PHOTOSENSITIZATION OF PYRIMIDINE DIMER SPLITTING BY A COVALENTLY BOUND INDOLE

Abstract— Photosensitized pyrimidine dimer splitting characterizes the enzymatic process of DNA repair by the DNA photolyases. Possible pathways for the enzymatic reaction include photoinduced electron transfer to or from the dimer. To study the mechanistic photochemistry of splitting by a sensitizer representative of excited state electron donors, a compound in which an indole is covalently linked to a pyrimidine dimer has been synthesized. This compound allowed the quantitative measurement of the quantum efficiency of dimer splitting to be made without uncertainties resulting from lack of extensive preassociation of the unlinked dimer and sensitizer free in solution. Irradiation of the compound with light at wavelengths absorbed only by the indolyl group (approximately 280 nm) resulted in splitting of the attached dimer. The quantum yield of splitting of the linked system dissolved in N₂0-saturated aqueous solution was found to be 0.04 ± 0.01. The fluorescence typical of indoles was almost totally quenched by the attached dimer. A splitting mechanism in which an electron is efficiently transferred intramolecularly from photoexcited indole to ground state dimer has been formulated. The surprisingly low quantum yield of splitting has been attributed to inefficient splitting of the resulting dimer radical anion. Insights gained from this study have important mechanistic implications for the analogous reaction effected by the DNA photolyases.     

Stereoselective synthesis of 3-substituted 2-aminocyclopentanecarboxylic acid derivatives and their incorporation into short 12-helical beta-peptides that fold in water

A stereoselective synthetic route is reported for the introduction of side chains at the 3-position of trans-2-aminocyclopentanecarboxylic acid (ACPC). Ring opening of the aziridine 2-benzyloxymethyl-6-azabicyclo[3.1.0]hexane with selected nucleophiles occurs in a regioselective manner and provides ACPC precursors with functional groups at the 3-position, trans to the 2-amino group. Oligomers composed of the 3-substituted ACPC residues maintain the 12-helical conformation displayed by the nonsubstituted analogues, as shown by their similar circular dichroism signatures. The added diversity of the new residues provides good dispersion of NMR signals, allowing the assignment of nearly all the NOE signals of a selected hexamer in aqueous solution. The NOEs between protons on nonadjacent residues are characteristic of the 12-helix. 3-Substituted ACPC residues allow one to arrange specific functional groups in a geometrically defined fashion, which should facilitate the design of beta-peptides for biological applications.     

Vibrational spectrum of I(H2O)

The infrared spectrum of the ionic cluster I⁻(H₂O) was recorded from 3170 to 3800 cm⁻¹ by vibrational predissociation spectroscopy. A strong multiplet observed at 3415 cm⁻¹ and a narrow band at 3710 cm⁻¹ were assigned as a hydrogen-bonded OH stretch and free OH stretch respectively, indicating that H₂O forms a single hydrogen bond with the iodide anion. Ab initio vibrational frequencies and intensities were computed at the second-order Møller-Plesset (MP2) level for the minimum energy configuration, a nearly linear hydrogen-bonded isomer, and for a low-lying saddlepoint, a symmetric C_2v bridged isomer. The spectrum predicted for the hydrogen-bonded isomer agreed well with experiment.     

Total synthesis of (-)-dysibetaine via a nitrenium ion cyclization-dienone cleavage strategy

The diastereoselective total synthesis of the marine natural product (-)-dysibetaine is reported. The key steps in this venture are i) a diastereoselective nitrenium ion spirocyclization, which serves to generate the pyrrolidinone ring and quaternary stereocenter of the target, and ii) use of the 2-methoxycyclohexa-2,5-dienone ring formed during cyclization as a masked 2-amino-1,3-dicarbonyl synthon.     

Suppression of non-specific adsorption using sheath flow

The use of a confining sheath fluid within a microfluidic channel in order prevent non-specific adsorption of analytes to the walls of microchannels is demonstrated. A sheath-flow channel fabricated using laser cutting of Mylar films is developed. Numerical simulations of convective and diffusive mass transport within the channel are presented. The device is characterized experimentally using epifluorescence microscopy. It is demonstrated that the device is capable of preventing the adsorption of Rhodamine B to the walls of the channel for a period that would allow for adsorption-free T-sensor measurements to be made within the core of the flow channel. Generalized scaling rules based on the diffusion coefficient, sheath thickness and affinity of the potential adsorbant for the surface material are discussed. The controlled adsorption of the protein bovine serum albumin (BSA) to a gold surface is also demonstrated using SPR microscopy.     

Crystal engineering of novel cocrystals of a triazole drug with 1,4-dicarboxylic acids

Cocrystals of the poorly soluble antifungal drug cis-itraconazole (1) with 1,4-dicarboxylic acids have been prepared. The crystal structure of the succinic acid cocrystal with 1 was determined to be a trimer by single-crystal X-ray. The trimer is comprised of two molecules of 1 oriented in antiparallel fashion to form a pocket with a triazole at either end. The extended succinic acid molecule fills the pocket, bridging the triazole groups through hydrogen-bonding interactions rather than interacting with the more basic piperazine nitrogens. The solubility and dissolution rate of some of the cocrystals are approximately the same as those of the amorphous drug in the commercial formulation and are much higher than those for the crystalline free base. The results suggest that cocrystals of drug molecules have the possibility of achieving the higher oral bioavailability common for amorphous forms of water-insoluble drugs while maintaining the long-term chemical and physical stability that crystal forms provide.     

Isospectral points and edges in graph theory

The relationship of isospectral points to symmetrically equivalent points in a graph is described. Many isospectral points are related to symmetrically equivalent verticesvia an equivalence-preserving perturbation. A graph having isospectraledges is examined for clues to assist in finding other such graphs. Two families are found in this manner. Application of equivalence-preserving perturbations to edges that are initially symmetrically equivalent leads to an unlimited number of families of graphs, many with more than one pair of isospectral edges.     

Asymmetric autocatalysis: product recruitment for the increase in the chiral environment (PRICE)

Asymmetric catalytic reactions are possible via efficient transfer of the chiral environment of a reaction to the transition state. In theory any asymmetric structure may contribute to this, including the product of the reaction itself. For product influence to be significant, a nonlinear effect needs to operate, whereby one diastereomer of the product/catalyst assists the reaction, and the other does not. When these conditions are satisfied, we obtain an asymmetric autocatalytic reaction in which the enantiomeric excess of a compound (that is both product and catalyst) actually increases as the reaction iterates. It is only recently that we have seen reports of such processes. Of particular interest are Soai's reports of the alkylation of aromatic heterocycles. Such reactions, aside from their inherent interest, may offer clues into the origins of asymmetric molecular replication that predated the origin of life.