Synthesis of gramicidin S and its analogues via an on-resin macrolactamization assisted by a predisposed conformation of the linear precursors

A simple and efficient preparation of gramicidin S and its analogues is described. It involves solid-phase peptide synthesis and on-resin macrolactamization without side chain protection, affording cyclic products in high yield and high purity. The high specificity of the cyclization reaction was shown to originate in the formation of a pre-organized conformation of the linear biosynthetic precursor of gramicidin S. This facile method will provide convenient access to the analogues of the natural product for functional optimization to counter microbial resistance.     

A radioanalytical technique to study the behavior of organic toxicants applied to a study of the photodegradation of 2,3,7,8-tetrachlorodibenzo-p-dioxin

A general method for tritium labeling of organic compounds by the use of thermal activation of tritium is described. It allows obtaining uniformly tritium-labeled organic compounds with high specific activity (up to 50 Ci/mmol) which permits tracing the majority of the biodegradation products of compounds studied. More than 40 compounds were labeled using this simple, rapid and inexpensive method. Separation of the biodegradation products is performed by thin layer chromatography. Quantification is performed by direct measurement of the radioactivity by liquid scintillation counting after transfer of the layer from TLC plates into scintillation vials, or by densitometry of autoradiographs. The technique is useful for a wide range of organic compounds, including ones with unknown structure, and can be applied to various in vivo and in vitro studies.     

DNA cleavage reaction of antitumour antibiotic, kapurimycin A3, with deoxytetranucleotide d(CGCG)2

Kapurimycin A3 (kap A3, 1 ), an antitumour antibiotic, alkylates N7 of guanine₂ (G₂) and G₄ of d(C₁G₂C₃G₄)₂ to produce their covalent adducts 2 (64 %) and 3 (7.0 %), respectively. Heating at 90 °C for 5 min degraded both adducts to kap A3 - G adduct (5) with the concurrent release of their respective abasic-site containing oligomers 4 and 6.     

Dipole-bound anions of highly polar molecules: ethylene carbonate and vinylene carbonate

Results of experimental and theoretical studies of dipole-bound negative ions of the highly polar molecules ethylene carbonate (EC, C3H4O3, mu=5.35 D) and vinylene carbonate (VC, C3H2O3, mu=4.55 D) are presented. These negative ions are prepared in Rydberg electron transfer (RET) reactions in which rubidium (Rb) atoms, excited to ns or nd Rydberg states, collide with EC or VC molecules to produce EC- or VC- ions. In both cases ions are produced only when the Rb atoms are excited to states described by a relatively narrow range of effective principal quantum numbers, n*; the greatest yields of EC- and VC- are obtained for n*(max)=9.0+/-0.5 and 11.6+/-0.5, respectively. Charge transfer from low-lying Rydberg states of Rb is characteristic of a large excess electron binding energy (Eb) of the neutral parent; employing the previously derived empirical relationship Eb=23/n*(max)(2.8) eV, the electron binding energies are estimated to be 49+/-8 meV for EC and 24+/-3 meV for VC. Electron photodetachment studies of EC- show that the excess electron is bound by 49+/-5 meV, in excellent agreement with the RET results, lending credibility to the empirical relationship between Eb and n*(max). Vertical electron affinities for EC and VC are computed employing aug-cc-pVDZ atom-centered basis sets supplemented with a (5s5p) set of diffuse Gaussian primitives to support the dipole-bound electron; at the CCSD(T) level of theory the computed electron affinities are 40.9 and 20.1 meV for EC and VC, respectively.     

Design considerations and computer modeling related to the development of molecular scaffolds and peptide mimetics for combinatorial chemistry

Summary A critical issue in drug discovery utilizing combinatorial chemistry as part of the discovery process is the choice of scaffolds to be used for a proper presentation, in a three-dimensional space, of the critical elements of structure necessary for molecular recognition (binding) and information transfer (agonist/ antagonist). In the case of polypeptide ligands, considerations related to the properties of various backbone structures (-helix, -sheets, etc.; , space) and those related to three-dimensional presentation of side-chain moieties (topography; (chi) space) must be addressed, although they often present quite different elements in the molecular recognition puzzle. We have addressed aspects of this problem by examining the three-dimensional structures of chemically different scaffolds at various distances from the scaffold to evaluate their putative diversity. We find that chemically diverse scaffolds can readily become topographically similar. We suggest a topographical approach involving design in chi space to deal with these problems.     

