Robert A. Zambias

Microchemical structural determination of a peptoid covalently bound to a polymeric bead by matrix-assisted laser desorption ionization time-of-flight mass spectrometry

Abstract New methodology utilizing matrix-assisted laser desorption ionization time-of-flight mass spectroscopy (MALDI-TOF MS) for the direct identification of a ligand covalently attached to a polymeric bead is reported. The method allows for structure determination without relying on encoding strategies. Gaseous TFA cleavage of a peptoid from a single bead followed by mounting in MALDI matrix and irradiation with a beam at 337 nm gave abundant molecular ions and structurally informative fragment ions produced by post source decay (PSD).

Biochemical and biological activities of 2,3-dihydro-6-[3-(2-hydroxymethyl)phenyl-2-propenyl]-5-benzofuranol (L-651,896), a novel topical anti-inflammatory agent

The biochemical and biological profile of a topical anti-inflammatory agent, 2,3-dihydro-6-[3-(2-hydroxymethyl)phenyl-2-propenyl]-5-benzofuranol (L-651,896 inhibited the 5-lipoxygenase of rat basophilic leukemia cells with an IC50 of 0.1 microM and leukotriene synthesis by human PMN and mouse macrophages with IC50 values of 0.4 and 0.1 microM respectively. L-651,896 also inhibited prostaglandin E2 synthesis by mouse peritoneal macrophages (IC50 = 1.1 microM). This compound inhibited ram seminal vesicle cyclooxygenase activity at considerably higher concentrations, and this effect was directly related to substrate concentration. When applied topically to the mouse ear, L-651,896 lowered elevated levels of leukotrienes associated with arachidonic acid-induced skin inflammation and delayed hypersensitivity induced by oxazolone. However, while L-651,896 inhibited the increased vascular permeability induced by arachidonic acid, it had no effect on the edema associated with the immune-based response to oxazolone in the same tissue. Thus, it is possible that leukotrienes may play a role in some but not all inflammatory responses.

ANTIFUNGAL LIPOPEPTIDES : STRUCTURE-ACTIVITY RELATIONSHIPS OF 3-HYDROXYGLUTAMINE-MODIFIED PNEUMOCANDIN B0 DERIVATIVES

Abstract Selective methanolysis or dehydration followed by reduction of the 3-hydroxyglutamine residue of pneumocandin B0 (1) or its dideoxy analog 5 (L-692,289) gave the methyl 3-hydroxyglutamate and 3-hydroxyornithine analogs 6 and 9, respectively. Further derivatization of these analogs allowed a study of the SAR at this position. In general, carboxylic acid-containing derivatives were poorer antifungal agents than neutral derivatives while amine-bearing analogs displayed the greatest potency.

Lipopeptide antifungal agents: Amine conjugates of the semi-synthetic pneumocandins L-731,373 and L-733,560

Abstract Amine conjugates of the semi-synthetic 1,3-β-(D)-glucan synthesis inhibitors L-731,373 (3) and L-733,560 (4) were prepared and evaluated for in vitro and in vivo antifungal activity. Tricationic analogs were more potent than the dicationic which were more potent than the monocationic. The L-ornithine conjugate of 4 possessed excellent pharmacokinetic parameters but lacked sufficient antifungal spectrum for development.

The inhibition of C5a receptor binding by analogs of L-156,602, a cyclic hexadepsipeptide antibiotic

Abstract The cyclic hexadepsipeptide antibiotic L-156,602 ( 1 ) was found to be an inhibitor of anaphylatoxin C5a binding to its receptor (IC 50 =1.7 μg/mL). This compound also caused nonspecific degranulation of neutrophils, but not through interactions with the C5a or other receptors. The effects of chemical modification of the structure of 1 on C5a receptor inhibition and nonspecific actions are reported.