Showing papers by "Drake S. Eggleston published in 1994"

Design, synthesis, and kinetic evaluation of high-affinity fkbp ligands and the x-ray crystal-structures of their complexes with fkbp12.

Abstract: The design and synthesis of high-affinity FKBP12 ligands is described. These compounds potently inhibit the cis-trans-peptidylprolyl isomerase (rotamase) activity catalyzed by FKBP12 with inhibition constants (K i,app ) as low as 1 nM, yet they possess remarkable structural simplicity relative to FK506 and rapamycin, from which they are conceptually derived. The atomic structures of three FKBP12-ligand complexes and of one unbound ligand were determined by X-ray crystallography and are compared to the FKBP12-FK506 and FKBP12-rapamycin complexes

Structure determination of racemic trichogin A IV using centrosymmetric crystals

Abstract: Direct methods of crystal structure solution are greatly facilitated in centrosymmetric space groups where the complexity of the phase-problem is reduced. For most peptides and proteins, crystallization in a centrosymmetric arrangement is precluded by an intrinsic dissymmetry due to the constituent chiral amino acid residues. The synthetic accessibility of peptide sequences containing amino acids of either chirality offers the possibility for co crystallization of racemic crystals. We report here the first use of such an approach for the de novo structure determination of a medium-sized molecule, trichogin A IV, which is a constituent of a fungal lipopeptaibol mixture possessing membrane-modifying properties of biological interest.

Stereoselective syntheses of substituted 5,6-dihydro-2(1H)-pyridinones in polyphosphate media

Abstract: delta-Lactams have been synthesized with excellent stereocontrol of substituents by condensing 3-alkenamides with aryl aldehydes in polyphosphoric ester. The scope of the condensation of 3-alkenamides with aryl aldehydes in several phosphate media is examined, and a rationale is proposed regarding gamma-lactam versus delta-lactam formation.

Stereocontrolled construction of condensed gamma-lactam ring-systems by cationic cyclizations - rearrangement of a gamma-lactam to a delta-lactam

Abstract: A new condensation of 3-alkenamides with benzaldehyde in acidic media, notably polyphosphoric acid, leads to gamma-lactam rings with high regio- and stereocontrol. One such gamma-lactam was shown to undergo a novel and stereocontrolled ring-expansion to a delta-lactam.

Facile biocatalytic reduction of the carbon–carbon double bond of 5-benzylidenethiazolidine-2,4-diones. Synthesis of (±)-5-(4-{2-[methyl(2-pyridyl)amino]ethoxy}benzyl)thiazolidine-2,4-dione (BRL 49653), its (R)-(+)-enantiomer and analogues

Abstract: A novel biotransformation system for the reduction of carbon-carbon double bonds in 5-benzylidenethiazolidine-2, 4-diones, to give the corresponding 5-benzylthiazolidine-2, 4-diones, using whole cells of red yeasts is described. These reduced compounds, which are recovered in good yield, are of potential use in the treatment of non-insulin dependent diabetes mellitus. The mild reaction conditions developed allow reduction of 5-benzylidenethiazolidine-2, 4-diones containing other functionalities which are not compatible with alternative reduction methods. The biocatalytic reduction is enantioselective and the synthesis of R-(+)-5-(4-{2-[methyl(2-pyridyl)amino]ethoxy}benzyl)thiazolidine-2, 4-dione by Rhodotorula rubra CBS 6469 and structure confirmation by X-ray crystallography is detailed. Optimisation of reaction conditions (including immobilisation) for these whole cell reduction systems is described.

(E)-3-[[[[6-(2-carboxyethenyl)-5-[[8-(4- methoxyphenyl)octyl]oxy]-2-pyridinyl]-methyl]thio]methyl]benzoic acid and related compounds: high affinity leukotriene B4 receptor antagonists.

