Acridines, resistance

Quinacrine (49) is an acridine that was used extensively from the mid-1920s to the end of World War 11. It acts much like chloroquine and is reasonably effective. Because it causes the skin to turn yellow and, in high doses, causes yellow vision, the dmg is no longer in use as an antimalarial. Pyronaridine (77), a 1-azaacridine developed in China, appears to be effective against mefloquine-resistant, but not entirely against chloroquine-resistant, strains of P falciparum. 

Some of the older, and cheaper, drugs are still in use despite the problems of resistance and have thus been included in this review of the use of heterocycles in coccidiosis control. Both academic and industrial research in this area continues apace with field trials on arprinocid (68) and reports of activity in new structural classes, e.g. azauracils (69) and acridines (70). Whether these very recent discoveries will have any longer lasting utility than many of their predecessors remains to be seen. 

To enhance the cellular uptake and nuclease resistance of oligonucleotides, different terminal modifications at the 5 or 3 terminus of oligonucleotides have been attempted. Polylysine, avidin (such as acridine), and cholesterol have been used to improve cellular uptake and antisense effects of oligos (Nechers, 1989, 1993). However, the value of these approaches remains uncertain and needs to be further determined, especially in in vivo settings. 

The ability of a light-drug combination to kill microorganisms is not a new idea and has been known for over 100 years [3]. In fact the concept of PDT was initiated in 1900 when Raab described the antimicrobial action of acridine and light on Paramecium species [4], Flowever, only recently has the search for alternative treatments for antibiotic-resistant pathogens stimulated the PACT development. 

Increased MICs of some biocides have been observed in S. aureus strains possessing a plasmid carrying genes encoding resistance to gentamicin (5) [214-220], Such biocides are chlorhexidine, QACs, acridines and diamidines together with ethidium bromide which is often studied in a similar manner. 

QACs, ethidium bromide and acridines was prevalent in the staphylococcal population long before gentamicin resistance emerged, then antiseptic resistance could be of particular significance in terms of the potential for the survival of these strains in the hospital environment. This aspect is considered later (see p. 181). 

A large number of papers has appeared on the subject of excimer laser exposure of polymer films (16-21). Most of these have dealt with the phenomenon of photoablation. A few have observed intensity dependent photochemistry (22,23). The latter authors were concerned with the effect of exposure intensity on resist development characteristics. The utility of nonlinear photochemistry for image modification has not been explored except in our earlier communication, in which strongly nonlinear irreversible bleaching was observed for KrF laser irradiation of acridine/PMMA films with lOnsec pulses (5). 

Another dual inhibitor of topoisomerase I and topoisomerase II is XR 5000 (N-2-[(dimethylamino)ethyl]acri-acridine-4-carboxamine). Its cytotoxicity was not affected by the presence of P-glycoprotein, and it seems to be a promising candidate, even in highly resistant tumor cells. However, neither complete nor partial remission was observed during a phase II trial in 20 patients with advanced or metastatic colorectal cancer (21). 

From the same class of light sensitive and heat resistant polymers, poly[4,4 -hexafluoro-isopropylidene)-diphthalic anhydride-a/f-acridine yellow G], HCI is given as another example. The structure of this polymer is shown below ... 

The TGA curve indicates a complex decomposition process. The Py-GC/MS result for poly[4,4 -hexafluoro-isopropylidene)-diphthalic anhydride-aff-acridine yellow G] HCI is given in Figure 13.4.3. This is a light sensitive polymer (X max. 273 nm) but also with high heat resistance, and the pyrolysis was performed at 850 C in He. Other conditions were kept similar to those for other examples previously described (see Table 4.2.2). The separation was done on a Carbowax column. The peak identification was done using MS spectral library searches only and is given in Table 13.4.4. 

Many molecules with pH-dependent fluorescence properties are known and used only in aqueous media, which essentially precludes them from resist applications. To be of use in resist applications, fluorescent molecules must be soluble in organic solvents of moderate polarity and also be compatible with polymer films.Aromatic monazines such as acridine have been known to be essentially nonfluorescent in non-hydrogen-bonding solvents, whereas their protonated forms are highly fluorescent in aqueous solutions, which makes this class of materials interesting candidates for potential acid sensors. ... 

Synthesis, structure—activity relationship and biological activity of acridine derivatives as potent multidrug resistance-reversing agents 13CMD 4070. 

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