrahydroacridine

The oral administration of 9-amino-1,2,3,4-tetrahydroacridine (THA) is purported to increase the mental function of Alzheimer's disease patients (Summers et al. (1986) N. Engl. J. Med. 315, 1241–1245). Numerous erythrocyte membrane proteins are known to be identical or highly similar to neuronal proteins. In a previous study (Butterfield and Palmieri ((1990) Free Radical Res. Commun., in press), we showed that THA greatly increased skeletal protein-protein interactions in erythrocyte membranes as monitored by a spin label specifically bound to membrane proteins. In this report, a structure-activity study has been performed to determine which THA structural components are involved in its effect on the physical state of human erythrocyte membrane skeletal proteins. The results imply that both the planarity of the molecule and the amino group at the 9-position of the parent acridine molecule are important in the mechanism of interaction with membrane proteins.

Identification of an acridine photoaffinity probe for trypanocidal action.

Twenty-four acridine derivatives were screened for trypanocidal activity in Trypanosoma brucei in order to determine which structural features of the acridine molecule confer maximal antiparasitic activity. The synthesis of several new azidoacridine derivatives are also reported as well as an assessment of their value as possible photoaffinity probes for the study of acridine trypanocidal action. The most effective and selective acridine trypanocides, with and without irradiation, were the 3-amino-10-methylacridinium salt derivatives. With brief irradiation, one azidoacridine, 3-amino-6-azido-10-methylacridinium chloride, showed considerable trypanocidal activity at very limiting drug concentrations (10(-7)M) and warrants consideration as a possible photoaffinity probe.

Genotoxicity of acridine orange and acriflavine in Drosophila melanogaster

Acridine compounds and their derivatives are widely used in medicine, industry and science (Browning, 1964; Albert, 1966; Nasim and Brychcy, 1979). Acridine orange (AO) and acriflavine (AF), as other acridine derivatives, are compounds that are mutagenic in a wide variety of organisms. (For more detailed information see the excellent review of Nasim and Brychcy, 1979.) The mutagenicity of these compounds is postulated as being due to the intercalation of the acridine molecule between adjacent nucleotide pairs o f DNA (Drake, 1970). This results in the addition or removal of one or several base pairs, producing frame-shift mutations (Roth, 1974). Only two early experiments have been done on the mutagenic activity of acridine orange (Clark, 1953) and acriflavine (Demerec, 1949) in Drosophi la melanogaster . From these experiments there is evidence that both acridines are weakly mutagenic in the sex-linked recessive lethal test. Nevertheless, only one spermatogenic stage was analysed and a low number of chromosomes was tested. In view of this, we decided to investigate in males the induction of sex-linked recessive lethals and sexchromosome loss caused by AO and AF to obtain a more comprehensive picture of the mutagenic properties of these compounds in D. melanogaster .

Protolytic reactions of acridine in the triplet state

The triplet—triplet (T—T) absorption spectrum of the acridinium ion (λ max=490 nm) was measured in acidic aqueous solution at pH 1.0 by means of the triplet energy transfer from the disodium salt of naphthalene disulphonic acid to the acridinium ion. The triplet acridinium ion decays by a first order process with a rate constant of 1.5 × 10 3 s −1 at a pH below about 3.8. The p Ka of acridine in the triplet state was determined to be 5.6 at 23°C from the measurements of T—T absorption spectra of both the acridine molecule and the acridinium ion. The rate constants for protonation and deprotonation in the triplet state were determined to be (3.4 – 3.8) × 10 10 M −1 s −1 and (8.5 – 9.5) × 10 4 s −1 respectively.

