A short synthesis of troglitazone: an antidiabetic drug for treating insulin resistance.

Troglitazone was obtained in 5 steps from 4-bromo-1,1-dimethoxy-3-methylbut-2-ene with an overall yield of 7.5%. The formation of the chromane ring was achieved by condensing an unsaturated acetal with trimethylhydroquinone in the presence of bis(trifluoromethylsulfonyl)imide.

Children's moral and ecological reasoning about the Prince William Sound oil spill.

Sixty 2nd, 5th, and 8th graders were interviewed on their moral and ecological reasoning about the 1990 Exxon Valdez oil spill that occurred in Prince William Sound, Alaska. Results showed that children understood that the oil spill negatively affected the local Alaskan shoreline, marine life, fishermen, recreationists, and the oil company. Children cared that harm occurred to the shoreline and marine life and conceived of both types of harm as violating a moral obligation. Fifth and 8th graders, compared with 2nd graders, used a greater proportion of anthropocentric reasoning (e.g., that nature ought to be protected to protect human welfare) and biocentric reasoning (e.g., that nature has intrinsic value, rights, or a teleology). Discussion focuses on how studying children's reasoning about nature not only extends the bounds of what counts as moral--to include a relationship with the natural world--but also provides a unique means by which to conduct basic research on children's moral development.

Children's obligatory and discretionary moral judgments.

This study examined children's obligatory moral judgments (which reflect a moral requirement) and discretionary moral judgments (which reflect moral worthiness, but not a requirement). 72 children participated across grades 2, 5, and 8 (mean ages, 8-3, 11-0, and 13-11). Children were interviewed in response to stimulus stories that controlled for the degree of agent's cost (low and high) for performing positive moral acts (giving money for food to an impoverished, hungry person) and negative moral acts (not stealing money for food). Results showed that negative moral acts were more often conceived as obligatory than positive moral acts. In addition, the results support the proposition that children's concepts of obligation underlie judgments to codify law, that justice reasoning builds on concepts of welfare, and that with increasing age discretionary moral reasoning incorporates such character traits as benevolence, sacrifice, and supererogation. Discussion includes consideration of how the study's conceptualization and analysis can provide guidance to a moral-developmental research program.

Theoretical design of a bistetrapeptide derivative of mitoxantrone targeted towards the double-stranded hexanucleotide sequence d(GGCGCC)2.

The hexanucleotide d(GGCGCC)2 is encountered in recurrent fashion within transcriptional activating sequences in retroviruses and protooncogenes. Our first theoretical design of novel oligopeptide derivatives of mitoxantrone, MTX (1), had enabled us to predict derivatives depsiGly-Lys(L) and depsiGly-Gly-Orn(D) to preferentially target the tetrameric core d(CCGG)2. Owing to the crucial importance of hexamer d(GGCGCC)2, we have attempted to extend the realm of our approach by now targeting this specific hexanucleotide. For that purpose, we undertook the design of further oligopeptide derivatives of MTX, in which each arm was identically amidated (rather than esterified as in (1)) by tri- or tetrapeptides of varying sequences and individual residue configurations. The binding affinities of these derivatives to the palindromic sequences d(GGCGCC)2, d(CGCGCG)2, d(GCCGGC)2 and d(CCCGGG)2, were compared by energy-minimization. We report here the results obtained with the most promising derivative, having the sequence Arg(L)-Gly-Val(L)-Glu(L), and displaying a considerable energy preference for d(GGCGCC)2 over the other candidate hexameric sites (referred to as I). In the corresponding complexes, the two arms are in two mutually antiparallel directions in the major groove, and adopt a beta-sheet like arrangement stabilized by two H-bonds involving the carbonyl and amide groups of the Gly residues. Each Arg side chain on a given arm chelates O6 and N7 atoms of G1, G2/G1', G2' with its imino and cis amino hydrogen, and is simultaneously bound through two amino hydrogens in a bidentate interaction with the Glu residue.

Theoretical design of novel, 4 base pair selective derivatives of mitoxantrone.

Mitoxantrone (MTX) is a recently synthesized antitumor intercalative molecule, currently in use in chemotherapy. Previous theoretical computations showed that the base pair selectivity of MTX is limited to the sole two base-pair sequence making up the intercalation site. In order to further extend the recognition site, we undertook, by means of theoretical computations, the design of novel MTX derivatives, in which the terminal hydroxyl group of each side chain is esterified with oligopeptides. We compare in the present study the binding affinities of two derivatives, depsiGly-Lys(D) and depsiGly-Gly-Orn(L), for the palindromic sequences d(CCCGGG)2, d(GCCGGC)2, d(GGCGCC)2, and d(CGCGCG)2. Major groove binding of the oligopeptide arms was shown to be significantly more favourable than either minor groove binding, or binding to the sole phosphate groups. With the two arms adopting two antiparallel directions, two distinct arrangements were investigated in the major groove: (a) the two oligopeptides are brought closer together by means of two hydrogen bonds involving the backbone of their second residue in a beta-sheet like arrangement; (b) the two arms are remote from each other so as to reduce their mutual electrostatic repulsion. Whatever the disposition, the optimal binding configurations were invariably found to be those in which the cationic side chains of the terminal residues chelate N7/O6 of two successive guanines, whenever present on a given strand. A distinct energetical preference for arrangement (a) was obtained with the depsiGly-Gly-Orn(L) derivative. Replacement of the central Gly residue by a Cys one, as in the sequence depsiGly-Cys-Orn(L), was proposed subsequently, so as to further stabilize such a beta-sheet arrangement by means of a disulfide bridge between the two Cys residues. The two investigated compounds were shown to preferentially bind sequences d(CCCGGG)2 and d(GCCGGC)2, with a tetrameric core CCGG rather than sequences d(GGCGCC)2 and d(CGCGCG)2, with a tetrameric core GCGC.

An antibody purified with a lambda GT11 fusion protein precipitates enkephalinase activity.

An antiserum was raised against the neutral endopeptidase "enkephalinase" in guinea pig and used to probe a rabbit kidney cDNA expression library. A positive clone has been isolated and sequenced. The identity of the corresponding fusion protein was ascertained by its ability to select, from the crude antiserum, antibodies which specifically immunoprecipitate neutral endopeptidase enzymatic activity. This approach eliminates the uncertainty inherent to clone identification obtained from oligonucleotide probe derived from a partial sequence of the protein.