Micelle-sequestered dissociation of cationic DNA-intercalated drugs: unexpected surfactant-induced rate enhancement

Detergent sequestration using micelles as a hydrophobic sink for dissociated drug molecules is an established technique for determination of dissociation rates. The anionic surfactant molecules are generally assumed not to interact with the anionic DNA and thereby not to affect the rate of dissociation. By contrast, we here demonstrate that the surfactant molecules sodium dodecyl sulfate (SDS), sodium decyl sulfate, and sodium octyl sulfate all induce substantial rate enhancements of the dissociation of intercalators from DNA. Four different cationic DNA intercalators are studied with respect to surfactant-induced dissociation. Except for the smallest intercalator, ethidium, the dissociation rate constants increase monotonically with surfactant concentration both below cmc and (more strongly) above cmc, much more than expected from electrostatic effects of increased counterion concentration. The rate enhancement, most pronounced for the bulky, multicationic, hydrophobic DNA ligands in this study, indicates a reduction of the activation energy for the ligand to pass out from a deeply penetrating intercalation site of DNA. The discovery that surfactants enhance the rate of dissociation of cationic DNA-intercalators implies that rate constants previously determined by micelle-sequestered dissociation may have been overestimated. As an alternative, more reliable method, we suggest instead the addition of excess of dummy DNA as an absorbent for dissociated ligand.     

Stereochemistry of contiguous cyclopropane formation from cascade cyclization of a skipped dienyl homoallyl triflate

Solvolysis of asymmetric homoallylic triflates bearing a terminal stannyl substituent gives disubstituted cyclopropanes and bicyclopropanes bearing differentiated termini in high enantiopurity.     

Total synthesis of polycavernoside A, a lethal toxin of the red alga Polycavernosa tsudai

[structure: see text] Two approaches to the synthesis of the aglycon 120 of polycavernoside A (1) were developed, only one of which was completed. The successful "second-generation" route assembled the aglycon seco acids 102 and 106 via Nozaki-Hiyama-Kishi coupling of aldehyde 70, prepared from methyl (S)-3-hydroxy-2-methylpropionate (72) and (S)-pantolactone (73), with vinyl bromide 71. The latter was obtained from a sequence which commenced from the silyl ether 24 of 3-hydroxypropionaldehyde and entailed cyclization of (Z)-zeta-hydroxy-alpha,beta-unsaturated ester 82. Regioselective Yamaguchi lactonization of trihydroxycarboxylic acids 102 and 106 and subsequent functional-group adjustments led to macrolactone 120, to which the fucopyranosylxylopyranoside moiety was attached. Stille coupling of the glycosidated aglycon 128 with dienylstannane 129 furnished polycavernoside A in a synthesis for which the longest linear sequence was 25 steps. The overall yield to lactone 120 was 4.7%.     

Aminocyclodextrins to facilitate the deprotonation of 4-tert-butyl-alpha-nitrotoluene

6A-Amino-6A-deoxy-beta-cyclodextrin enhances the rate of the deprotonation of 4-tert-butyl-alpha-nitrotoluene. The rate constants for reaction of the cyclodextrin-bound species, kinc = 4 x 10(-3), 9 x 10(-3) and 19 x 10(-3) s(-1), at pH 6.0, 6.5 and 7.0, respectively, in 0.1 mol dm(-3) aqueous phosphate buffer containing 1% methanol at 298 K. These rate constants correspond to a rate acceleration (kinc/kun) of ca. 10 times at each pH. Under the same conditions, 6A-dimethylamino-6A-deoxy-beta-cyclodextrin and 6A-(2-aminoethylamino)-6A-deoxy-beta-cyclodextrin are more effective; at pH 6.0, 6.5 and 7.0, for the former, kinc = 3 x 10(-2), 7 x 10(-2) and 12 x 10(-2) s(-1), whilst for the latter, kinc = 4 x 10(-2), 5 x 10(-2) and 9 x 10(-2) s(-1), respectively. Each cyclodextrin also decreases the pKa of the nitrotoluene, from 6.8 in free solution, to 6.2 when bound. The accelerated deprotonation by 6A-amino-6A-deoxy-beta-cyclodextrin is reflected in the enhanced rates of hydrogen-deuterium exchange of the nitrotoluene in deuterium oxide, and in the conjugate addition of the nitrotoluene to methyl vinyl ketone in aqueous solution.     

