Coacervates, prepared by adding inorganic and organic salts to aqueous solutions of Aerosol OT (AOT), were analyzed for their AOT, salt, and water content. In addition, the volumes of the coacervates generated under standard conditions were determined. It was found that for inorganic salts, there is a "critical salt concentration" below and above which the volume of coacervate is very small. For example, NaCl has a critical concentration of 0.3 M, a concentration that will convert 50 mL of 0.02 M AOT into more than 7 mL coacervate (the remainder being equilibrium liquid that floats above the immiscible coacervate phase). At 0.2 or 0.6 M NaCl, the coacervate volume is reduced to 2 mL or less. The coacervate formed at the critical salt concentration has an [AOT] ) 0.2 M and a [NaCl] ) 0.3 M. Thus, a coacervate of 0.2 M AOT and 0.3 M NaCl is immiscible with 0.3 M NaCl despite the highly aqueous nature of both. This is attributed to the enthalpic requirements for breaking up three-dimensional AOT structures composed of bilayers. Critical concentrations of the alkali metals Li + , Na + , K + , Rb + , and Cs + are 1, 0.3, 0.1, 0.1, and 0.1 M, respectively. Organic coacervators, such as n-octylammonium chloride and used in place of NaCl, have a profound effect upon the coacervation process. Thus, n-octylammonium ion has no critical salt maximum. Instead, the coacervate volume remains small until about 0.25 M added salt, whereupon the insoluble layer increases dramatically in volume to become the dominate phase. Coacervation is rationalized in terms of positiveto-negative changes in the spontaneous mean curvature of bilayers.
2-Nitroaryl amides of general structure I are proposed as bioreducible prodrugs, capable of releasing cytotoxic aminoaniline mustards V on bioactivation by spontaneous cyclization of the resulting 2-aminoarylamides II via a tetrahedral intermediate, III. This concept allows separate optimization of the substituent effects influencing nitro-group reduction and mustard reactivity. A series of model 2-aminoaryl amides has been synthesized, and their rates of cyclization have been studied; these varied by a factor of more than 50,000-fold (kobs from 0.00040 to 21 min-1) at pH 2.4. For three compounds studied in detail, the rates were linearly dependent of pH, indicating that no change in the mechanism of the rate-determining step occurs over the pH range studied. The nucleophilicity of the amino group had a modest influence on the kinetics of cyclization, with electron-withdrawing groups slowing the rate. The geometry of the compound was also important, with structure-activity relationships indicating that the rate of cyclization is greatly enhanced by the preorganization of the molecule. In contrast, 4-substitution on the leaving aniline by a variety of groups had little effect on the cyclization reaction. These results are consistent with the rate-determining step being formation of the tetrahedral intermediate. These model studies suggest that the phenyldimethylacetamide system could be developed as a prodrug system for the bioreductively-triggered release of amines. Further substantial rate enhancements appear possible by alterations in the geometry of the system, whereas substitution of electron-withdrawing groups (required to raise the nitro-group reduction potential into the appropriate range) has only relatively modest retardation effects on rates of cyclization. More rigid systems may also be useful; a nitronaphthaleneacetamide analogue cyclized spontaneously during nitro-group reduction, suggesting a very short half-life for the reduced intermediate (amine or hydroxylamine).
A series of N-dinitrophenylamino acid amides [(4-CONHZ-2, 6-diNO2Ph)N(R)C(X,Y)CONHPhOMe] were prepared as potential bioreductive prodrugs and reduced radiolytically to study their rates of subsequent intramolecular cyclization. Compounds bearing a free NH group (R = H) underwent rapid cyclization in neutral aqueous buffers (t1/2 < 1 min) following 4-electron reduction, with the generation of a N-hydroxydihydroquinoxalinone and concomitant release of 4-methoxyaniline. Amine release from analogous N-methyl analogues (R = Me) was relatively slow. These results are consistent with intramolecular cyclization of a monohydroxylamine intermediate. The high rates of cyclization/extrusion by these very electron-deficient hydroxylamines suggest that the process is greatly accelerated by the presence of an H-bonding "conformational lock" between the anilino NH group and the adjacent o-nitro group (Kirk and Cohen, 1972). Changes in the phenylcarboxamide side chain or in C-methylation in the linking chain had little effect on the rate of cyclization. The model compounds had 1-electron reduction potentials in the range appropriate for cellular reduction (-373 mV for a measured example) and appeared suitable for development as prodrugs that release amine-based effectors following enzymic or radiolytic reduction. Prodrug examples containing 4-aminoaniline mustard and 5-amino-1-(chloromethyl)benz[e]indoline alkylating units were evaluated but were not activated efficiently by cellular nitroreductases. However, cell killing by the radiation-induced reduction of the latter prodrug was demonstrated.
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