Tiruchanduramine 1 was prepared using a convergent strategy with the longest linear sequence being eight steps. Synthetic 1, displayed a broader range of inhibition than reported previously and, in addition to α-glucosidases, 1 also inhibits almond β-glucosidase, β-galactosidase and β-N-acetylglucosaminidase from jack bean.The alkaloid tiruchanduramine 1 was prepared in racemic form from 3-aminopropan-1-ol and tryptophan using a convergent strategy with the longest linear sequence being eight steps.Download high-res image (121KB)Download full-size image

•The role of the C7-OH group in the activity of cylindrospermopsin 1 is unknown.•Synthetic analogues (11a–c) of cylindrospermopsin 1 were prepared.•Toxicity of these analogues was compared with 1 using human neutrophils in vitro.•The greatest toxicity was found in 11c with a 6-carbon tether and an –OH group.•An analogue closely resembling 1 but lacking the C7-OH group had low toxicity.Cylindrospermopsin (CYN) is a naturally occurring alkaloid produced by a variety of cyanobacteria and known to induce oxidative stress-mediated toxicity in eukaryotic cells. Despite extensive research on the mechanism of CYN toxicity, an understanding of the structural features responsible for this toxicity and the mechanism by which it can enter the cell are still not clear. It was established that the presence of both the uracil and guanidine groups is essential in biological activity of CYN whilst not much is known in this regard on the role of tether that separates them and the attached hydroxyl group. Therefore, in the present study we have prepared three synthetic analogues possessing uracil and guanidine groups separated by a variable length tether (4–6 carbons) and containing a hydroxyl function in a position orientation to CYN, together with a tetracyclic analogue of CYN lacking the hydroxyl group at C-7. The toxicity of these compounds was then compared with CYN and guanidinoacetate (GAA; the primary substrate in CYN biosynthesis) in an in vitro model using human neutrophils isolated from healthy subjects. The lowest activity measured by means of reactive oxygen species generation, lipid peroxidation and cell death was observed for GAA and the tetracyclic analogue. The greatest toxicity was found in an analogue with a 6-carbon tether, but all three analogues and CYN caused rapid onset of redox imbalance. These results add to the general understanding of CYN toxicity and preliminary findings suggest that the –OH group at C-7 may be significant for the cellular transport of CYN and/or be involved in its toxic activity inside the cell, a hypothesis which requires further testing.Analogues 11a–c of the alkaloid cylindrospermopsin 1, containing the key guanidine, hydroxyl and uracil motifs, have shown comparable cytotoxic activity to the natural material.Download high-res image (151KB)Download full-size image

A range of guanidinium catalysts was prepared in six or seven synthetic steps and applied to the phase transfer alkylation of a glycinate Schiff's base in 21–86% ee as well as the phase transfer epoxidation of some chalcones in 85–94% ee. Using a spectrophotometric method, pKa values in the range 13.2–13.9 in DMSO have been determined for some of the catalysts highlighting an increase in basicity relative to achiral tetramethylguanidine (pKa=13.0) and a mechanism involving the protonated guanidinium ion as a phase transfer catalyst is proposed. The use of two of the catalysts for the addition of nucleophiles in Michael addition reactions was investigated and both were found to be effective catalysts. A counterion effect was apparent in these reactions, but no enantioselectivity was observed.

Two tricyclic guanidine model compounds 28 and 29 have been prepared in 12 steps from 1,5-pentanediol using a biomimetic synthetic approach. The pivotal reaction in the sequence is a tethered Biginelli condensation between 21/22 and β-keto esters 23 and 24.

The tethered Biginelli condensation between hemiaminal 21 and β-keto ester 22 is reported, leading to a model tricyclic core of the cylindrospermopsin alkaloids.

The synthesis, electrochemical and spectroscopic properties of a series of thiophene-substituted 1,3-dithiole-2-ones is described. The derivatives Th-3,3, Th-2,2, Th-2,3, Th-3,3(2,2′-Me), and Th3,3-(2,5,2′,5′-Me), have been successfully polymerized by cyclic voltammetry. From the UV−visible spectra of the neutral films, it was determined that PTh-3,3, PTh-2,2 and PTh-2,3 have a bandgap of 2.04, 2.30, and 2.18 eV, respectively. The voltammetric response of Th-3,3(2,2′-Me) was noticeably different from the other polymers. The SNIFTIRS data suggested that Th-3,3(2,2′-Me) was formed by bonding via the β-positions of the thiophene ring, resulting in a poorly conductive polymer. The in situ solid-state modification of PTh-3,3 to produce a new TTF-derivatized polythiophene was carried out. The cyclic voltammetry of the modified polymer confirmed the inclusion of TTF into the backbone of the film.

The cyclisation of N-allyl- and N-homoallylguanidines using DMDO leading to the formation of novel 5- and 6-membered guanidine heterocycles is reported. Several of the products formed displayed weak inhibition of glycosidase enzymes.

The tethered Biginelli condensation between hemiaminal 21 and β-keto ester 22 is reported, leading to a model tricyclic core of the cylindrospermopsin alkaloids.