Timothy J. Snape

Chiral 1,1-diaryl compounds as important pharmacophores

Compounds containing a 1,1-diaryl motif are numerous, and compounds of this type have found use as catalysts and molecular building blocks, however, this review focusses solely on chiral compounds, wherein the two aromatic rings attached to a central carbon are not identical, and highlights their use and importance as drugs and biologically active molecules.

Anionic Antimicrobial and Anticancer Peptides from Plants

Anionic antimicrobial peptides (AAMPs) have been identified in a wide variety of plant species with net charges that range between −1 and −7 and structures that include: extended conformations, α-helical architecture and cysteine stabilized scaffolds. These peptides commonly exist as multiple isoforms within a given plant and have a range of biological activities including the ability to kill cancer cells as well as phytopathogenic bacteria, fungi, pests, molluscs, and other predatory species. In general, the killing mechanisms underpinning these activities are poorly understood although they appear to involve attack on intracellular targets such as DNA along with compromise of cell envelope integrity through lysis of the cell wall via chitin-binding and/or permeabilisation of the plasma membrane via lipid interaction. It is now becoming clear that AAMPs participate in the innate immune response of plants and make a major contribution to the arsenal of defence toxins produced by these organisms to compensate for their lack of some defence mechanisms possessed by mammals, such as mobility and a somatic adaptive immune system. Based on their biological properties, a number of potential uses for plant AAMPs have been suggested, including therapeutically useful anticancer agents and novel antimicrobial compounds, which could be utilized in a variety of scenarios, ranging from the protection of crops to the disinfection of hospital environments.

Foldamers as Anticancer Therapeutics: Targeting Protein–Protein Interactions and the Cell Membrane

Targeting important protein–protein interactions involved in carcinogenesis or targeting the cell membrane of a cancer cell directly are just two of the ways in which foldamers (oligomeric molecules that fold into distinct shapes in solution) hold considerable potential in the treatment of cancer. From mimicking the local topography of the helical compound of interest by using covalently constrained foldamers to mimicking the topography of the natural helix such that the positions of key functional motifs are in an identical spatial orientation to match those presented by the original α‐helix, synthetic foldamers have been used to mimic the natural foldamers that interact with proteins or the cell membrane. These targeted approaches have become established over a timeframe of more than a decade, and they continue to be included in the assortment of cancer targets being studied and the arsenal of chemotherapy compounds in development. These approaches are reviewed herein.

Synthetic oligoureas of metaphenylenediamine mimic host defence peptides in their antimicrobial behaviour

Oligomeric ureas of m-phenylenediamine target anionic DMPG (dimyristoylphosphatidylglycerol) and possess promise as antimicrobial agents. Their similar size, shape and hydrophobicity to helical antimicrobial peptides (AMPs) may be important for activity to exist and the ability of these compounds to insert into a well ordered lipid environment.

Interactions between suitably functionalised conformationally distinct benzanilides and phospholipid monolayers

The interaction between phospholipid monolayers and two conformationally distinct benzanilides possessing suitably positioned n-octyl groups was examined. The results obtained suggest a strong link between conformation and membrane binding and that this is driven by amphiphilicity.

Exploiting conformationally restricted N,N′-dimethyl-N,N′-diarylureas as biologically active CC double bond analogues: synthesis and biological evaluation of combretastatin A-4 analogues

The biological efficacy of a number of suitably functionalised conformationally restricted N,N′-dimethyl-N,N′-diarylureas, which occupy a similar 3-dimensional space to combretastatin A-4 (CA4), has been evaluated for their ability to inhibit tubulin polymerisation and inhibit the growth of short term glioblastoma multiforme (GBM) cell cultures and an established GBM cell line (U251MG). The results show that the ureas most like CA4, with regards to benzene ring oxygenation and overall shape, are the most active.

Small-molecule clinical trial candidates for the treatment of glioma.

The evaluation of new glioma treatments, currently in clinical trials, is undertaken.

Development of a novel, multifunctional, membrane-interactive pyridinium salt with potent anticancer activity.

The synthesis and biological evaluation of a novel pyridinium salt is reported. Initial membrane interaction with isolated phospholipid monolayers was obtained with the pyridinium salt, and two neutral analogues for comparison, and the anticancer effects of the best compound established using a cytotoxicity screening assay against glioma cells using both an established cell line and three short-term cell cultures-one of which has been largely resistant to all chemotherapeutic drugs tested to date. The results indicate that the pyridinium salt exhibits potent anticancer activity (EC50s=9.8-312.5 μM) on all cell types, including the resistant one, for a continuous treatment of 72 h. Microscopic examination of the treated cells using a trypan blue exclusion assay showed membrane lysis had occurred. Therefore, this letter highlights the potential for a new class of pyridinium salt to be developed as a much needed alternative treatment for glioma chemotherapy.

Preliminary biological evaluation and mechanism of action studies of selected 2-arylindoles against glioblastoma.

A series of related 2-arylindoles have been evaluated for their anticancer activity against a range of glioblastoma cell lines using a number of different cell-based assays to determine cell viability after treatment with the compounds. The best indoles, which showed comparable activity to cisplatin against a U87MG cell line in the MTS assay, were taken forward and initial studies suggest that their mechanism of action is consistent with the generation of reactive oxygen species followed by autophagic cell death. Furthermore, activity was also observed in glioblastoma short-term cell cultures for the best lead compound and in some cases gave low micromolar IC50s.

Cn-AMP2 from green coconut water is an anionic anticancer peptide

Globally, death due to cancers is likely to rise to over 20 million by 2030, which has created an urgent need for novel approaches to anticancer therapies such as the development of host defence peptides. Cn‐AMP2 (TESYFVFSVGM), an anionic host defence peptide from green coconut water of the plant Cocos nucifera, showed anti‐proliferative activity against the 1321N1 and U87MG human glioma cell lines with IC50 values of 1.25 and 1.85 mM, respectively. The membrane interactive form of the peptide was found to be an extended conformation, which primarily included β‐type structures (levels > 45%) and random coil architecture (levels > 45%). On the basis of these and other data, it is suggested that the short anionic N‐terminal sequence (TES) of Cn‐AMP2 interacts with positively charged moieties in the cancer cell membrane. Concomitantly, the long hydrophobic C‐terminal sequence (YFVFSVGM) of the peptide penetrates the membrane core region, thereby driving the translocation of Cn‐AMP2 across the cancer cell membrane to attack intracellular targets and induce anti‐proliferative mechanisms. This work is the first to demonstrate that anionic host defence peptides have activity against human glioblastoma, which potentially provides an untapped source of lead compounds for development as novel agents in the treatment of these and other cancers. Copyright