Hybridization dynamics of surface immobilized DNA

We model the hybridization kinetics of surface attached DNA oligomers with solubilized targets. Using both master equation and rate equation formalisms, we show that, for surface coverages at which the surface immobilized molecules interact, barriers to penetration create a distribution of target molecule concentrations within the adsorbed layer. By approximately enumerating probe and target conformations, we estimate the probability of overlap between complementary probe and target regions as a function of probe density and chain length. In agreement with experiments, we find that as probe molecules interact more strongly, fewer nucleation sites become accessible and binding rates are diminished relative to those in solution. Nucleation sites near the grafted end of the probes are least accessible; thus targets which preferentially bind to this region show more drastic rate reductions than those that bind near the free end of the probe. The implications of these results for DNA-based biosensors are discussed.     

Fluorine in medicinal chemistry: A review of anti-cancer agents

In this review those fluorinated compounds which have found a role as anti-cancer agents are summarized. The emphasis is to highlight the important drugs but also to highlight the latest developments on emerging compounds. This has been done as comprehensively as possible with the objective of informing readers of some of the latest developments in this area.     

The role of organic fluorine in directing alkylation reactions via lithium chelation

The fluorine of a fluoromethyl group displays a measurable chelation effect to lithium during α-methylation of an ester with lithium diisopropylamide (LDA) and methyl iodide. A series of esters is compared with F, H and O, and the resultant diastereoselectivity is consistent with the intermediate capacity of F to chelate lithium relative to H and O. In a second system which involved comparing a tertiary organic fluorine with hydrogen, no such effect is apparent, most probably due to adverse steric effects. The absolute and relative stereochemistry of the predominant diastereoisomers are confirmed by X-ray crystallography of suitable crystalline derivatives in each case. It is concluded that there is a potential role for organic-bound fluorine to become involved in lithium chelation in well-designed enolate alkylation systems.     

Hindered fluorescence quenching in an insulated molecular wire

A [3]rotaxane 2 within 1(2) consisting of an anionic phenylene ethynylene dumbbell 2(4-) threaded through two cationic cyclophanes 1(2+) has been prepared using aqueous Glaser coupling. Stern-Volmer analysis of the fluorescence quenching using three different electron-acceptors (methyl viologen 13(2+), dipropyl-4,4'-bipyridinium disulfonate 14 and anthraquinone-2,6-disulfonate 15(2-)) shows that the threaded cyclophanes inhibit electron-transfer from the excited state of the dumbbell by steric shielding, and by electrostatic shielding in the case of methyl viologen.     

Single-molecule detection of nitrogen mustards by covalent reaction within a protein nanopore

Mustards, including sulfur mustards and nitrogen mustards, form a class of cytotoxic, vesicant chemical warfare agents. Mustards have also been used to treat cancer and played a vital role in the development of chemotherapy. Additionally, because of their destructive properties, ease of synthesis, and the lack of effective antidotes, mustards are unquestionably terrorist threats. Therefore, quick and convenient detection of mustards is a critical issue. In the present study, we achieved detection of various mustards on the basis of their chemical reactivity by using engineered alpha-hemolysin (alphaHL) protein pores as sensor elements. We describe four classes of reactions for detecting mustards. These reactions occur between mustards and thiol groups contributed by cysteine side-chains within the lumen of the alphaHL pore or on an internal molecular adapter. The approach is quick and straightforward. It can confirm the existence of mustards in as little as 10 min at 50 microM or lower.     

Mobile Molecules: Reactivity Profiling Guides Faster Movement on a Cysteine Track

We previously reported a molecular hopper, which makes sub-nanometer steps by thiol-disulfide interchange along a track with cysteine footholds within a protein nanopore. Here we optimize the hopping rate (ca. 0.1 s⁻¹ in the previous work) with a view towards rapid enzymeless biopolymer characterization during translocation within nanopores. We first took a single-molecule approach to obtain the reactivity profiles of individual footholds. The pK_a values of cysteine thiols within a pore ranged from 9.17 to 9.85, and the pH-independent rate constants of the thiolates with a small-molecule disulfide varied by up to 20-fold. Through site-specific mutagenesis and a pH increase from 8.5 to 9.5, the overall hopping rate of a DNA cargo along a five-cysteine track was accelerated 4-fold, and the rate-limiting step 21-fold.