Keith M. Morgan

How to Make Drugs Orally Active: A Substrate Template for Peptide Transporter PepT1

By building key structural features into hydrophilic drugs, they can be recognized by the PepT1 transporter system of the small intestine and rendered orally active. The model shown provides, for the first time, a 3D template for all known substrates of PepT1.

Peptide Mimics as Substrates for the Intestinal Peptide Transporter

4-Aminophenylacetic acid (4-APAA), a peptide mimic lacking a peptide bond, has been shown to interact with a proton-coupled oligopeptide transporter using a number of different experimental approaches. In addition to inhibiting transport of labeled peptides, these studies show that 4-APAA is itself translocated. 4-APAA transport across the rat intact intestine was stimulated 18-fold by luminal acidification (to pH 6.8) as determined by high performance liquid chromatography (HPLC); in enterocytes isolated from mouse small intestine the intracellular pH was reduced on application of 4-APAA, as shown fluorimetrically with the pH indicator carboxy-SNARF; 4-APAAtrans-stimulated radiolabeled peptide transport in brush-border membrane vesicles isolated from rat renal cortex; and inXenopus oocytes expressing PepT1, 4-APAA producedtrans-stimulation of radiolabeled peptide efflux, and as determined by HPLC, was a substrate for translocation by this transporter. These results with 4-APAA show for the first time that the presence of a peptide bond is not a requirement for rapid translocation through the proton-linked oligopeptide transporter (PepT1). Further investigation will be needed to determine the minimal structural requirements for a molecule to be a substrate for this transporter.

4‐Aminomethylbenzoic acid is a non‐translocated competitive inhibitor of the epithelial peptide transporter PepT1

1 4‐Aminomethylbenzoic acid, a molecule which mimics the spatial configuration of a dipeptide, competitively inhibits peptide influx in both Xenopus laevis oocytes expressing rabbit PepT1 and through PepT1 in rat renal brush border membrane vesicles. 2 This molecule is not translocated through PepT1 as measured both by direct HPLC analysis in PepT1‐expressing oocytes and indirectly by its failure to trans‐stimulate labelled peptide efflux through PepT1 in oocytes and in renal membrane vesicles. 3 However 4‐aminomethylbenzoic acid does reverse trans‐stimulation through expressed PepT1 of labelled peptide efflux induced by unlabelled peptide. Quantitatively this reversal is compatible with 4‐aminomethylbenzoic acid competitively binding to the external surface of PepT1. 4 4‐Aminomethylbenzoic acid (the first molecule discovered to be a non‐translocated competitive inhibitor of proton‐coupled oligopeptide transport) and its derivatives may thus be particularly useful as experimental tools.

Diastereo- and enantio-selectivity in the Pictet–Spengler reaction

The factors that control the relative and absolute stereochemistry of 1,3-disubstituted and 1,2,3-trisubstituted tetrahydro-β-carbolines formed via the Pictet–Spengler reaction are discussed. In particular, the stereochemical factors that lead to the predominance of cis-1,3-disubstituted products under conditions of kinetic control are presented, with the aid of X-ray crystallographic data on a number of compounds; methods for assigning relative stereochemistry on the basis of NMR data are given; the mechanism by which racemisation can occur during the Pictet–Spengler reaction has also been studied, and procedures for eliminating this problem are given.

Concise routes to pyrazolo[1,5-a]pyridin-3-yl pyridazin-3-ones

Cycloaddition of pyridine N-imine with 6-alkyl-4-oxohex-5-ynoates followed by condensation with hydrazine provides concise access to pharmacologically active 6-(pyrazolo[1,5-a]pyridin-3-yl)pyridazinones. For the first time alkynyl heterocycles are also shown to be effective dipolarophiles for pyridine N-imine, and analogous compounds can be accessed directly in modest yields through the reaction of 6-(alkyn-1-yl)pyridazin-3-one derivatives.

Spiro cyclisations of N-acyliminium ions involving an aromatic π-nucleophile

Spiro 2-pyrrolidin-5-ones were obtained from N-substituted succinimides by a two-step procedure, involving 5- or 6-endo-trig cyclisation of N-acyliminium ion intermediates with a tethered aromatic π-nucleophile.

Synthesis of polycyclic indolic structures

Abstract We report the development of routes for the synthesis of three types of polycyclic indolic compounds, all possessing a tetrahydro-β-carboline sub-structure to which an additional 5- or 6-membered heterocycle is attached across the 1,2-positions of ring C; all three routes involve a Pictet-Spengler reaction as a key step, which can be used to control the stereochemistry of up to 5 chiral centres.

SWERN OXIDATION OF TRYPTAMINE DERIVATIVES

Abstract The Swern oxidation of various indolic substrates is described, and a range of products resulting from overalloxidation at the 2-position were observed. In particular, depending on the substrate and reaction conditions, it was possible to achieve direct oxidation to α,β-unsaturated systems at the 2-position, to introduce a nucleophile at the 2-position, and to introduce a CH3-S-CH2 group at the indole 4-position via an unprecedented rearrangement of a Swern intermediate.

A total asymmetric synthesis of (–)-suaveoline

A new total synthesis of (–)-suaveoline from L-tryptophan is reported (overall yield ca. 14%); key steps include a high yielding cis-specific Pictet–Spengler reaction, a one-pot Horner–Wadsworth–Emmons/alkylation procedure, a vinylogous Thorpe cyclization and the direct formation of a pyridine from a 1,5-dinitrile.

The use of the aza-Diels–Alder reaction in the synthesis of pinidine and other piperidine alkaloids

Abstract The imine Ph 2 CHNCHCO 2 Et, generated from benzhydrylamine and ethyl glyoxylate, provides a Diels–Alder adduct with 1,3-pentadiene from which a range of cis -2,6-disubstituted piperidines can be accessed; the benzhydryl group confers high diastereocontrol for derivatising the six-membered ring, allowing access to 2,5,6-trisubstituted piperidines, and to 2,6-disubstituted piperidines such as pinidine.