Visualization of drug-nucleic acid interactions at atomic resolution: IV. Structure of an aminoacridine-dinucleoside monophosphate crystalline complex, 9-aminoacridine-5-Iodocytidylyl (3′–5′) guanosine

9-Aminoacridine forms a crystalline complex with the dinucleoside monophosphate, 5-iodocytidylyl(3′–5′)guanosine (iodoCpG). These crystals are monoclinic, space group P2 1 with a = 13.98 A ̊ , b = 30.58 A ̊ , c = 22.47 A ̊ and β = 113.9 °. The structure has been solved to atomic resolution by Patterson and Fourier methods, and refined by a combination of Fourier and sum-function Fourier methods. The asymmetric unit contains four 9-aminoacridine molecules, four iodoCpG molecules and 21 water molecules, a total of 245 atoms. 9-Aminoacridine demonstrates two different intercalative binding modes and, along with these, two slightly different intercalative geometries in this model system. The first of these is very nearly symmetric, the 9-amino group lying in the narrow groove of the intercalated base-paired nucleotide structure. The second shows grossly asymmetric binding to the dinucleotide, the 9-amino group lying in the wide groove of the structure. Associated with these two different intercalative binding modes is a difference in geometries in the structures. Although both structures demonstrate C3′ endo (3′–5′) C2′ endo mixed sugar puckering patterns (i.e. both cytidine residues have C3′ endo sugar conformations, while both guanosine residues have C2′ endo sugar conformations), with corresponding twist angles between base-pairs of about 10 °, they differ in the magnitude of the helical screw axis dislocation accompanying intercalation (Sobell et al., 1977 a,b). In the pseudosymmetric intercalative structure, this value is about +0.5 Å, whereas in the asymmetric intercalative structure this value is about +2.7 Å. These conformational differences can be best described as a “sliding” of base-pairs on the intercalated acridine molecule. Although the pseudosymmetric intercalative structure can be used in 9-aminoacridine-DNA binding, the asymmetric intercalative structure cannot since this poses stereochemical difficulties in connecting neighboring sugar-phosphate chains to the intercalated dinucleotide. It is possible, however, that the asymmetric binding mode is related to the mechanism of 9-aminoacridine-induced frameshift mutagenesis (Sakore et al., 1977), and we discuss this possibility here in further detail.

Radical pair formation from excited states in doped aromatic crystals. I. Epr studies of the guest-host system acridine-fluorene

Following light absorption in acridine doped fluorene single crystals formation of a triplet state complex (heteroexcimer) has been established earlier. More detailed EPR investigations presented here permit the clarification of the nature of this complex. Hyperfine structure has been resolved for three nuclear spins which could be assigned by selective deuteration experiments: the nitrogen and meso-proton spin located in the guest-constituent of the complex and one proton spin originating from the CH 2-group of a fluorene host molecule. The complete hyperfine tensors could be evaluated. The anisotropy is found to be that of a planar aromatic CH-fragment for both observed proton spins. As a consequence of the CH-fragment assignment the central CH 2-group of the fluorene constituent of the complex has to change from a sp 3 to a planar sp 2 configuration indicating a photoinduced radical pair formation involving hydrogen abstraction from a fluorene and hydrogen addition to an acridine molecule. The model is able to explain: (a) the high spin density located at the observed CH-fragments; (b) the geometry of the molecular partners involved in the complex, and (c) the fine structure tensor on the basis of a simple point charge dipole-dipole coupling of the two unpaired electron spins.

Linear and circular dichroism studies of DNA-monoaminoacridine complexes

The circular dichroism spectra of the DNA complexes with 1-, 2-, 3-, 4- and 9-aminoacridine and with four monoaminobenzacridines have been measured over a range of DNA-phosphate to dye ratios and, in the case of the 9-aminobenzo[a]acridine complex, over the pH range 3.3–10 and at high and low ionic strength. The linear dichroism spectra of streaming solutions of the DNA-dye complexes have been obtained with light propagated parallel and perpendicular to the flow-direction. The relations between the fraction of dye bound and the free dye concentration have been determined by spectrophotometric and by polarographic methods. The degree of binding at physiological pH is found to correlate with the relative antibacterial and mutagenic activities of the monoaminoacridines. The spectroscopic results support a modified intercalation model for the DNA-acridine complex in which the bound acridine molecule is sandwiched between two adjacent bases attached to a common sugar phosphate chain, and they indicate that a reduction of pH produces an unwinding of the two strands of the DNA helix additional to that due to the intercalation of bound dye.

