Acridine, 79 activated

An intruiging approach to site-selective RNA cleavage was reported by Kuzuya et al. [130]. In contrast to the previons examples, in this system the metal complex is free in solution (not localized). Site-selective activation for hydrolysis at single positions in a target RNA strand is achieved by covalent attachment of an acridine moiety to the template DNA strand, which canses local perturbation in the hybridized RNA strand opposite this position [131]. RNA strand scission is very site-specific for the localized perturbation (Fig. 9b). This approach was optimized for various metal ions inclnding Ca and Mg % transition metal ions, and lanthanide ions [132, 133]. Two sites in a single RNA conld be activated by incorporation of two acridines in the DNA template [134], and the rate of the process was further enhanced by the attachment of a ligand for Lu in close proximity to the acridine activator [135]. 

Hagan et al. utilized the Graebe-Ullmann process to synthesize polycyclic acridines 14 which exhibit anti-tumor activity. ... 

A few studies on solvolyses by alcohols and by water are available. The hydrolyses studied include displacement of alkylamino groups from acridine antimalarials and of halogen from other systems. In all cases, these reactions appeared to be first-order in the heterocyclic substrate. By a detailed examination of the acid hydrolysis of 2-halogeno-5-nitropyridine, Reinheimer et al. have shown that the reaction rate varies as the fourth power of the activity of water, providing direct evidence that the only reactive nucleophile is neutral water, as expected. 

It is notable that pyridine is activated relative to benzene and quinoline is activated relative to naphthalene, but that the reactivities of anthracene, acridine, and phenazine decrease in that order. A small activation of pyridine and quinoline is reasonable on the basis of quantum-mechanical predictions of atom localization encrgies, " whereas the unexpected decrease in reactivity from anthracene to phenazine can be best interpreted on the basis of a model for the transition state of methylation suggested by Szwarc and Binks." The coulombic repulsion between the ir-electrons of the aromatic nucleus and the p-electron of the radical should be smaller if the radical approaches the aromatic system along the nodal plane rather than perpendicular to it. This approach to a nitrogen center would be very unfavorable, however, since the lone pair of electrons of the nitrogen lies in the nodal plane and since the methyl radical is... 

The pioneering work carried out in Germany in the 1920s showed that appropriately substituted aminoquinolines and amino-acridines afforded a series of synthetic compounds that exhibited antimalarial activity.The exigencies of the Second World War led to a massive program aimed at the same goal in this country. This work led to the development of two distinct structural classes of quinoline antimalarials the 4-amino-7-chloroquino-... 

An acridine with a radically different substitution pattern, interestingly, still exhibits antimalarial activity. Condensation of acetone with diphenylamine in the presence of strong acid affords the partly reduced acridine, 20. Alkylation with 3-chloro-dimethylaminopropane (via the sodium salt of 20) affords dimethacrine (21). ... 

Acridine orange, pH-dependent change of fluorescence color 91 Activation of the layer 124ff. N-Acylglycine conjugates 176 ADB = 2-amino-2, 5-dichlorobenzophe-none 227... 

In other cases the activity ofthe drug is due to the ionized molecule. For example, with the antibacterial acridine dyestuffs it is the cation which is the active agent and factors favouring ionization, all other things being equal, enhance their antibacterial activity (see Chapter 12). 

Solubilization of an active H,K-ATPase is also a prerequisite for reconstitution of the enzyme into liposomes. With these H,K-ATPase proteoliposomes it is then possible to study the transport characteristics of pure H,K-ATPase, without the interference of residual protein contamination that is usually present in native vesicular H,K-ATPase preparations. Rabon et al. [118] first reported the reconstitution of choleate or n-octylglucoside solubilized H,K-ATPase into phosphatidylcholine-cholesterol liposomes. The enzyme was reconstituted asymmetrically into the proteoliposomes with 70% of the pump molecules having the cytoplasmic side extravesicular. In the presence of intravesicular K, the proteoliposomes exhibited an Mg-ATP-dependent H transport, as monitored by acridine orange fluorescence quenching. Moreover, as seen with native H,K-ATPase vesicles, reconstituted H,K-... 

Heald RA et al. (2002) Antitumor polycyclic acridines. 8.(1) Synthesis and telomerase-inhibitory activity of methylated pentacyclic acridinium salts. J Med Chem 45(3) 590-597... 

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... 

Pyridazines continued to play a central role in the construction of new biologically active compounds. 2,7-Dihydro-3//-pyridazino 5,4,3-17 acridin-3-ones were synthesized as cytotoxic agents <05BMC1969> and 6-(5-chloro-3-methylbenzofuran-2-sulfonyl)-2//-... 

Yamakoshi YN, Yagami T, Sueyoshi S, Miyata N (1996) Acridine Adduct of [60]Fullerene with Enhanced DNA-Cleaving Activity. J Org Chem 61 7236-7237. 

Recently, Jones et al. described the synthesis and antiproliferative activities of a series of C-12 carba artemisinin 1,2,4-trioxane-acridine hybrids 93-96 Fig. 7). HL-60 and HT-29 were more sensitive to hybrid 95 while the growth of MCF7 cancer cells and highly metastatic human breast cancer (MDA-MB-231) cells were dramatically affected by hybrids 95 and 93, respectively. Among all artemisinin 1,2,4-trioxane-acrimide hybrids evaluated, compound 92 was the least active against cancer cells. ... 

Jones M, Mercer AE, Stocks PA, La Pensee LJ, Cosstick R, Park BK, Kennedy ME, Piantanida 1, Ward SA, Davies J, Bray PO Rawe SL, Baird J, Charidza T, Janneh O, O Neill PM. (2009) Antitumor and antimalarial activity of artemisinin-acridine hybrids. Bioorg Med Chem Lett 19 2033-2037. 

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