Tristan A. Reekie

Body temperature and cardiac changes induced by peripherally administered oxytocin, vasopressin and the non‐peptide oxytocin receptor agonist WAY 267,464: a biotelemetry study in rats

There is current interest in oxytocin (OT) as a possible therapeutic in psychiatric disorders. However, the usefulness of OT may be constrained by peripheral autonomic effects, which may involve an action at both OT and vasopressin V1A receptors. Here, we characterized the cardiovascular and thermoregulatory effects of OT, vasopressin (AVP) and the non‐peptide OT receptor agonist WAY 267,464 in rats, and assessed the relative involvement of the OT and V1A receptors in these effects.

Application of a Raney-Cobalt-Mediated Tandem Reductive Cyclization Protocol to Total Syntheses of the Aspidosperma Alkaloids (±)-Limaspermidine and (±)-1-Acetylaspidoalbidine

The racemic modification of the Aspidosperma alkaloid limaspermidine (1) has been prepared in ten steps including one involving a Raney-cobalt-mediated tandem reductive cyclization of nitrile 8 to give the tetracyclic system 9b. Compound (±)-1 has been converted over two steps into (±)-1-acetylaspidoalbidine [(±)-13].

The Chemoenzymatic Total Synthesis of Phellodonic Acid, a Biologically Active and Highly Functionalized Hirsutane Derivative Isolated from the Tasmanian Fungus Phellodon melaleucus

A total synthesis of the title natural product, 1, has been achieved using the cis-1,2-dihydrocatechol 7 as starting material. Compound 7 is readily obtained in large quantity and in an enantiomerically pure form through the whole-cell biotransformation of toluene using the genetically engineered microorganism E. coli JM109 (pDTG601) that overexpresses the enzyme toluene dioxygenase (TDO). Three key chemical steps were employed in the synthesis, the first of which was the microwave-promoted Diels–Alder cycloaddition reaction between diene 8 and cyclopent-1-en-2-one to give adduct 9. The second key step was the photochemically promoted oxa-di-π-methane rearrangement of the bicyclo[2.2.2]octenone derivative 15 of 9 to give the epimers 16 and 17, and the third key step was the reductive cleavage of the last pair of compounds so as to afford the linear triquinane 19. Elaboration of compound 19 to target 1 followed established procedures. Single-crystal X-ray analyses were carried out on compounds 11 and 19.

A Raney-Cobalt-Mediated Tandem Reductive Cyclization Route to the 1,5-Methanoazocino[4,3-b]indole Framework of the Uleine and Strychnos Alkaloids

The readily accessible enones 8, 17, and 18 undergo 2-fold reductive cyclization reactions upon exposure to hydrogen in the presence of Raney-cobalt and thereby afford compounds 11 (72%), 19 (47%), and 20 (84%), respectively. These products embody the ABCD-ring system associated with the title alkaloids, and compound 11 can be converted, over four steps and in 33% yield, into congener 24 incorporating the ABCDE-ring system of the Strychnos alkaloids.

Structural Optimization and Pharmacological Evaluation of Inhibitors Targeting Dual-Specificity Tyrosine Phosphorylation-Regulated Kinases (DYRK) and CDC-like kinases (CLK) in Glioblastoma

The DYRK family contains kinases that are up-regulated in malignancy and control several cancer hallmarks. To assess the anticancer potential of inhibitors targeting DYRK kinases, we developed a series of novel DYRK inhibitors based on the 7-azaindole scaffold. All compounds were tested for their ability to inhibit DYRK1A, DYRK1B, DYRK2, and the structurally related CLK1. The library was screened for anticancer efficacy in established and stem cell-like glioblastoma cell lines. The most potent inhibitors (IC50 ≤ 50 nM) significantly decreased viability, clonogenic survival, migration, and invasion of glioblastoma cells. Target engagement was confirmed with genetic knockdown and the cellular thermal shift assay. We demonstrate that DYRK1As thermal stability in cells is increased upon compound treatment, confirming binding in cells. In summary, we present synthesis, structure-activity relationship, and efficacy in glioblastoma-relevant models for a library of novel 7-azaindoles.

Discovery and pharmacological evaluation of a novel series of adamantyl cyanoguanidines as P2X7 receptor antagonists

Here we report adamantyl cyanoguanidine compounds based on hybrids of the adamantyl amide scaffold reported by AstraZeneca and cyanoguanidine scaffold reported by Abbott Laboratories. Compound 27 displayed five-fold greater inhibitory potency than the lead compound 2 in both pore-formation and interleukin-1β release assays, while 35-treated mice displayed an antidepressant phenotype in behavioral studies. This SAR study provides a proof of concept for hybrid compounds, which will help in the further development of P2X7R antagonists.

Structure-activity relationship studies of SEN12333 analogues: determination of the optimal requirements for binding affinities at α7 nAChRs through incorporation of known structural motifs.

Alpha7 nicotinic acetylcholine receptors (nAChRs) have implications in the regulation of cognitive processes such as memory and attention and have been identified as a promising therapeutic target for the treatment of the cognitive deficits associated with schizophrenia and Alzheimers disease (AD). Structure affinity relationship studies of the previously described α7 agonist SEN12333 (8), have resulted in the identification of compound 45, a potent and selective agonist of the α7 nAChR with enhanced affinity and improved physicochemical properties over the parent compound (SEN12333, 8).

The Formation of Seven-Membered Heterocycles under Mild Pictet–Spengler Conditions: A Route to Pyrazolo[3,4]benzodiazepines

Reported is a method for the synthesis of seven-membered heterocycles via a Pictet-Spengler condensation reaction under very mild conditions. High substrate scope allows for use of aldehydes using catalytic amounts of acetic acid yielding 39-90% and ketones using catalytic amounts of trifluoroacetic acid yielding 25-83%.

Intramolecular Cycloaddition Reactions of cis-1,2-Dihydrocatechol Derivatives Incorporating C3-Tethered Diazoketones, Nitrile Oxides, and Azides: Stereocontrolled Routes to Enantiomerically Pure Spiro[5.5]undecanes and Related Systems

A series of enantiomerically pure cis-1,2-dihydrocatechol derivatives incorporating C3-tethered diazoketone, nitrile oxide, or azide residues has been prepared from the precursor iodide 7 using Negishi cross-coupling reactions. Such derivatives, including diazoketone 12, participate in regio- and stereo-selective intramolecular cycloaddition reactions to give adducts, for example, 15, that are readily elaborated to spiro[5.5]undecanes such as 18.

Pharmacological evaluation of a novel series of urea, thiourea and guanidine derivatives as P2X7 receptor antagonists

We report on P2X7 receptor antagonists based on a lead adamantly-cyanoguanidine-aryl moiety. We have investigated the importance of the central cyanoguanidine moiety by replacing it with urea, thiourea or guanidine moieties. We have also investigated the linker length between the central moiety and the aryl portion. All compounds were assessed for their inhibitory potency in a pore-formation dye uptake assay at the P2X7 receptor. None of the compounds resulted in an improved potency illustrating the importance of the cyanoguanidine moiety in this chemotype.