This is the first report that uses an unbiased functional genomics approach in cancer cells to study the mode of action of a potent cyanobacterial cytotoxin and also visualizes “apratoxin A in action” in zebrafish.
Genome-scale analysis has been extended from gene expression profiling to parallel cell-based functional profiling, allowing the characterization of gene function and small molecule actions in yeast and in mammalian cells.
Hendrik Luesch’s discovery of largazole and its producing cyanobacterium are featured in this annual Marine Natural Products review and on the journal cover, respectively.
The Luesch lab previously described the bioassay-guided isolation, structure determination, synthesis, and target identification of largazole, a marine-derived antiproliferative natural product that is a prodrug that releases the most potent natural inhibitor of class I histone deacetylases (HDACs), validated targets for cancer therapy. The cover highlights structure-activity studies using biochemical and molecular docking approaches. The article describes the characterization of the anticancer activity of largazole using in vitro and in vivo cancer models, including comparative transcriptomics, pharmacology, biochemical validation, stability, and efficacy studies.
Natural products are secondary metabolites that confer survival advantages to the producing organism. Many require activation before they exert their biological effects, perhaps as part of the organism's self‐resistance strategy or to aid targeted delivery. In this Concept article Luesch and Kwan outline several examples of “Weapons in Disguise”, natural products that use protecting group chemistry or intricate chemical cascades for activation beyond simple “prodrug” paradigms.
Small molecules that modulate histone acetylation by targeting key enzymes mediating this posttranslational modification – histone acetyltransferases and histone deacetylases – are validated chemotherapeutic agents for the treatment of cancer. Secondary metabolites from various biological sources target this epigenetic modification through distinct mechanisms of enzyme regulation by utilizing a diverse array of pharmacophores. We review the discovery of these compounds and discuss their modes of inhibition together with their downstream biological effects.
A tryptoline‐based ring distortion strategy enabled rapid access to an array of complex and diverse molecular scaffolds synthesized from the indole alkaloid, yohimbine. During these investigations, 70 complex and diverse small molecules were synthesized and subjected to a panel phenotype screen. These efforts led to the identification of several biologically active hit compounds, including one compound that demonstrates HIF‐dependent antiproliferative activity in HCT116 (colorectal cancer) cells.
The cover picture shows the destruction of a bacterial membrane by a new NH125 analogue. Through chemical synthesis and biological evaluation, the Huigens lab has identified potent N‐arylated compounds that rapidly kill MRSA persister cells and eradicate surface‐attached bacterial biofilms of multiple Gram‐positive pathogens. These N‐arylated NH125 analogues demonstrated enhanced activity in killing persister cells and eradicating biofilm when tested alongside a structurally diverse panel of membrane‐active agents.
The 2‐position of the halogenated quinoline (HQ) scaffold can be dramatically tuned through diverse and practical synthetic pathways, including reductive amination and alkylation reactions. New HQs discovered during these investigations potently eradicate methicillin‐resistant Staphylococcus aureus (MRSA), methicillin‐resistant Staphylococcus epidermidis (MRSE) and vancomycin‐resistant Enterococcus faecium (VRE) biofilms, which display high levels of tolerance towards conventional antibiotic therapies. The background image is reproduced with permission and copyright of the British Editorial Society of Bone and Joint Surgery (Bone Joint J. 2013, 95B, 678–682; Figure 2 b).
The Huigens lab reports a new series of antimicrobial peptide-inspired NH125 analogues that rapidly kill bacterial and fungal pathogens, including surface-attached biofilms.
The cover feature picture shows Ahp-cyclodepsipeptides, the producing marine cyanobacterium overgrowing a coral, and the compounds’ anticancer effects. These cyclodepsipeptides inhibit human neutrophil elastase and, as a consequence, the migration of invasive breast cancer cells through the modulation of gene expression and proteolytic processing of membrane proteins.
The front cover picture shows a versatile biocatalytic synthesis of hydroxylated di‐N‐methylated aromatic diketopiperazines (ADKPs). Di‐N‐methylated ADKPs were synthesized from two amino acids with TxtA and TxtB (yellow) from Streptomyces scabies, or from ADKP with one N‐methyltransferase Amir_4628 (green) from Actinosynnema mirum. Human methionine adenosyltransferase hMAT2A (purple) was recruited to synthesize the methyl donor SAM. The P450 TxtC (pink) along with the NADPH‐recycling glucose dehydrogenase (cyan) from Bacillus subtilis promoted aliphatic and/or aromatic C−H hydroxylation on di‐N‐methylated ADKPs.
The cover image illustrates the multidisciplinary research that linked a natural product discovered from the depicted marine cyanobacteria to GPCR modulation. The portrayed peptide, amantamide, was isolated, synthesized, and characterized as a selective CXCR7 agonist. Molecular modeling of amantamide provides the starting point for rational optimization.
Re-engineering biological activities of the plant-derived indole alkaloid vincamine through dramatic synthetic alterations of its complex structure for target-based screens by the Huigens lab and co-workers at the University of Florida. Artwork created by Ella Marushchenko.
This cover shows a novel antiplasmodial agent attacking Plasmodium falciparum parasites in infected red blood cells. This new compound was re-engineered from the indole alkaloid yohimbine using a “ring distortion” chemical synthesis approach reported by the Huigens lab. Artwork created by Ella Marushchenko
Fluorophores are greatly influenced by their environment. In their full paper, L. Cui et al. show that triggering the aggregation of a self‐condensing scaffold labeled with a fluorophore induces changes in the emission spectrum, polarization, and lifetime. The aggregates exhibited a shorter lifetime detectable in cells by fluorescence lifetime imaging microscopy, thus suggesting that triggered aggregation strategies can be used in the probes for various biological events through lifetime imaging.
Smoking is the dominant risk factor for lung cancer, but many smokers fail to quit due to addiction. An intervention, not only inhibiting tobacco-associated lung carcinogenesis but also reducing smoking, may be necessary to minimize lung cancer risk. Built upon the stimulating epidemiological indication, ample lab animal lung carcinogenesis data, and armed with innovative mechanism-based non-invasive quantitative biomarkers, our group in collaboration with clinicians performed a pilot human trial of one-wee kava use among addicted smokers. The results published in Cancer Prevention Research for the first time demonstrate the potential of kava to not only reduce the risk of lung carcinogenesis but also help smokers reduce tobacco use.
Surfing across the blood-brain barrier with a purpose and a splash: The marine natural product and potent class I HDAC inhibitor largazole has activity against glioblastoma cells and induces neuroprotective and antiproliferative functional responses in the brain through modulation of gene expression of entire networks underlying CNS diseases.
This work reports the biochemical, genetic, and structural characterization of cyanobacterial dihydroxyacid dehydratase essential to the biosynthesis of branched-chain amino acids. Selective inhibition of the cyanobacterial enzyme by aspterric acid but not tartronic acid leads to the growth inhibition of representative bloom-forming cyanobacterial strains, a promising strategy for bloom management.
Mitragynine is the most abundant alkaloid in kratom (Mitragyna speciosa) which is widely consumed for the self-treatment of pain and opioid withdrawal symptoms. An active metabolite of mitragynine, 7-hydroxymitragynine, is a potent and efficacious opioid. Exclusively in human plasma, 7-hydroxymitragynine metabolizes to the even more potent opioid, mitragynine pseudoindoxyl.
This review discusses the principles of molecular imaging with known sigma-1 receptor (S1R) radioligands, along with S1Rs labeling applications in various disease states. Highlighted here are S1R radioligands that have demonstrated considerable potential as biomarkers in humans with the ultimate goal of better healthcare outcomes.