Effects of methyl substitution on radiative and solvent quenching rate constants of [Ru(phen)2dppz]2+ in polyol solvents and bound to DNA

Methyl substituents on the distant benzene ring of the dppz ligand in the "light switch" complex [Ru(phen)(2)dppz](2+) have profound effects on the photophysics of the complexes in water as well as in the polyol solvents ethylene glycol, glycerol, and 1,2- and 1,3-propanediol. Whereas 11,12-dimethyl substitution decreases the rate of quenching by diminishing hydrogen bonding by solvent, the 10-methyl substituent in addition also decreases both the radiative and the nonradiative rate constant for decay to the ground state of the non-hydrogen-bonded excited state species. For both the 10-methyl and the 11,12-dimethyl derivatives, the effect of methyl substitution on the equilibrium of solvent hydrogen bonding to the excited state is due to changes in the entropy terms, rather than in the enthalpy, indicating that the effect is a steric perturbation of the solvent cage around the molecule. When intercalated into DNA, the effects of methyl substitution is smaller than those in polyol solvent or water, suggesting that the water molecules that quench the excited state by hydrogen bonding to the phenazine aza nitrogens mainly access them from the same groove as in which the Ru(II) ion resides. Since the Delta-enantiomer of [Ru(phen)(2)10-methyl-dppz](2+) has an absolute quantum yield of up to 0.23 when bound to DNA, a value 7000 times higher than in pure water solution, it is promising as a new luminescent DNA probe.     

Molecular reactors and machines: applications, potential, and limitations

Molecular reactors are miniature vessels for the assembly of reactants at the molecular level, in order to change the nature of chemical transformations. It seems probable that those that will find most immediate applications are those that change product ratios or give products which would not readily form in the absence of the reactors, and thereby afford easy access to materials that are otherwise difficult to obtain. Molecular machines consist of interrelated parts with separate functions and perform some kind of work, at the molecular level. Practical examples are likely to be relatively uncomplicated and not based on individual functions of single-molecule devices. Instead they will probably rely on extensive redundancy of the molecular components and their interactions and reactions, as well as of the machines themselves.     

DNA-binding of semirigid binuclear ruthenium complex delta,delta-[mu-(11,11'-bidppz)(phen)(4)ru(2)](4+): extremely slow intercalation kinetics

We here report a remarkably slow rearrangement of binding modes for a binuclear ruthenium(II) complex upon interaction with DNA. It has been previously shown that Delta,Delta-[mu-(11,11'-bidppz)(phen)4Ru2]4+ binds to DNA in one of the grooves. However, we find that this is only an initial, metastable, binding mode, which is extremely slowly reorganized into an intercalative binding geometry. The slow rearrangement and dissociation, revealed by flow linear dichroism and fluorescence spectroscopy, are concluded to be a result from the complex being threaded through the DNA, with one of the bridging aromatic dppz ligands intercalated between the base pairs of the DNA, placing one metal center in the minor groove and one in the major groove. A negative LD, a high luminescence quantum yield, and long luminescence lifetimes, similar to the intercalating complex Delta-[Ru(phen)2dppz]2+, indicate intercalation of the bidppz moiety. The unique slow dissociation of the complex in its final DNA-binding mode suggests that this class of threading, partially intercalated binuclear complexes may be interesting in the context of cancer therapy. Also, their unique optical and photophysical properties could make such complexes, either alone or scaffolded by DNA structures, of interest for the development of nanometer-sized molecular optoelectronic devices.     

Formation of Metallo-6(A)-((2-(bis(2-aminoethyl)amino)ethyl)amino)-6(A)-deoxy-beta-cyclodextrins and Their Complexation of Tryptophan in Aqueous Solution

A pH titration study shows that 6(A)-((2-(bis(2-aminoethyl)amino)ethyl)amino)-6(A)-deoxy-beta-cyclodextrin (betaCDtren) forms binary metallocyclodextrins, [M(betaCDtren)](2+), for which log(K/dm(3) mol(-)(1)) = 11.65 +/- 0.06, 17.29 +/- 0.05, and 12.25 +/- 0.03, respectively, when M(2+) = Ni(2+), Cu(2+), and Zn(2+), where K is the stability constant in aqueous solution at 298.2 K and I = 0.10 mol dm(-)(3) (NaClO(4)). The ternary metallocyclodextrins [M(betaCDtren)Trp](+), where Trp(-) is the tryptophan anion, are characterized by log(K/dm(3) mol(-)(1)) = 8.2 +/- 0.2 and 8.1 +/- 0.2, 9.5 +/- 0.3 and 9.4 +/- 0.2, and 8.1 +/- 0.1 and 8.3 +/- 0.1, respectively, where the first and second values represent the stepwise stability constants for the complexation of (R)- and (S)-Trp(-), respectively, when M(2+) = Ni(2+), Cu(2+), and Zn(2+). From comparisons of stabilities and UV-visible spectra, the binary and ternary metallocyclodextrins appear to be six-coordinate when M(2+) = Ni(2+) and Zn(2+) and five-coordinate when M(2+) = Cu(2+). The factors affecting the stoichiometries and stabilities of the metallocyclodextrins, are discussed and comparisons are made with related systems.