Dequalinium

Small-conductance (SKCa) Sleep apnea Dequalinium, Tubocurarine,... 

C, H2 l2 16355-92-3) see Dequalinium chloride 5-[[3,5-diiodo-4-(4-methoxyphenoxy)phenyl]metbyl]-5-metbyl-2,4-imidazolidinedione (C,jH,6l2Ni04 J/65-0J-9) see Etiroxate... 

Figure 1 Chemical structures of commonly used typical mitochondriotropic molecules (A) rhodamine 123 (B) methyltriphenylphosphonium (Q dequalinium chloride.

Dequalinium salts can be purchased from Sigma Chemical Co., St. Louis, Missouri, U.S.A. Analogues of dequalinium, however, are not commercially available they can be synthesized according to protocols by Galanakis et al. (44 6). In a structure-activity relationship study (38), we found that the methyl group in ortho position to the quaternary nitrogen at the quinolinium ring system seems to play an essential role in the... 

Figure 6 (Top) Chemical structure of dequalinium (bottom) possible conformations of single-chain bola amphiphiles. Amphiphiles in a stretched conformation (bola) would form monolayers, while amphiphiles in a bended conformation (horseshoe) would form bilayers.

To prepare DQAsomes or vesicles composed of dequalinium derivatives, the appropriate amount of bola-lipid (10 mM final) was dissolved in methanol, dried using a rotary evaporator, suspended in 2.5 mL 5mM N-2-hydroxyethylpiperazine-N -2-ethane sulfonic acid (HEPES), pH 7.4, bath sonicated for about one hour followed by probe sonication for 45 minutes (10 W). The sample was then centrifuged for 30 minutes at 3000 rpm, the clear, or in some cases, opaque supernatant collected and the remaining non-solubilized residue lyophilized. The concentration of solubilized bola-lipid can be determined spectrophotometrically or can be inferred from the amount of recovered compound after lyophilization. 

Based on the intrinsic mitochondriotropism of dequalinium and its unique self-assembly behavior, we have developed a strategy for direct mitochondrial transfection (47-49), which involves the transport of a DNA-mitochondrial leader sequence (MLS) peptide conjugate to mitochondria using DQAsomes, the liberation of this conjugate from the cationic vector upon contact with the mitochondrial outer membrane followed by DNA uptake via the mitochondrial protein import machinery. We have demonstrated that DQAsomes fulfill all essential prerequisites for a mitochondria-specific DNA delivery system they bind and condense pDNA (24), protect it from... 

Dequalinium chloride (10 mM final) and paclitaxel (10 mM final) were dissolved in methanol in a round-bottom flask followed by removing the organic solvent with a rotary evaporator. After adding 5 mM HEPES, pH 7.4, the suspension was sonicated with a probe sonicator until a clear opaque solution of DQAsomes with encapsulated paclitaxel was obtained (usually for about one hour). To remove undissolved material, the preparation was centrifuged for 10 minutes at 3000 rpm. 

The solubility of paclitaxel in water at 25°C at pH 7.4 is 0.172mg/L (0.2 pM), extremely low, making any separation procedure of nonencapsulated paclitaxel from DQAsomes unnecessary i.e., in an aqueous environment, only paclitaxel encapsulated in DQAsomes would stay in colloidal solution. However, for control, a paclitaxel suspension was probe sonicated under identical conditions used for the encapsulation of paclitaxel into DQAsomes, but in the complete absence of dequalinium chloride. As expected, upon centrifugation, no paclitaxel was detectable in the supernatant using ultraviolet (UV) spectroscopy at 230 nm. 

The amount of dequalinium in DQAsomes was measured using fluorescence spectroscopy (ex. 335 nm, em. 360 nm). At these wavelengths, paclitaxel does not display any fluorescence and therefore does not interfere with the determination of dequalinium. For measurements, 3 pL DQAsomes were dissolved in 3mL methanol, resulting in a concentration of dequalinium, which lies within the linear range of a previously determined standard curve. 

Because the UV spectra of paclitaxel and dequalinium in methanol strongly overlap between 200 and 240 nm, before being able to measure... 

In a reproducible way, paclitaxel can be incorporated into DQAsomes at a molar ratio paclitaxel to dequalinium of about 0.6. In comparison to the free drug, encapsulation of paclitaxel into DQAsomes increases the drug s solubility by a factor of about 3000. 

Weiss MJ, Wong JR, Ha CS, et al. Dequalinium, a topical antimicrobial agent, displays anticarcinoma activity based on selective mitochondrial accumulation. Proc Natl Acad Sci USA 1987 84(15) 5444-5448. 

Weissig V, Lasch J, Erdos G, Meyer HW, Rowe TC, Hughes J. DQAsomes a novel potential drug and gene delivery system made from Dequalinium. Pharm Res 1998 15(2) 334-337. 

Lasch J, Meye A, Taubert H, Koelsch R, Mansaard J, Weissig V. Dequalinium vesicles form stable complexes with plasmid DNA which are protected from DNase attack. Biol Chem 1999 380(6) 647-652. 

Galanakis D, Ganellin CR, Malik S, Dunn PM. Synthesis and pharmacological testing of dequalinium analogues as blockers of the apamin-sensitive Ca (2+)-activated K+ channel variation of the length of the alkylene chain. J Med Chem 1996 39 3592-3595. 

Galanakis D, Davis CA, Del Rey Herrero B, Ganellin CR, Dunn PM, Jenkinson DH. Synthesis and structure-activity relationships of dequalinium analogues as K(+) channel blockers. Investigations on the role of the charged heterocycle. J Med Chem 1995 38 595-606. 

Chemical Name l,l -Decamethylenebis(4-aminoquinaldinium chloride) Common Name Dechalinium chloride, Dequalinium chloride Structural Formula ... 

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