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Linear free-energy relationships between the rate constants for hydrolysis and the pK, of the leaving group are obtained for both mono-and dianions of phosphate esters, ROPO(OH)2. The reactivity of the monoanions depends only weakly on the leaving group, but that of the dianions is nine times more sensitive to the basicity of RO~. Both ionic species are considered to be hydrolyzed by unimolecular mechanisms, involving the elimination of the leaving group from ROPCVor RO+HPOs2-, and the formation of monomeric metaphosphate, although nonselective phosphorylation of mixed alcohol-water solvents is not in general observed. The hydrolysis of the dianion of 2,4-dinitrophenyl phosphate is accelerated many hundredfold in the presence of dipolar aprotic solvents.

Abstract“One of the great intellectual challenges presented to Science by Nature is a proper understanding of how enzymes work. At one level we can ‘explain’ enzyme catalysis—what an enzyme does is bind, and thus stabilize, selectively the transition state for a particular reaction.A. R. Fersht, Enzyme Structure and Mechanism, 2nd ed., Freeman, New York, 1985. But our current level of understanding fails the more severe, practical test—that of designing and making artificial enzyme systems with catalytic efficiencies which rival those of natural enzymes.” This was the introduction to a recent Highlight in Angewandte Chemie, A. J. Kirby, Angew. Chem. 1994, 106, 573–576; Angew. Chem. Int. Ed. Engl. 1994, 33, 551–553. prompted by the appearance of a paper that appeared to defy established ideas, by claiming artificial enzyme systems that did indeed attain catalytic efficiency rivaling that of natural enzymes. The “Pepzymes” of Atassi and ManshouriM. Z. Atassi, T. Manshouri, Proc. Natl. Acad. Sci. USA 1993, 90, 8282–8286. were relatively small (29‐residue) peptides modeled on the active site structures of trypsin and chymotrypsin by “surface simulation.” One was claimed to hydrolyze the simple trypsin “substrate” N‐tosyl‐L‐arginine methyl ester with kcat and Km values comparable to those of the native enzyme, and also to hydrolyze the peptide bonds of test proteins to give comparable peptide profiles. This extraordinary result provoked as much skepticism as excitement, and several groups tried to reproduce the results. They failed, comprehensively., D. R. Corey, M. A. Phillips, Proc. Natl. Acad. Sci. USA 1994, 91, 4106–4109. Some specific reasons why this failure came as no surprise have been summarized by Matthews et al.J. A. Wells, W. J. Fairbrother, J. Otlewski, M. Lagowski, J. Burnier, Proc. Natl. Acad. Sci. USA 1994, 91, 4110–4114. This review examines the problems involved in the design of enzyme mimics in more general terms, with the emphasis specifically on the efficiency of catalysis.

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The superior surfactant properties of cationic gemini surfactants are applied to the complex problem of introducing genes into cells. Of almost 250 new compounds tested, of some 20 different structural types, a majority showed very good transfection activity in vitro. The surfactant is shown to bind and compact DNA efficiently, and structural studies and calculations provide a working picture of the "lipoplex" formed. The lipoplex can penetrate the outer membranes of many cell types, to appear in the cytoplasm encapsulated within endosomes. Escape from the endosome--a key step for transfection--may be controlled by changes in the aggregation behavior of the lipoplex as the pH falls. The evidence suggests that DNA may be released from the lipoplex before entry into the nucleus, where the new gene can be expressed with high efficiency.