Abstract: (E)-3-[[[[6-(2-Carboxyethenyl)-5-[[8-(4- methoxyphenyl)octyl]oxy]-2-pyridinyl]methyl]thio]methyl]benzoic acid (11, SB 201993) is a novel, potent LTB4 receptor antagonist. Compound 11 arose from a structure-activity study of a series of trisubstituted pyridines that demonstrated LTB4 receptor antagonist activity. The placement of an additional methylene unit in the sulfur containing chain linking the pyridine and benzoic acid moieties of lead compound 8 (K(i) = 80 nM) resulted in a greater than 10-fold increase in receptor affinity. Additionally, in this new series of compounds, the oxidation state of the sulfur was found to be critical to the activity, i.e., the sulfoxide and sulfone showed substantially lower affinity for the LTB4 receptor. Compound 11 competitively inhibits the binding of [3H]LTB4 to LTB4 receptors on human polymorphonuclear leukocytes with a Ki of 7.1 nM and blocks both the LTB4-induced calcium mobilization and the LTB4-induced degranulation responses in these cells with IC50 values of 131 and 271 nM, respectively. Compound 11 demonstrated oral LTB4 antagonist activity as well as topical antiinflammatory activity in the mouse.

Synthesis of Imidazoles via Hetero‐Cope Rearrangements.

Abstract: A novel synthetic approach to heterocycles containing the imidazole moiety based on the multihetero-Cope rearrangement is described. Oximes are reacted with benzenecarboximidoyl chlorides 4 affording adducts that readily undergo the hetero-Cope rearrangement at slightly elevated temperatures. Acid treatment of the resulting amidines 8 provides imidazoles in very high yields

Synthesis and Structure‐Activity Relationships of Macrocyclic FKBP Ligands.

Abstract: A number of pipecolinate dilactones have been synthesized as simplified macrocyclic mimics of the binding domains in rapamycin (1) and FK506 (2). Crystallographic studies of these compounds indicate that the conformation of the pipecolinyl α-ketoamide region is preorganized for binding to FKBP. This is confirmed by the ability of these analogs to inhibit the FKBP cis-trans peptidyl-prolyl isomerase activity.

Peptide crystal growth via sulfonate salt formation: The structure of bis-glycylglycine-1,5-naphthalenedisulfonate hydrate

Abstract: Continuing a line of investigations on methods for formation and growth of high-quality crystals of peptides, the glycylglycine sequence has been crystallized by evaporation methods as a salt with 1,5-naphthalenedisulfonic acid. The structure of the peptide is highly extended, and is conformationally quite similar to the structures which have been characterized for other zwitterionic and salt forms of this sequence. Thus, crystallization as a salt with this sulfonic acid has imposed no undue influence upon the molecular conformation. These results offer further indication that the preparation of peptide sulfonate salts, particularly with arene templates, may have broad general utility for crystallization of interesting sequences which until now have not been approachable in their zwitterionic forms.

Stereoselective Syntheses of Substituted 5,6-Dihydro-2(1H)-pyridinones in Polyphosphate Media.

Abstract: delta-Lactams have been synthesized with excellent stereocontrol of substituents by condensing 3-alkenamides with aryl aldehydes in polyphosphoric ester. The scope of the condensation of 3-alkenamides with aryl aldehydes in several phosphate media is examined, and a rationale is proposed regarding gamma-lactam versus delta-lactam formation.

Heteroarylation of 6‐Aryl‐2,3‐dihydroimidazo(2,1‐b)thiazole with N‐( Ethoxycarbonyl)heteroaromatic Salts.

Abstract: The ethyl chloroformate salts of a variety of benzo-fused six membered π-deficient heteroaromatics, including quinoline, isoquinoline, 4-chloroquinoline, 3-bromoquinoline, phthalazine, and quinazoline, reacted with 6-aryl-2,3-dihydroimidazo[2,1-b]thiazole at the 5-position. The dihydroheteroaromatic adducts were oxidized by o-chloranil, sulfur, or electrochemical methodology to form the 5-heteroaromatic-6-aryl- 2,3-dihydroimidazo[2,1-b]thiazoles (10-15). In each example, the regiochemistry of addition to the heteroaromatic ring was established