Fine Structure of Bacteria Grown in the Presence of Acriflavine

The effect of acridine derivatives on bacterial growth has been shown to be dependent upon the concentration used, pH, temperature, and the position of the amino substituents on the acridine molecule. These factors, in turn, affect the amount of acridine bound to cell constituents. Many bacterial species, when grown in media containing acridities, become filamentous, or pleomorphic, or growth may be entirely prevented. The fine-structure of two species of bacteria treated with acriflavine was investigated. Both were Gram-positive bacilli, one was a Corynebacterium, and the other an aerobic spore-bearing Bacillus.Organisms were incubated at 21°c in the presence of concentrations of acriflavine ranging from 0.25 ug/ml to 12 ug/ml in phosphate buffered peptone water yeast extract medium at pH 7.5. Viable counts were carried out and the amount of acriflavine bound, either reversibly or irreversibly, was estimated at 450 mu, using a DB spectrophotometer. Cultures were observed by light microscopy and, after four days growth, were processed for electron microscopy by fixation in veronal-acetate pH 6.1 buffered 0.8% Os O4 for one hour and embedding in Epon 812 resin.

Relationships between antiseptic action and chemical constitution with special reference to compounds of the pyridine, quinoline, acridine and phenazine series

In the course of investigations on the antiseptic properties of certain basic benzene derivatives, it was shown that the methochloride of diaminoacridine was very highly antiseptic, and that, unlike other powerful antiseptics then known, its antibacterial activity was not reduced by the presence of blood serum (Browning, Gilmour, Gulbransen, Kennaway and Thornton, 2, 7). Diaminoacridine methochloride had been prepared by Benda (1) for Ehrlich, and was named by them trypaflavin on account of its powerful therapeutic properties in experimental trypanosome infections. We are not aware that its action on bacteria had been investigated prior to the work recorded in the above paper (2), although Shiga (10) published almost simultaneously results of his investigations on its action onV. choleræThe hydrochloride and sulphate of diaminoacridine were then found to be practically equal to the methochloride in antiseptic properties and in efficacy of action in serum (8). In the case of these aminoacridine substances the power of killing bacteria is exerted slowly; thus, with the methochloride acting onB. coliin serum, the concentration which proves lethal in 2 hours (1:20000) is five to ten times greater than that required to produce sterility after 24 hours; on the other hand, mercuric chloride and carbolic acid produce their maximum effect within 2 hours, whether they be tested in a solution containing a minute amount of protein (0·7 per cent, of Witte’s peptone) or in a rich protein medium such as serum. The acridine compounds, therefore, may be said to act especially as bacteriostatic agents (7, 8). This property, coupled with their relative innocuousness for mammalian tissues, as tested by toxicity for the living animal as a whole (4, 7), effect on phagocytosis (3, 7), and slight irritating action on the conjunctiva (7), suggested that these substances should be specially applicable for the purpose of restraining bacterial infections in the tissues. Thus the methochloride, under the name of acriflavine, and the sulphate of diaminoacridine base, as proflavine, found extensive use in the treatment of infected wounds during the late war, and also in the treatment of such relatively accessible infections as gonorrhoea. The present work records the investigations which have been made with lire view of tracing the source of the antiseptic property of diaminoacridine compounds by examining substances which may be regarded as fragments of the acridine molecule. The parent substance of the acridine derivatives is a compound of the following formula that is, a combination of two benzene and a pyridine ring. If the two side wings are removed, a pyridine nucleus remains; if only one wing is detached, a quinoline nucleus results. It seemed, therefore, possible that the antiseptic activity of acriflavine (diamino acridine methochloride) might reside either in the pyridine or quinoline nucleus, reinforced by one or more amino groups. It is for this reason that substances of this type were first examined. In addition, a series of acridine derivatives have been prepared and tested for their antiseptic power in order to determine, if possible, whether any law could be established relating chemical structure and antiseptic action within the group. Also, observations have been made upon phenazine compounds, on account of their close chemical relationship to the acridine group.

