The ability of protein–protein interactions to regulate cellular processes in both beneficial and detrimental ways has made them obvious drug targets. The Bcl‐2 family of proteins undergo a series of protein–protein interactions which regulate the intrinsic cell‐death pathway. The pro‐survival members of the Bcl‐2 family, including Bcl‐2, Bcl‐xL, and Mcl‐1, are commonly overexpressed in a number of human cancers. Effective modulators of members of the Bcl‐2 family have been developed and are undergoing clinical trials, but the efficient modulation of Mcl‐1 is still not represented in the clinic. In addition, Mcl‐1 is a major cause of resistance to radio‐ and chemotherapies, including inhibitors that target other Bcl‐2 family members. Subsequently, the inhibition of Mcl‐1 has become of significant interest to the scientific community. This review covers the progress made to date in modulating the activity of Mcl‐1, by both stapled peptides and small molecules. The development of peptides as drug candidates, and the advancement of experimental and computational techniques used to discover small molecules are also highlighted.

Natural products, their derivatives or compounds based on natural product leads constitute ~50 % of clinically used pharmaceuticals. This review highlights pharmaceuticals currently used in Australia and New Zealand that have their origins in fungal metabolites, discussing the natural products chemistry and medicinal chemistry leading to their application as pharmaceuticals

A synthetic approach accessing the pestalotiopsones, fungal chromones possessing a rare skeletal subtype, is reported for the first time. The synthesis of pestalotiopsone A (1) has been achieved in 7 linear steps (28%), from commercially available 3,5-dimethoxybenzoic acid and subsequently the first syntheses of pestalotiopsone B (2), C (3) and F (4) were performed utilising this chemistry. The key steps include a newly described homologation of a substituted benzoic acid to afford phenylacetate derivatives utilising Birch reductive alkylation conditions, a microwave mediated chromanone formation proceeding through an oxa-Michael cyclisation, and an IBX induced dehydrogenation to the desired chromone skeleton. The synthetic natural products were completely characterised for the first time, confirming their structures and their biological activities evaluated against a panel of bacterial pathogens.

Targeting PPIs with small molecules can be challenging owing to large, hydrophobic binding surfaces. Herein, we describe a strategy that exploits selective α‐helical PPIs, transferring these characteristics to small molecules. The proof of concept is demonstrated with the apoptosis regulator Mcl‐1, commonly exploited by cancers to avoid cell death. Peptide‐directed binding uses few synthetic transformations, requires the production of a small number of compounds, and generates a high percentage of hits. In this example, about 50 % of the small molecules prepared showed an IC50 value of less than 100 μm, and approximately 25 % had IC50 values below 1 μm to Mcl‐1. Compounds show selectivity for Mcl‐1 over other anti‐apoptotic proteins, possess cytotoxicity to cancer cell lines, and induce hallmarks of apoptosis. This approach represents a novel and economic process for the rapid discovery of new α‐helical PPI modulators.

Development of selective hDM2/X p53 inhibitors is key to further develop this anticancer target. This method displayed a 50% success rate and identified hDMX selective compounds.

Magic mushrooms: The investigation of an edible Boletopsis mushroom that is used traditionally in Papua New Guinea as treatment for gastrointestinal complaints led to the discovery of two new heterocyclic p‐terphenyl ethers, boletopsin (1) and 12 (2), along with the known metabolites boletopsin 4 and 7 and cycloleucomelone. Evaluation of the antibiotic activity of the compounds isolated from this Boletopsis sp. supported the traditional medicinal use of the mushroom.

Cell migration towards a chemotactic stimulus relies on the re-arrangement of the cytoskeleton, which is triggered by activation of small G proteins RhoA, Rac1 and Cdc42, and leads to formation of lamellopodia and actin polymerisation amongst other effects. Here we show that Rac1 is important for CXCR4 induced chemotaxis but not for CCR1/CCR5 induced chemotaxis. For CXCL12-induced migration via CXCR4, breast cancer MCF-7 cells are reliant on Rac1, similarly to THP-1 monocytes and Jurkat T-cells. For CCL3-induced migration via CCR1 and/or CCR5, Rac1 signalling does not regulate cell migration in either suspension or adherent cells. We have confirmed the involvement of Rac1 with the use of a specific Rac1 blocking peptide. We also used a Rac1 inhibitor EHT 1864 and a Rac1-GEF inhibitor NSC23766 to probe the importance of Rac1 in chemotaxis. Both inhibitors did not block CCL3-induced chemotaxis, but they were able to block CXCL12-induced chemotaxis. This confirms that Rac1 activation is not essential for CCL3-induced migration, however NSC23766 might have secondary effects on CXCR4. This small molecule exhibits agonistic features in internalisation and cAMP assays, whereas it acts as an antagonist for CXCR4 in migration and calcium release assays. Our findings strongly suggest that Rac1 activation is not necessary for CCL3 signalling, and reveal that NSC23766 could be a novel CXCR4 receptor ligand.

Boletopsins 7 (1), 11 (2), and 12 (3) are p-terphenyl dibenzofuran compounds, isolated from the Papua New Guinean medicinal mushroom Boletopsis sp. The first syntheses of these fungal metabolites are reported, allowing for an investigation of their antibiotic activity. The key steps include sequential Suzuki-Miyaura couplings to rapidly form the p-terphenyl backbone and an Ullmann ether synthesis on a formate ester to create the dibenzofuran moiety. Biological evaluation of the synthetic compounds and intermediates against a panel of bacterial nosocomial pathogens was performed.