9-Aminoacridines, synthesis

Fermentation, 22, 53 Ferric nitrate, 23, 20 Fieser s solution, 21, 110 Filter fabric, Pyrex glass, 22, 33, 65 Vinyon, 22, 33, 67 Filter paper, hardened, 22, 45 Fischer indole synthesis, 22, 98 Flash distillation, 21, 85 Flask, modified Claisen, 22, 11 Fluorescence of 9-aminoacridine hydrochloride, 22, 7 Formaldehyde, 20, 60 Formalin, 22, 66 Formic acid, 20, 66, 102 23, 43 Formic acid, chloro-, benzyl ester, 23, 13... 

Ullmann and Fetvadjian reported the modification which made the synthesis more generally useful, when they heated together equimolar amounts of an aromatic amine and a phenol with paraformaldehyde or with benzaldehyde, thus making it possible to obtain unsymmetrical acridines (03CB1027). Thus, from 2-naphthol and 1-naphthylamine they obtained dibenzo[c,/]acridine (613), and from 2-naphthol and 2-naphthylamine dibenzo[c,fi]acridine (614). In a similar manner, from 1-aminoacridine and the two naph-thols are obtained the benzo [a]- and benzo[c]-naphtho[2,3-fi]acridines (615) and (616), and from 2-aminoacridine and the naphthols the benzo[a]- and benzo[c]-naphtho[2,3-/]acridines (617) and (618) (69JCS(C)1337). The isomeric benzofa]- and benzo[c]-... 

Filter paper, hardened, 22, 45 Shark skin, 25, 97 Fischer indole synthesis, 22, 98 Flash distillation, 21, 85 Flask, modified Claisen, 22,11 Fluorescence of 9-aminoacridine hydrochloride, 22, 7... 

Acridine Syntheses and Reactions. Part III. Synthesis of Aminoacridines from Formic Acid and Amines. 

In an extension of this method, the corresponding 9-arylamino derivatives result directly when the ester, cyclohexanone and an arylamine hydrochloride are heated with phosphorus pentoxide and -dimethylcyclohei lamine. Under these conditions, anthranilamide affords the unsubstituted 9-aminoacridine, presumably yia the nitrile (N.S. Girgis and E.B. Pedersen, Synthesis, 1985. 547). 

The cyclocondensation of enaminones with an aromatic nitrile was previously used for the synthesis of 9-aminoacridines analogous to Tacrine, which is a pharmaceutical agent against Alzheimer s disease (equation 34). Similarly acyclic enaminones serve as useful precursors for synthesis of the quinoline ring system as shown in equation 35. ... 

JOC865). They used 4-aminoacridone 88 and 4-aminoacridine 89 as the starting materials (Scheme 16). The Skraup synthesis was also applied to the preparation of quino[8,7-h][l,10]phenanthroline 91 and its 7-oxo derivative 92 (62JOC865). 

P. E. Nielsen, J. B. Hansen and O. Buchardt, Photochemical cross-linking of protein and DNA in chromatin. 1. Synthesis and application of a photosensitive cleavable derivative of 9-aminoacridine with 2 photoprobes connected through a disulfide-containing linker, Biochem. J., 1984, 223, 519-526. 

It has been shown, in vitro, that proflavine (30 /xM) inhibits bacterial DNA polymerase by 85% and RNA polymerase by 30% (Hurwitz etaL, 1962). Some typical data for the RNA system are shown in Fig. 10.4. The inset graph (of the reciprocal of the velocity plotted against the reciprocal of the DNA-primer concentration) points to the site of action of proflavine as being mainly on this primer, thus inhibiting DNA and RNA synthesis in the living bacterium. The intercalating mechanism by which aminoacridines combine with DNA helices and impede strand separation is outlined in the next Section (10.3.2). 

At least of historic interest, suggested modes of action, other than intercalation into DNA, for the antibacterial aminoacridines will be briefly discussed. It has been considered whether acridines exert some of their antibacterial action by inhibiting other enzymes. However, the known inhibitions do not seem to be very serious and usually require high concentrations, whereas quite low concentrations of aminoacridines upset the synthesis and functioning of nucleic acids (see Chapter 22 in Albert, 1966). 

Albert, A. Acridine syntheses and reactions. III. Synthesis of aminoacridines from formic acid and amines. J. Chem. Soc. 1947, 244-250. 

Reagents for the syntheses were obtained from Aldrich Chemical Co. (organic) and MCB (CUCI2 2H2O). The six bis(9-aminoacridine) compounds were supplied by the Drug Synthesis and Chemistry Branch, Division of Cancer Treatment, National Cancer Institute. 3-Methoxy-o-benzoquinone was prepared by a published method , m.p. 114-116 C, reported 107-110 C27. 

Envelope-free chloroplasts were prepared and essayed as previously (de Kouchkovsky et al., 1982) for the ApH (9-aminoacridine method) and ATP synthesis (ferricyanide photoreduction). AH was related to the electro-chromic absorbance variation at 520 nm measured on the same sample than the other phenomena, just shifting the analytic wavelength and using appropriate filters. The assay medium was sorbitol 0.2 M + Tricine 0.01 M + Hepes 0.01 M + KCl 0.01 M + MgCl2 6 mM + K2HPO4 2 mM + ADP 0.5 mM + 9-aminoacridine 4 yM. DimethyIquinone (0.5 mM) or pyocyanin (50 yM) were added when indicated. Chlorophyll concentration was 15 yM. Aerobic conditions. 

Actinomycin D is remarkably specific in inhibiting the synthesis of ribosomal RNA (DNA-primed) without any effect on the synthesis of DNA (Reich et al,y 1962). Use of radioactive actinomycin showed that it was covalently bound to the guanine of the DNA starter, and did not combine with any other cell component at concentrations that block RNA synthesis. The phenoxazine nucleus intercalates into DNA near to a G-C pair, and the peptide portions project into the minor groove (Muller and Crothers, 1968) (for more on intercalation see Section 10.3b). Whereas the action of the aminoacridines is sensitive to magnesium ions and insensitive to urea, precisely the reverse is true of actinomycin. Again, proflavine prevents the enzymatic synthesis of guanine-free polynycleotides, but actinomycin does not. 

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