Societies and Academies

LONDON. Royal Society, February 16.—Sir Charles Sherring-ton, president, in the chair.—L. Hill, D. H. Ash, and J. A. Campbell: The heating and cooling of the body by local application of heat and cold. When the hands are heated or cooled by water the amount of heating or cooling is large, but not constant for a given range of temperature. The degree of heating or cooling is obtained from the temperature of the skin over the median vein at the elbow, the thermometer used being coiled and insulated from the air. Loss of 20 to 25 kilo-calories of heat from the hands in thirty minutes, i.e. a loss almost equal to the basal metabolism, does not appreciably affect the body metabolism.—J. B. Cohen, C. H. Browning, R. Gaunt, and R. Gulbransen: Relationships between antiseptic action and chemical constitution, with special reference to compounds of the pyridine, quinoline, acridine, and phenazine series. Certain acridine derivatives, salts of diamino-acridine and the methochloride of this base, are extremely potent antiseptics. Pyridine and quinoline derivatives (“fragments” of the acridine molecule), a number of acridine derivatives, and some phenazine compounds were also investigated, but none approximate to diamino-acridine in antiseptic properties. Dealing with the acridine group, the presence of amino-groups increases antiseptic power, and effectiveness in serum Is a characteristic of compounds with unsubstituted amino-groups, and especially of their methochlorides. Other radicals replacing the methyl group in the methochloride do not alter the antiseptic action, but substitution of alkyls in the amino-group tends to diminish antiseptic action, while acetylation or replacement of the amino-group destroys it. Antiseptic action on organisms of different types shows marked irregular variation.—D. T. Harris: Active hyperasmia. The lingual nerve contains true vaso-dilator and the sympathetic vaso-constrictor fibres; both are equally Independent of the intervention of metabolites. Experiments show that increased blood-supply during muscular activity is due entirely to the products of metabolism, and of the metabolites estimated carbon dioxide and α-hydroxy organic acids were increased. Vaso-dilator nerves are concerned with the control of body temperature; active hyperaemia in the dog's tongue may be induced by reflex excitation of the vaso-dilator nerves through the stimulation of heat receptors in the skin.—B. B. Sarkar; The depressor nerve of the rabbit. The depressor nerve of the rabbit is connected in part with a special collection of ganglion-cells in the vagus, distinct from the ganglion of the trunk, which may extend into the superior laryngeal or the vagus trunk. These cells probably give rise to the afferent fibres of the depressor. The nerve is usually formed by two branches, one from the superior laryngeal and one from the vagus, and is connected with the inferior cervical ganglion, the root of the aorta, and the base of the heart. The left nerve of the pair is generally larger and contains more fibres than the right. The depressor contains medium-sized and very fine myelinated fibres, and others which are non-myelinated. Probably it is not wholly formed of afferent fibres, for these fine myelinated and non-myelinated fibres presumably belong to the autonomic nervous system and are efferent.—A. Lipschütz, B. Ottow, C. Wagner, and F. Bormann: The hypertrophy of the interstitial cells in the testicle of the guinea-pig under different experimental conditions. Partial castration often causes enormous hypertrophy of the interstitial tissue. This hypertrophy is not compensatory, for the tendency to hypertrophy of interstitial cells is more marked in fragments with improved blood-supply. Hypertrophy appears to be independent of the internal secretory function of the testicle in its relation to the organism as a whole, and is a response to local conditions.