John N. Lambert

A direct method for the formation of peptide and carbohydrate dendrimers

Two new methods for the modification of PAMAM dendrimers have been developed which allow the covergent synthesis of either peptide or carbohydrate-bearing dendrimer molecules. Both methods involve condensation between hydroxylamino nucleophiles and appropriate carbonyl-bearing reaction partners.

Expression of progastrin-derived peptides and somatostatin in fundus and antrum of nonulcer dyspepsia subjects with and without Helicobacter pylori infection.

The hypergastrinemia and hyperacidity associated with Helicobacter pylori infection has been explained by either a primary excess of gastrin or a lack of inhibitory influence by somatostatin (SOM). The objective of the present study was to compare the concentrations of fundic and antral SOM- and antral progastrin-derived peptides in nonulcer dyspepsia (NUD) subjects with and without H. pylori infection. Antral and fundic mucosal biopsies were extracted and assayed for SOM and gastrin amide, glycine–extended gastrin (gastrin gly), progastrin, and total gastrin. There was a significant sixfold reduction in antral SOM but no change in fundic SOM content in H. pylori-infected subjects compared to uninfected subjects. Antral gastrin amide concentrations were significantly higher in infected subjects. However, the concentrations of the nonamidated gastrin forms (progastrin and glycine-extended gastrin) were significantly lower in the infected subjects, indicating an increased conversion of the precursor forms of gastrin to amidated gastrin, the type known to stimulate gastric acidity. The present study demonstrates that the elevated gastrin concentrations associated with H. pylori infection may be due to a reduction in the paracrine inhibitory effect of SOM on antral gastrin release. In addition, the posttranslational processing of gastrin to the amidated forms is increased in infected subjects, explaining why the elevation in antral gastrin is confined to the amidated form.

Efficient synthesis of thioether-based cyclic peptide libraries

Abstract A new method for the synthesis of cyclic peptide libraries has been developed where the key cyclisation step involves reaction between a C-terminal cysteine side chain and an N-terminal bromoacyl group. We report conditions whereby liberation of peptides from the solid support and cyclisation occur concurrently to form thioether-linked cyclic peptides in generally >95% yield.

The palladium-mediated cross-coupling of bromotropolones with organostannanes; application to concise syntheses of β-dolabrin, β-thujaplicin, 7-methoxy-4-isopropyltropolone, and β-thujaplicinol

The bromotropolones (1), (2), and (3) cross-couple with organostannanes in the presence of palladium(0) to produce alkyl, alkenyl, or aryl substituted tropolones; the methodology has been applied to the synthesis of the monoterpenes β-dolabrin (4), β-thujaplicin (5), 7-methoxy-4-isopropyltropolone (7), and β-thujaplicinol (8).

Parallel modification of tropane alkaloids

Abstract Various tropane alkaloids have been prepared by structural modification of the readily available natural product, scopolamine 1 . Reaction of isocyanates with 6,7-dehydrotropine 5 provided a number of urethanes 6a – e . Reductive amination of tropinone 7 and subsequent reaction with isocyanates provided ureas 9a – f . Mitsunobu inversion of the C-3 alcohol of tropine 10 afforded the epimeric ester 11 .

A biomimetic and fully regiocontrolled total synthesis of (±)-colchicine

The first fully regiocontrolled total synthesis of the alkaloid colchicine 1 is described; the key step of the reaction sequence is the efficient biomimetic conversion of the σ-homo-o-benzoquinone monoacetal 11 into the α-tropolone-O-methyl ether 13.

New DNA Modification Strategies Involving Oxime Formation

A new method for the formation of covalently linked DNA conjugates is described. The method involves installation of a 5´-hydroxylamine nucleophile onto synthetic DNA and condensation with a suitable electrophilic carbonyl compound to form an oxime linkage. Various protection strategies for the hydroxylamine group and their merits are discussed and the formation of an oligonucleotide–peptide conjugate is described.

A chemoenzymatic synthesis of differentially protected D-talose derivatives

The synthesis of the D-talose derivatives (10)-(14) from the readily available and enantiomerically pure cis-1,2-dihydrocatechol (2) is described. The structures of compounds (7) and (13) have been established by single-crystal X-ray analyses.

Fully regiocontrolled synthesis of (±)-12a, 12b-secocolchicine and studies concerning its cyclisation to the alkaloid colchicine

A fully regiocontrolled synthesis of the title compound 6, an AC-ring analogue of the alkaloid colchicine 1, is reported. The key step associated with the sequence used was condensation of lithium halogenocarbenoid 10—a synthetic equivalent for the inaccessible 7-methoxytropon-3-yl anion 12—with 3,4,5-trimethoxycinnamaldehyde 17 to produce the 1,2-addition product 18 as a mixture of diastereoisomers. Elaboration of compound 18 provided benzoate 23 which, on treatment with base, underwent ring-expansion to give troponoid 24 in excellent yield. Replacement of the C-7 benzoate group in compound 24 by an acetamido moiety was readily achieved and produced compound 6 in good overall yield. Unsuccessful attempts to convert compound 6 and the deacetamido analogue 38 into colchicine and deacetamidocolchicine 3, respectively, are described.

Synthesis of an Electrophilic Polymer by Ring-Opening Metathesis Polymerization

A new class of modifiable polymer is described. The electrophilic polymer is readily prepared using ring-opening metathesis polymerization (ROMP), and it is shown that amine nucleophiles can be introduced to the polymer.