Showing papers by "Drake S. Eggleston published in 1998"

ATP-Citrate lyase as a target for hypolipidemic intervention. 2. Synthesis and evaluation of (3R,5S)-omega-substituted-3-carboxy-3, 5-dihydroxyalkanoic acids and their gamma-lactone prodrugs as inhibitors of the enzyme in vitro and in vivo

Abstract: A series of (3R,5S)-omega-substituted-3-carboxy-3, 5-dihydroxyalkanoic acids have been synthesized and evaluated as inhibitors of the recombinant human form of ATP-citrate lyase. The best of these have Ki's in the 200-1000 nM range. As the corresponding thermodynamically favored gamma-lactone prodrugs, a number of compounds are able to inhibit cholesterol and fatty acid synthesis in HepG2 cells and reduce plasma triglyceride levels in vivo. The best of these, compound 77, is able to induce clear hypocholesterolemic and hypotriglyceridaemic responses when administered orally to rat and dog. These results provide evidence to support the hypothesis that compounds which inhibit ATP-citrate lyase have the potential to be a novel class of hypolipidemic agent, which possess combined hypocholesterolemic and hypotriglyceridemic activities.

Crystallographic structure of a multiple β-turn containing, glycine-rich heptapeptide: A synthetic precursor of the lipopeptaibol antibiotic Trichodecenin I

Abstract: In continuation of our studies on the structure and function of peptaibol antibiotics, the conformational properties of a sequence analogous to that of Trichodecenin I (Z-Gly-Gly-D-Leu-Aib-Gly-D-Ile-D-Leu-OMe, where Z = benzyloxycarbonyl, Aib = alpha-aminoisobutyric acid, and OMe = methyl ester) have been investigated crystallographically. This sequence is the mirror image of the naturally occurring molecule and also of the C-terminal heptapeptide of the related lipopeptaibol Trichogin A IV (where, however, the Leu-OMe residue has replaced the original Leuol residue). The molecule crystallized in the monoclinic system, space group P21, Z = 4, and cell parameters a = 11.610(5), b = 33.342(8), c = 11.735(4) A, beta = 110.42(1) degrees, V = 4257(3) A3. The crystallographic refinement converges at residual values of R = 0.047 and wR2 = 0.134 on F2. In the 1-5 segment the molecular conformation is virtually identical to that one reported from solution nmr studies of a similarly protected sequence [Biopolymers (1995), Vol. 35. pp. 21-29)] and is characterized by beta-turns of type I at Gly1-Gly2, II' at Leu3-Aib4, and I at Aib4-Gly5. In the crystal structure, a beta-sheet-like arrangement is seen at the C-terminus.

Chromatographic resolution of antihypertensive benzopyrans by closed-loop recycling enantioselective high pressure preparative chromatography and their X-ray analysis

Abstract: The resolution of (±)-trans-3,4-dihydro-2,2-dimethyl-4-(2-oxopiperidin-1-yl)-2H-pyrano[3,2-c]pyridin-3-ol 1, [1] a potassium channel opener, has been achieved using closed-loop recycling enantioselective preparative chromatography. The resolved enantiomers showed an ee of >97% based on analytical HPLC and 1H NMR. The absolute configuration has been determined by X-ray analysis of the (R)-(+)-α-methylphenylcarbamoyl derivative of one of the enantiomers.