Oliver J. McConnell

Halogen chemistry of the red alga Asparagopsis

Ethanol extraction of fresh Asparagopsis taxiformis and A. armata, followed by pentane partition, results in the isolation of a series of halomethanes, among them MeI, CHCl3, and CCl4. Under these extraction conditions, esterification readily occurs, allowing the isolation and identification of a series of polyhaloethyl acetates and acrylates. The recognition of acetone and polyhaloacetones in these extracts suggests biological halogenations occur which result in haloform reactions.

Bifurcarenone, an inhibitor of mitotic cell division from the brown alga bifurcaria galapagensis

A C27 hydroquinone, bifurcarenone, apparently produced via mixed biosynthesis, has been isolated from the brown seaweed Bifurcaria galapagensis (Cystoseiraceae). The structure of bifurcarenone was determined by chemical and spectral methods, and this compound was found to exhibit antibacterial properties, as well as to inhibit cell cleavage of the fertilized egg from the urchin Strongylocentrotus purpuratus.

Halogen chemistry of the red alga Bonnemaisonia

Abstract Complete accounts of the natural products chemistry of Bonnemaisonia nootkana, B. asparagoides, B. hamifera and Trailliella intricata are described. In contrast to the chemistry of the closely related alga Asparagopsis, Bonnemaisonia spp. do not produce halomethanes, but instead an array of C7-C9 halogen-containing ketones, alcohols and carboxylic acids. Biomimetic syntheses of these compounds suggest they are precursors and products of in vivo Favorsky rearrangements.

Duryne, a new cytotoxic agent from the marine sponge Cribrochalinadura

Abstract Duryne, 1 , a cytotoxic metabolite which inhibits the growth of both mouse and human tumor cell lines in vitro has been isolated from the marine sponge Cribrochalina dura . Its structure has been assigned by spectral methods.

Tricyclic diterpenoids of the dolastane ring system from the marine alga dictyota divaricata

Four new oxygenated tricyclic diterpenoids have been isolated from the Caribean brown alga Dictyota dicaricato. The strures of these new compounds were secured by an X-ray analysis of a convenient diol derivative ,followed by interconversion where possible. the new diterpenoids belong to the dolastane group first isolated from the herbivorous molluse Dolabella auricularia,and their isolation here indicated that the sea hare most likely derived these compounds from brown seaweeds of the family dictyotaceae.

In Vitro Glucuronidation of Thyroxine and Triiodothyronine by Liver Microsomes and Recombinant Human UDP-Glucuronosyltransferases

Glucuronidation, which may take place on the phenolic hydroxyl and carboxyl groups, is a major pathway of metabolism for thyroxine (T4) and triiodothyronine (T3). In this study, a liquid chromatography/mass spectrometry (LC/MS) method was developed to separate phenolic and acyl glucuronides of T4 and T3. The method was used to collect the phenolic glucuronide of T4 for definitive characterization by NMR and to determine effects of incubation pH, species differences, and human UDP-glucuronosyltransferases (UGTs) involved in the formation of the glucuronides. Formation of T4 phenolic glucuronide was favored at pH 7.4, whereas formation of T4 acyl glucuronide was favored at pH 6.8. All the UGTs examined catalyzed the formation of T4 phenolic glucuronide except UGT1A4; the highest activity was detected with UGT1A3, UGT1A8, and UGT1A10, followed by UGT1A1 and UGT2B4. Formation of T3 phenolic glucuronide was observed in the order of UGT1A8 > UGT1A10 > UGT1A3 > UGT1A1; trace activity was observed with UGT1A6 and UGT1A9. UGT1A3 was the major isoform catalyzing the formation of T4 and T3 acyl glucuronides. In liver microsomes, phenolic glucuronidation was the highest in mice for T4 and in rats for T3 and lowest in monkeys for both T4 and T3. Acyl glucuronidation was highest in humans and lowest in mice for T4 and T3. Phenolic glucuronidation was higher than acyl glucuronidation for T4 in humans; in contrast, the acyl glucuronidation was slightly higher than phenolic glucuronidation for T3. UGT activities were lower toward T3 than T4 in all the species. The LC/MS method was a useful tool in studying glucuronidation of T4 and T3.

