9-Substituted acridines

Because of the close relations between lucigenin, N-alkylacridones, and other 9-substituted acridines, it appears appropriate to consider the chemiluminescence reactions of all these compounds simultaneously. 

In the Bernthsen synthesis, diphenylamine 61 and carboxylic acids form 9-substituted acridines 62 (Scheme 31). 

Diphenylamine reacts with carboxylic acids in the presence of Lewis acids (e.g. AICI3, ZnCl2) forming 9-substituted acridines 20 (Bernthsen synthesis) ... 

A mixture of 0.06 mol diphenylamine, 0.03 mol benzoic acid, and 230-250 g polyphos-phoric acid was heated with stirring at 195-205°C for 15 min. The reaction mixture was then poured onto ice and filtered or decanted. Examination of the infrared spectra of the gummy solid indicated that it contained mainly diphenylamine, a small amount of ketonic product, and possibly some 9-substituted acridine. Treatment of the solution with 25% sodium hydroxide solution caused the precipitation of a solid (while the solution was still acidic), which was apparently the phosphate salt of the 9-phenyl acridine. This product was washed with water and alcohol to give analytically pure material after drying in vacuo. The yield was 18%, m.p. 184-185°C. 

Kitani, K. The syntheses of 9-substituted acridines, ni. Reaction of 9-amino- and 9-(alkylamino) acridines with amines. Nippon Kagaku Kaishi 1954, 75, 477 80 Chem. Abstr. 1955, 49, 53549. 

A modification of the Bemthsen reaction uses polyphosphoric acid instead of zinc chloride however, the conditions are also quite vigorous with respect to the temperature (200 °C 15 min) in addition, the yields of 9-substituted acridines were low (1962JOC2658). In 2002, two synthetic procedures have been published, which use microwave conditions and zinc chloride as catalyst to prepare 125 from 124 (2002SC729 2002MI390 Scheme 44). Reaction conditions for the synthesis of 9-substituted acridines have been optimized for microwave conditions in the presence of 2,2-dime-thoxypropane as water scavenger very recendy (2014H(89) 1877). 

Harrison RJ et al. (1999) Human telomerase inhibition by substituted acridine derivatives. Bioorg Med Chem Lett 9(17) 2463-2468... 

Di GC, De MM, Chiron J, Delmas F (2005) Synthesis and antileishmanial activities of 4, 5-di-substituted acridines as compared to their 4-mono-substituted homologues. Bioorg Med Chem 13 5560-5568... 

Figure 13. CD spectra of various substituted acridines upon binding to calf thymus DNA. Data are shown for (a) 1-aminoacridine, (b) 2-aminoacridine,...

Fig. 3 (a) General reaction of reversible amine exchange between a 9-amino substituted acridine and a large excess of free amine, (b) Proposed mechanism of the amine exchange reaction via formation of a 9,9-diaminoacridine hemiaminal intermediate... 

Reaction of the tetraketone 355 with nitroanilines in the presence of catalytic amount of P2O5 in ethanol gave 356. Reduction of the m-nitro group to the amine with Zn/HCl was successful whereas the p-nitro was unsuccessful. The reaction of 355 with N-amino ethyl piprazine or thiosemicarbazides in acetic acid gave the respective N-substituted acridines 356 (04ARK124). 

Fig, 20. Synthesis of substituted acridine-9-carboxyIic acids according to the method of StoIIe (S46), where / = H or MeO [adapted from Zomer et al. (Z6)]. 

Fig. 22. Conversion via the acid chloride of a substituted acridine-9-carboxylic acid into an ester...

The anthraquinone derivative (2) represents the first example from 1997, with numerous others following in rapid succession, including the dibenzo-phenanthroline derivatives and tri-substituted acridines (3), which were reported to inhibit telomerase action in tumour cell lines with IC50 values of up to 28 and 60 nM, respectively. The tri-substituted acridines (3) were developed from the simple acridine (4) on the basis of structure-based design principles to maximise the quadruplex binding affinity. Thus, inhibition of telomerase by these compounds appears to be correlated to selective stabilisation of the human DNA quadruplex structure. Tetra-(A-methyl-4-pyridyl)-porphyrins... 

Dibenz[c/][l,2]oxazepines (81) are obtained as the principal products from the photolysis of the substituted acridine A-oxides (80) in benzene. The electron-withdrawing substituents help stabilize the antiaromatic 1,2-oxazepine moiety. On refluxing in benzene, (81b) is converted mainly back to the starting A-oxide, while on heating (81a) in aqueous acetonitrile at 60 °C, the main product is an... 

This reaction has generally been used to prepare substituted acridines, which can be converted into quinolines. ... 

Giorgio, C.D., Shimi, K., Boyer, G., Dehnas, F. and Galy, J.R 2007. Synthesis and antUeish-manial activity of 6-mono-substituted and 3,6-di-substituted acridines obtained by acylation of proflavine. Eur. J. Med Chem. 42(10) 1277-1284. 

Ferguson, L. R. Denny, W. A. MacPhee, D. G. Three consistent patterns of response to substituted acridines in a variety of bacterial tester strains used for mutagenicity testing. Mutat. Res. 1985, 157, 29-37. 

Formation of 5-substituted acridines by heating diarylamines in organic acids or anhydrides, usually in the presence of zinc chloride ... 

On the other hand, when o -adducts of arylacetonitrile carbanions to para-substituted nitroarenes are converted into substituted nitrosoarenes in aprotic media via silylation in the presence of trialkylamines, the produced o-nitrosoaryl acetonitriles can undergo further hetero-cyclization on alternative pathway to produce substituted acridines [28]. Reactions of arylacetonitriles with nitroarenes unsubstituted in the para position under identical protic conditions result in the formation of p-nitrosoaryl arylacetonitriles that can be isolated in the tautomeric form of p-arylcyanomethylene quinone oximes (Scheme 11.13) [27b]. 

AMI studies of the 2 - - 2-cycloaddition of ketenimines with imines show that the reaction involves a stepwise mechanism via an intermediate and two transition states. A computational investigation of the thermal 2 - - 2-cycloaddition between imines and ketiminium cations finds that the reaction takes place via a stepwise mechanism.The reaction of benzyne with Schiff bases, diimines, yields l,4-bis(2-substituted acridin-10-yl)benzene via an initial double 2 - - 2-cycloaddition. 

The diamino-substituted acridine derivatives proflavine (5c) and acridine orange (5d) are classical representatives of this dye class and their DNA intercalating properties have been studied in detail. Both dyes were shown early to intercalate into DNA [192-194], and in both cases the dye properties, i.e., absorption and emission in the UV/vis area, could be used to... 

In addition to N9-substituted acridines, several C9-substituted acridines have been described as biologically active compounds. Examples are shown... 

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