ABSTRACT
Streptazoneâ A and abikoviromycin are alkaloids that both feature an unusual arrangement of reactive functionalities within a compact tricyclic ring system. Here, we report a highly concise asymmetric synthesis of both natural products. The route first constructs another family member, streptazoneâ B1 , using a rhodium-catalyzed distal selective allene-ynamide Pauson-Khand reaction. A regio- and enantioselective epoxidation under chiral phase-transfer catalytic conditions directly afforded streptazoneâ A in 8â steps overall. In one additional step, a chemoselective, iridium-catalyzed reduction of the enaminone system then gave abikoviromycin. The reactivity of streptazoneâ A towards a cysteine mimic, N-acetylcysteamine, was studied and revealed unanticipated transformations, including bis-thiol conjugation which may proceed via formation of a cyclopentadienone intermediate. With flexible access to these compounds, studies aimed to identify their direct biological targets are now possible.
Subject(s)
Molecular Structure , Pyridines/chemical synthesis , Pyridines/chemistry , StereoisomerismABSTRACT
The transcription factor Nrf2 is a critical regulator of inflammatory responses. If and how Nrf2 also affects cytosolic nucleic acid sensing is currently unknown. Here we identify Nrf2 as an important negative regulator of STING and suggest a link between metabolic reprogramming and antiviral cytosolic DNA sensing in human cells. Here, Nrf2 activation decreases STING expression and responsiveness to STING agonists while increasing susceptibility to infection with DNA viruses. Mechanistically, Nrf2 regulates STING expression by decreasing STING mRNA stability. Repression of STING by Nrf2 occurs in metabolically reprogrammed cells following TLR4/7 engagement, and is inducible by a cell-permeable derivative of the TCA-cycle-derived metabolite itaconate (4-octyl-itaconate, 4-OI). Additionally, engagement of this pathway by 4-OI or the Nrf2 inducer sulforaphane is sufficient to repress STING expression and type I IFN production in cells from patients with STING-dependent interferonopathies. We propose Nrf2 inducers as a future treatment option in STING-dependent inflammatory diseases.
Subject(s)
Membrane Proteins/metabolism , NF-E2-Related Factor 2/metabolism , Animals , Cell Line, Tumor , Cells, Cultured , DNA Viruses/metabolism , Gene Expression/drug effects , Humans , Interferon Type I/metabolism , Leukocytes, Mononuclear/immunology , Leukocytes, Mononuclear/metabolism , Membrane Proteins/genetics , Mice , NF-E2-Related Factor 2/genetics , RAW 264.7 Cells , RNA, Messenger/metabolism , Succinates/pharmacologyABSTRACT
The natural products pantomycin and stendomycin were both reported as antimicrobial agents. We demonstrate by gene cluster analysis, LC-MS analysis, and isolation that these polypeptides are identical, and we identify previously unknown congeners. We show that stendomycin can be chemically modified at its electrophilic dehydrobutyrine moiety yielding the first bioactive analogue of this natural product which can undergo additional functionalization. This compound may be a valuable starting point for molecular probe development, and we invite its distribution to the scientific community.
Subject(s)
Biological Products/chemistry , Peptides/chemistry , Animals , Antimicrobial Cationic Peptides , Candida/drug effects , Cell Line , Chromatography, Liquid/methods , Rats , Tandem Mass Spectrometry/methodsABSTRACT
Tumour hypoxia is speculated to be a key driver of therapeutic resistance and metastatic dissemination. Consequently, the discovery of new potent agents that selectively target the hypoxic cell population may reveal new and untapped antitumour mechanisms. Here we demonstrate that the BE-43547 subclass of the APD-CLD (amidopentadienoate-containing cyclolipodepsipeptides) natural products possesses highly hypoxia-selective growth-inhibitory activity against pancreatic cancer cells. To enable this discovery, we have developed the first synthesis of the BE-43547-macrocyclic scaffold in 16 steps (longest linear sequence), which also allowed access to the full panel of relative stereoisomers and ultimately to the assignment of stereochemical configuration. Discrepancies between the spectroscopic signatures of the synthetic compounds with that originally reported for the BE-43547 members stimulated us to re-isolate the natural product from a BE-43547-producing microorganism during which we elucidated the biosynthetic gene clusters for the BE-43547 family as well as for all other known APD-CLDs. Our studies underline the exciting possibilities for the further development of the anticancer activities of these natural products.
Subject(s)
Antineoplastic Agents/chemical synthesis , Biological Products/metabolism , Depsipeptides/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/toxicity , Bacteria/enzymology , Bacterial Proteins/metabolism , Biological Products/chemistry , Biological Products/toxicity , Cell Hypoxia , Cell Line, Tumor , Cell Survival/drug effects , Depsipeptides/toxicity , Humans , Lipopeptides/biosynthesis , Lipopeptides/chemistry , Lipopeptides/toxicity , Molecular Conformation , Peptides, Cyclic/chemistry , Peptides, Cyclic/toxicity , Polyketide Synthases/metabolism , Stereoisomerism , Tandem Mass SpectrometryABSTRACT
We report a concise asymmetric synthesis of rakicidinâ A, a macrocyclic depsipeptide that selectively inhibits the growth of hypoxic cancer cells and stem-like leukemia cells. Key transformations include a diastereoselective organocatalytic cross-aldol reaction to build the polyketide portion of the molecule, a highly hindered ester fragment coupling reaction, an efficient Helquist-type Horner-Wadsworth-Emmons (HWE) macrocyclization, and a new DSC-mediated elimination reaction to construct the sensitive APD portion of rakicidinâ A. We further report the preparation of a simplified structural analogue (WY1) with dramatically enhanced hypoxia-selective activity.
Subject(s)
Lipopeptides/chemical synthesis , Lipopeptides/pharmacology , Peptides, Cyclic/chemical synthesis , Peptides, Cyclic/pharmacology , Cell Line, Tumor , Drug Discovery , HumansABSTRACT
In this review we investigate the use of complex ester fragment couplings within natural product total synthesis campaigns. We first outline the different biosynthetic and chemical strategies for performing complex ester couplings and on this mechanistic background we then present and discuss a collection of successful examples from the literature.