Juliette Ellen Neve

Sideroxylonal C, a new inhibitor of human plasminogen activator inhibitor type-1, from the flowers of Eucalyptus albens

Sideroxylonal C (3), a new phloroglucinol dimer, was isolated from the flowers of Eucalyptus albens through bioassay-guided fractionation. The structure elucidation was based on 1D and 2D NMR experiments, MS analysis, and comparison with sideroxylonals A (1) and B (2). Sideroxylonal C inhibited human plasminogen activator inhibitor type-1 at 4.7 microM without any significant effect on human tissue plasminogen activator.

Euodenine A: A Small-Molecule Agonist of Human TLR4

A small-molecule natural product, euodenine A (1), was identified as an agonist of the human TLR4 receptor. Euodenine A was isolated from the leaves of Euodia asteridula (Rutaceae) found in Papua New Guinea and has an unusual U-shaped structure. It was synthesized along with a series of analogues that exhibit potent and selective agonism of the TLR4 receptor. SAR development around the cyclobutane ring resulted in a 10-fold increase in potency. The natural product demonstrated an extracellular site of action, which requires the extracellular domain of TLR4 to stimulate a NF-κB reporter response. 1 is a human-selective agonist that is CD14-independent, and it requires both TLR4 and MD-2 for full efficacy. Testing for immunomodulation in PBMC cells shows the induction of the cytokines IL-8, IL-10, TNF-α, and IL-12p40 as well as suppression of IL-5 from activated PBMCs, indicating that compounds like 1 could modulate the Th2 immune response without causing lung damage.

Aminimides as Potential CNS Acting Agents. II* Design, Synthesis, and Receptor Binding of 4′-Arylalkyl Aminimide Analogues of Clozapine as Prospective Novel Antipsychotics

A series of substituted 1-[4-(8-chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)-1-methylhexahydropyrazin-1-ium]-1-aminimide derivatives were designed on the basis of the physicochemical properties of the aminimide functional group and synthesized as potential antipsychotic agents for the treatment of schizophrenia. The target compounds were readily prepared in two steps from clozapine (8-chloro-11-(4-methylpiperazino)-5H-dibenzo[b,e][1,4]diazepine) and involved N-acylation of a common hydrazinium salt intermediate by an acyl chloride or activated ester in the presence of a strong base. The aminimides were tested for in vitro activity at the dopamine D4 and serotonin 5-HT2A receptors and were found to possess modest affinity for both receptor systems.

The First Aminimide Synthesis from Benzoyl Azide and Pyridine

Irradiation of benzoyl azide 1 at 254 nm in the presence of some amines produces aminimides: in the presence of pyridine the aminimide 13 can be isolated in 41% yield; in the presence of N,N-dimethylaniline a CH insertion product 7 is obtained via an intermediate aminimide 12. This is the first reported synthesis of aminimides from a benzoyl azide.

Design, synthesis and spectroscopic characterisation of a focused library based on the polyandrocarpamine natural product scaffold.

A focused library based on the marine natural products polyandrocarpamines A (1) and B (2) has been designed and synthesised using parallel solution‐phase chemistry. In silico physicochemical property calculations were performed on synthetic candidates in order to optimise the library for drug discovery and chemical biology. A library of ten 2‐aminoimidazolone products (3–12) was prepared by coupling glycocyamidine and a variety of aldehydes using a one‐step stereoselective aldol condensation reaction under microwave conditions. All analogues were characterised by NMR, UV, IR and MS. The library was evaluated for cytotoxicity towards the prostate cancer cell lines, LNCaP, PC‐3 and 22Rv1. Copyright

Aminimides as Potential CNS-Acting Agents. III. Design, Synthesis, and Receptor Binding of Aminimide Analogues of Dopamine, Serotonin, Morphine, and Nicotine

A series of aminimide derivatives of centrally acting agents, namely dopamine, serotonin, morphine and nicotine, were designed on the basis of the physicochemical properties of the aminimide functional group and synthesized to investigate their central nervous system (CNS) receptor affinity. The target compounds were readily prepared from an appropriate tertiary amine by N-acylation of a hydrazinium salt intermediate using acetic anhydride or acetyl chloride. The aminimides were tested for in vitro affinity at the dopaminergic D4, serotonergic 5-HT2A, opiate (μ, κ, and non-selective) and nicotinic acetylcholine receptors and were found to possess mixed affinities for the aforementioned receptor systems.

Corrigendum to “Solid-phase synthesis of Biotin-S-Farnesyl- l -Cysteine, a surrogate substrate for isoprenylcysteine Carboxylmethyltransferase (ICMT)” [Bioorg. Med. Chem. Lett. 23 (2013) [5671–5673]

The authors would like to apologise and point out that the following corrections are required to Fig. 1, Fig. 2, Scheme 1 and Scheme 2. Hydrogens are missing from the structure of the Biotin ring system:

Solid-phase synthesis of Biotin-S-Farnesyl-L-Cysteine, a surrogate substrate for isoprenylcysteine Carboxylmethyltransferase (ICMT).

Inhibition of isoprenylcysteine Carboxylmethyltransferase (ICMT) is of particular interest as a potential target for the development of cancer chemotherapeutic agents. Screening for inhibitors of ICMT utilises a scintillation proximity assay (SPA) in which Biotin-S-Farnesyl-L-Cysteine (BFC) acts as a surrogate substrate. A solid-phase synthesis protocol for the preparation of BFC using 2-chlorotrityl chloride resin as a solid support has been developed to provide sufficient supply of BFC for high throughput screening (HTS) and subsequent chemistry campaigns to target inhibitors of ICMT. The BFC prepared by this method can be produced quickly on large scale and is stable when stored at -20 °C as a solid, in solution, or on the resin.