A Complex Pyrrolo-oxazinone and Its Iodo Derivative Isolated from a Tunicate

Two cytotoxic triphenylpyrrolo-oxazinones were isolated from a tunicate and their structures elucidated by spectral methods. Lukianol A ( = 3,7,8-tris(4-hydroxyphenyl)pyrrolo[2,1-c][1,4]oxazin-1 (1H)-one; 1 ) had MIC of 1 μg/ml in KB cytotoxicity tests; MIC value for 2 was 100 μg/ml.     

Electron-density topology in molecular systems: paired and unpaired densities

This work studies the partitioning of the electron density into two contributions which are interpreted as the paired and the effectively unpaired electron densities. The topological features of each density field as well as of the total density are described localizing the corresponding critical points in simple selected molecules (local formalism). The results show that unpaired electron-density concentrations occur out of the topological bonding regions whereas the paired electron densities present accumulations inside those regions. A comparison of these results with those arising from population analysis techniques (nonlocal or integrated formalisms) is reported.     

Solid-phase synthesis of quinoxaline, thiazine, and oxazine analogs through a benzyne intermediate

A solid-phase synthetic route to quinoxaline, thiazine, and oxazine analogs is described. N-Alloc-3-amino-3-(2,4-difluoro-5-nitrophenyl)propanoic acid was tethered to Rink resin via its carboxylic acid group. The 4-arylfluorine was displaced with a primary amine, alcohol, or thiol to create, respectively, a resin bound aniline, phenol, or thiophenol derivative with one diversity element and one single atom (e.g., N, S, or O) diversity point. A fused heterocyclic system was subsequently created via a benzyne heterocyclization initiated by dehydrofluorination with strong base. Acid treatment released the desired products in high yield and moderate purity.     

Two new double Rydberg anions plus access to excited states of neutral Rydberg radicals via anion photoelectron spectroscopy

We have observed and characterized two new double Rydberg anions N6H19- and N7H22- through their anion photoelectron spectra. The vertical detachment energies of these anions were found to be 0.443 and 0.438 eV, respectively. In addition, for three of the seven double Rydberg anions now known, we measured photodetachment transitions not only to the ground electronic states of their corresponding neutral Rydberg radicals but also to their first electronically excited states. In each spectrum, the energy spacing between the resulting peaks provided the ground-to-first electronically excited-state transition energy for the double Rydberg anion's corresponding neutral Rydberg radical. For the radicals, N4H13, N5H16, and N6H19, the spacings were found to be 0.83, 0.70, and 0.67 eV, respectively. These values are in excellent agreement with ground-to-first excited-state transition energies measured in absorption for the same neutral Rydberg radicals by Fuke and co-workers [Eur. Phys. J. D 9, 309 (1999); J. Phys. Chem. A 106, 5242 (2002).] The duplication of this neutral Rydberg property by photodetachment of double Rydberg anions further confirms that double Rydberg anions are indeed the negative ions of their corresponding neutral Rydberg molecules and cluster-like systems.     

Barrier-free intermolecular proton transfer induced by excess electron attachment to the complex of alanine with uracil

The photoelectron spectrum of the uracil-alanine anionic complex (UA)(-) has been recorded with 2.540 eV photons. This spectrum reveals a broad feature with a maximum between 1.6 and 2.1 eV. The vertical electron detachment energy is too large to be attributed to an (UA)(-) anionic complex in which an intact uracil anion is solvated by alanine, or vice versa. The neutral and anionic complexes of uracil and alanine were studied at the B3LYP and second-order M?ller-Plesset level of theory with 6-31++G(*) (*) basis sets. The neutral complexes form cyclic hydrogen bonds and the three most stable neutral complexes are bound by 0.72, 0.61, and 0.57 eV. The electron hole in complexes of uracil with alanine is localized on uracil, but the formation of a complex with alanine strongly modulates the vertical ionization energy of uracil. The theoretical results indicate that the excess electron in (UA)(-) occupies a pi(*) orbital localized on uracil. The excess electron attachment to the complex can induce a barrier-free proton transfer (BFPT) from the carboxylic group of alanine to the O8 atom of uracil. As a result, the four most stable structures of the uracil-alanine anionic complex can be characterized as a neutral radical of hydrogenated uracil solvated by a deprotonated alanine. Our current results for the anionic complex of uracil with alanine are similar to our previous results for the anion of uracil with glycine, and together they indicate that the BFPT process is not very sensitive to the nature of the amino acid's hydrophobic residual group. The BFPT to the O8 atom of uracil may be relevant to the damage suffered by nucleic acid bases due to exposure to low energy electrons.