Avery Rosegay

5-Methyltetrahydrofolic Acid as a Mediator in the Formation of Pyridoindoles

Enzymes from chick and rat tissues catalyze the reaction of N-methyl tryptamine with 5-methyltetrahydrofolic acid to form 2,3,4,9-tetrahydro-2-methyl-1H-pyrido[3,4b] indole. N,N-Dimethyltryptamine was not formed. With tryptamine as substrate the product is 2,3,4,9-tetrahydro-1H-pyrido[3,4b] indole and not N-methyltryptamine. These pyridoindoles were not formed when S-adenosylmethionine was cosubstrare.

Ophiobolin M and analogues, noncompetitive inhibitors of ivermectin binding with nematocidal activity

A series of ophiobolins were isolated from a fungal extract based on their nematocidal activity. These compounds are non-competitive inhibitors of ivermectin binding to membranes prepared from the free-living nematode, Caenorhabditis elegans, with an inhibition constant of 15 microM. The ophiobolins which were most potent in the biological assays, ophiobolin C and ophiobolin M, were also the most potent compounds when evaluated in a C. elegans motility assay. These data suggest that the nematocidal activity of the ophiobolins is mediated via an interaction with the ivermectin binding site. The isolation, structure and biological activity of ophiobolins have been described.

The first synthesis of a tricyclic homodetic peptide employing coordinated orthogonal protection

Abstract In an effort to cause significant conformational distortion and thereby possibly generate a pure SRIF antagonist, we undertook the synthesis of 2 , the first homodetic tricyclic peptide. This required five dimensional orthogonal amino protection and three carboxyl protecting groups to allow the selective closure of the three rings and to differentiate the e-amino groups of the two lysines. We also exploited acid catalyzed removal from the resin to achieve selective deprotection of a side chain carboxyl moiety simultaneously with its partner amino group for subsequent cyclization.

Syntheses of (R) [4-2H2] 2-Amino-3-Butenoic Acid (Vinylglycine) and (R) [4-2H2, 5-2H3] Methionine

Abstract Treatment of (R) methionine sulfoxide with NaOD led to exchange of the C-4 methylene and C-5 methyl protons; exchange of the chiral C-2 proton did not occur. Reducation with mercaptoacetic acid gave (R)-[4-2H2, 5-2H3] methionine. The latter was converted into its carbobenzyloxy methyl ester sulfoxide, pyrolysis of which followed by deprotection yielded (R)-[4-2H2] vinylglcine as the hydrochloride.

SYNTHESIS OF THE FIRST TRICYCLIC HOMODETIC PEPTIDE. USE OF COORDINATED ORTHOGONAL DEPROTECTION TO ACHIEVE DIRECTED RING CLOSURE

Abstract The discovery of somatostatin antagonists at one or more receptor subtypes remains an important goal. We therefore undertook the synthesis of the homodetic tricyclic peptide ( 1 ) hoping to cause conformational distortion and thereby achieve this biological goal. The synthetic strategy called for five dimensional orthogonal amino protection. The carboxyl and amino protecting groups were selected to assure the desired selective ring closures. The amino protecting groups were also chosen to permit differentiation between the two lysine e-amino groups. An improved general cyclization procedure was achieved, which provided the complex c -octapeptide 13 in 93% yield. Biological assay results for 1 are also presented.

Determination of enantiomeric concentrations of a 2,5-diaryltetrahydrofuran (L-668,750), a platelet-activating factor receptor antagonist, in rat plasma using a chiral α1-acid glycoprotein high-performance liquid chromatographic column

Racemic sulfonylated 2,5-diaryltetrahydrofuran [L-668,750, (+-)-trans-2-[3-methoxy-5-(2-hydroxy)ethylsulfonyl-4-n-propoxy]-p henyl-5-(3,4,5-trimethoxyphenyl)-tetrahydrofuran, I] is a potent, specific and orally active platelet-activating factor (PAF) receptor antagonist. Its (-)-(2S,5S) enantiomer [L-680,573, (S)-I] exhibited higher PAF antagonistic potency than the (+)-(2R,5R) enantiomer [L-680,574, (R)-I] in vitro and in animal models. For assay of drug concentrations in plasma of rats dosed intravenously or orally with tritium-labeled I, we have developed a high-performance liquid chromatographic (HPLC) method which directly resolved the two enantiomers. The column contained alpha 1-acid glycoprotein as the chiral stationary phase and was eluted with phosphate buffer, methanol and ethanol at neutral pH. The concentration of each enantiomer in the plasma was then determined by reverse isotope dilution assay. Results showed that the plasma clearance rate of the more potent (S)-I enantiomer was more than ten-fold faster than that of the (R)-I enantiomer; the enantioselective clearance resulted in nearly ten-fold higher concentrations of the latter in plasma at all time points regardless of the dosing route. This paper describes the HPLC chiral resolution method and its application in plasma analysis.

THE OXIDATIVE REARRANGEMENT OF KETONES TO CARBOXYLIC ACIDS

The oxidation of cyclic ketones by hydrogen peroxide catalyzed by selenium dioxide to produce ring-contracted carboxylic acids was reported by Payne and Smith in 1957. For example, cyclohexanone yields cyclopentane carboxylic acid (Reaction 1). They proposed that selenic acid is the effective oxidant. Sonoda and Tsutsumi,z and the present author^^*^ have reported the application to acylic ketones. As examples, acetone produces propionic acid (Reaction 2) and methyl cyclopropyl ketone gives cyclopropylacetic acid (Reaction 3) as the sole rearrangement product.