Metabolism of Intravenous Methylnaltrexone in Mice, Rats, Dogs, and Humans

Methylnaltrexone (MNTX), a selective μ-opioid receptor antagonist, functions as a peripherally acting receptor antagonist in tissues of the gastrointestinal tract. This report describes the metabolic fate of [3H]MNTX or [14C]MNTX bromide in mice, rats, dogs, and humans after intravenous administration. Separation and identification of plasma and urinary MNTX metabolites was achieved by high-performance liquid chromatography-radioactivity detection and liquid chromatography/mass spectrometry. The structures of the most abundant human metabolites were confirmed by chemical synthesis and NMR spectroscopic analysis. Analysis of radioactivity in plasma and urine showed that MNTX underwent two major pathways of metabolism in humans: sulfation of the phenolic group to MNTX-3-sulfate (M2) and reduction of the carbonyl group to two epimeric alcohols, methyl-6α-naltrexol (M4) and methyl-6β-naltrexol (M5). Neither naltrexone nor its metabolite 6β-naltrexol were detected in human plasma after administration of MNTX, confirming an earlier observation that N-demethylation was not a metabolic pathway of MNTX in humans. The urinary metabolite profiles in humans were consistent with plasma profiles. In mice, the circulating and urinary metabolites included M5, MNTX-3-glucuronide (M9), 2-hydroxy-3-O-methyl MNTX (M6), and its glucuronide (M10). M2, M5, M6, and M9 were observed in rats. Dogs produced only one metabolite, M9. In conclusion, MNTX was not extensively metabolized in humans. Conversion to methyl-6-naltrexol isomers (M4 and M5) and M2 were the primary pathways of metabolism in humans. MNTX was metabolized to a higher extent in mice than in rats, dogs, and humans. Glucuronidation was a major metabolic pathway in mice, rats, and dogs, but not in humans. Overall, the data suggested species differences in the metabolism of MNTX.

SYNTHETIC STUDIES OF MICROCOLIN B

Abstract The octanoyl and desacetyl analogue of the lipopeptide microcolin B isolated from Lyngbya majuscula was synthesized using a segment condensation strategy. To achieve this the unique 1-prolyl-methyl-2-pyrroline unit was prepared from Boc-Pro-Ala-OH in a five step synthesis. This segment was coupled to the dipeptide Boc-Thr-MeVal-OH using PyBoP®. Deprotection followed by PyBroP®-mediated coupling with octanoyl-MeLeu-OH finally led to the octanoyl analogue of desacetylmicrocolin B.

Synthesis of microcolin analogs using trimethylsilylated lactams

Abstract The synthesis of microcolin analogs is described using an approach that could be of considerable practical interest for structure-activity studies on microcolin and related peptides. This synthetic pathway is more efficient than the methods reported to date, and allows the variation of the Xaa-pyrrolin-2-one unit of these molecules, which has been shown to be crucial for the biological activity.

Discovery of a new series of monoamine reuptake inhibitors, the 1-amino-3-(1H-indol-1-yl)-3-phenylpropan-2-ols.

A novel series of monoamine reuptake inhibitors, the 1-amino-3-(1H-indol-1-yl)-3-phenylpropan-2-ols, have been discovered by combining virtual and focused screening efforts with design techniques. Synthesis of the two diastereomeric isomers of the molecule followed by chiral resolution of each enantiomer revealed the (2R,3S)-isomer to be a potent norepinephrine reuptake inhibitor (IC(50)=28 nM) with excellent selectivity over the dopamine transporter and 13-fold selectivity over the serotonin transporter.