Abstract The first total synthesis of chondrochloren A is accomplished using a 1,2‐metallate rearrangement addition as an alternative for the Nozaki‐Hiyama‐Kishi reaction. This transformation also avoids the inherent challenges of this polyketide segment and provides a new, unprecedented strategy to assemble polyketidal frameworks. The formation of the Z‐enamide is accomplished using a Z‐selective cross coupling of the corresponding amide to a Z‐vinyl bromide.
Two solutions for one problem: Of the four isomers of chondramide C synthesized, the two shown in the scheme exhibit nearly the same conformation of the peptide segment and consequently unfold equal biological activities. Detailed facts of importance to specialist readers are published as "Supporting Information". Such documents are peer-reviewed, but not copy-edited or typeset. They are made available as submitted by the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Die Verknüpfungen dreier Fragmente durch eine Wittig-Reaktion und eine anschließende selektive Heck-Reaktion bilden die Schlüsselschritte der ersten Totalsynthese des cytotoxisch sowie antibiotisch wirksamen Polyketids Ratjadon. Mit dieser Synthese wurde die absolute Konfiguration des Naturstoffs aufgeklärt. Auf diesem Weg sollten sich auch gezielt Strukturanaloga herstellen lassen, mit denen die von Ratjadon beeinflussten biologisch aktiven Zentren untersucht werden können.
Myxobacteria are well-established sources for novel natural products exhibiting intriguing bioactivities. We here report on haprolid (1) isolated from Byssovorax cruenta Har1. The compound exhibits an unprecedented macrolactone comprising four modified amino acids and a polyketide fragment. As configurational assignment proved difficult, a bioinformatic analysis of the biosynthetic gene cluster was chosen to predict the configuration of each stereocenter. In-depth analysis of the corresponding biosynthetic proteins established a hybrid polyketide synthase/nonribosomal peptide synthetase origin of haprolid and allowed for stereochemical assignments. A subsequent total synthesis yielded haprolid and corroborated all predictions made. Intriguingly, haprolid showed cytotoxicity against several cell lines in the nanomolar range whereas other cells were almost unaffected by treatment with the compound.
Hepatocellular carcinoma (HCC) represents a major health burden with limited curative treatment options. There is a pressing need for novel strategies to impact the development of inoperable HCC. Haprolid is a novel natural product isolated from the myxobacterium Byssovorax cruenta. Recent studies have reported Haprolid as a potent selective cytotoxin against several tumor cell lines including HCC cells. The aim of the present study is to assess whether Haprolid could be used to prevent HCC progression.
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Leading the way: The synthesis of natural products with new biological targets is one of the driving forces for the development of new antibiotics. The synthesis of the two secondary metabolites corallopyronin and myxopyronin (see picture) have been achieved, which are prominent leads for the inhibition of bacterial RNA polymerase. Detailed facts of importance to specialist readers are published as ”Supporting Information”. Such documents are peer-reviewed, but not copy-edited or typeset. They are made available as submitted by the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.
310 Background: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with a 5-year survival rate of < 5%. Early diagnosis is rare and treatment options are often limited. Recent studies have reported that the proteasome inhibitor Argyrin A, a cyclic peptide derived from the myxobacterium Archangium gephyra, shows antitumoral activities. The aim of the present study is to explore the anti-tumor activity of this analogue Argyrin F (AF) + Gemcitabine (G) in PDAC carcinogenesis. Methods: We analyzed the effect of AF on proliferation and epithelial plasticity of different human pancreatic cancer cell lines by using MTT-, wound healing-, invasion-, colony formation-, apoptosis- and senescence assay, as well as cell cycle analysis and Western Blot. In vivo, we assessed the effects of AF and combinational (AF + G) therapy in a genetically engineered mouse model (Pdx1- Cre; LSL-KrasG12D; p53 lox/+ ) of PDAC. Results: AF inhibited pancreatic cancer cell proliferation, migration, invasion and colony formation compared to their respective untreated controls (DMSO). We also found that AF impairs epithelial-mesenchymal-transition (EMT) and induces considerable apoptosis and senescence in a dose-and time-dependent manner. AF application resulted in cell cycle G1/S phase transition. Most importantly, double treatment by AF + G showed prolonged survival and caused significant tumor reduction. Expression of Ki67 (anti-proliferative marker) and CD34 (tumor angiogenesis marker) was reduced both after AF and AF + G treatment of PDAC tumors in mice. Conclusions: Our work demonstrates that treatment with AF can successfully inhibit the growth of PDAC cells and combinational treatment with AF + G might be also a new and promising combinational therapy for human PDAC treatment.
