Natural Product Synthesis and Derivatisation
Many natural products are only produced in minor amounts and a full structural characterization is nearly impossible. In addition, many pharmaceutically interesting compounds are too toxic and need derivatisation to improve their pharmacological properties.
Therefore, we are establishing synthetic strategies towards sphingoid-type natural products and functionalized lipids, which represent important signaling molecules in our ecological mdoel systems.
Synthesis of new cysteinolic acid containing lipids
We report the structural revision of a new group of sulfonolipids (SALs), which we have named cysteinolides. Combining analytical techniques with isolation, degradation and total synthesis, we found that—contrary to earlier proposals—cysteinolides do not contain homotaurine-based structures. Instead, they feature an N,O-acylated cysteinolic acid head group bearing a range of different (α-hydroxy)carboxylic acids. Using the first validated targeted network-based analysis of these compounds, we mapped the distribution and structural diversity of cysteinolides across bacterial lineages. In addition to clarifying their structures, our work provides reference standards and validated analytical data to support future studies of bacterial sulfonolipid metabolism and biogeochemical nutrient cycling in marine environments.
For more details see:
Structure Revision of a Widespread Marine Sulfonolipid Class Based on Isolation and Total Synthesis
Roman D, Meisinger P, Guillonneau R, Peng C, Peltner L, Jordan P, Haensch V, Götze S, Werz O, Hertweck C, Chen Y, Beemelmanns C, Angew. Chem. Int. Ed. 2024,1433-7851, DOI: 10.1002/anie.202401195
Synthesis of halisphingosine - a sponge-derived functionalized sphingosine
We report the total synthesis and structural revision of halisphingosine A, a sphingoid base first isolated from marine sponges. To resolve inconsistencies in the original NMR interpretation, we developed a synthetic route featuring a late-stage enantioselective Henry reaction. This approach provided access to multiple regio- and diastereoisomers of the proposed structure. A library of 32 synthetic sphingolipids enabled us to establish the corrected structure of halisphingosine A. We also assessed how structural variation influences antimicrobial and cytotoxic activities. Our study provides a previously unreported compound library and validated analytical datasets for marine sphingoid base derivatives—resources that can support future ecometabolomic research and help identify inhibitors of sphingolipid metabolism or antagonists of sphingoid base-sensing receptors.
Structure Revision of Halisphingosine A via Total Synthesis and Bioactivity Studies
Sauer M, Kany A, Götze S, Müller R, Beemelmanns C, Angew. Chem. Int. Ed., 2024, DOI: 10.1002/anie.202416036
Synthesis of new sulfonolipids
Sphingolipids and sphingolipid-like natural products are essential signaling molecules involved in a range of important cellular processes. They also mediate communication between organisms. We have shown that the novel sulfonolipid RIF-1 induces morphogenesis in predatory choanoflagellates. Following up on these findings, we accomplished the first total syntheses of two RIF-2 diastereomers and one congener, completed in 15 and eight synthetic steps, respectively. The synthesis of the RIF-2 congeners combined a decarboxylative cross-coupling reaction to prepare the required branched α-hydroxy fatty acids with a Garner aldehyde strategy to construct the capnine base, which contains three stereogenic centres. Bioactivity studies in the choanoflagellate Salpingoeca rosetta showed that the rosette-inducing activity of RIFs is inhibited in a dose-dependent manner by the co-occurring sulfonosphingolipids sulfobacins D and F. We also found that RIF activity is specific to isolates obtained from Algoriphagus.
For references, see:
Bacterial lipids activate, synergize, and inhibit a developmental switch in choanoflagellates
Woznica A, Cantley A, Beemelmanns C, Freinkman E, Clardy J, King N, Proc. Natl. Acad. Sci. U.S.A. 2016, 113, 7894-9, DOI: 10.1073/pnas.1605015113
Structural and Functional Analysis of Bacterial Sulfonosphingolipids and Rosette-Inducing Factor 2 (RIF-2) by Mass Spectrometry-Guided Isolation and Total Synthesis
Leichnitz D, Peng C, Raguž L, Rutaganira F, Jautzus T, Regestein L, King N, Beemelmanns C, Chem. Eur. J. 2022, 28, DOI: 10.1002/chem.202103883
Synthesis of new NRPS-derived natural products
Genome mining of anaerobic Epsilonproteobacterium (Sulfurospirillum barnesii) allowed to identify a unique NRPS-PKS hybrid gene cluster. Phylogenetic analysis of key biosynthetic genes, gene expression studies, and comparative metabolomics resulted in the identification of the first anoxically biosynthesized NRPS-PKS hybrid metabolite: a lipo-dipeptide with a vinylogous side chain, called barnesin A. The absolute structure was verified by a modular total synthesis, and barnesin and derivatives were found to have antimicrobial activity, as well as selective and nanomolar inhibitory activity, against pharmacological important cysteine proteases, such as cathepsin B.
Following up on these findings, we applied and optimized a solid support (SP)-based Horner–Wadsworth–Emmons reagent to prepare SP-bound vinylogous amino acids. Subsequent SP-based peptide synthesis, global deprotection, and chemical modifications yielded 14 lipodipeptides carrying vinylogous amino acids, including the natural product barnesin A (1). Biological evaluation revealed that several synthesized derivatives show micromolar to nanomolar inhibitory activity against papain-like cysteine proteases, human cathepsin L, and rhodesain.
For references, see:
Modular Solid-Phase Synthesis of Antiprotozoal Barnesin Derivatives
Roman D, Raguž L, Keiff F, Meyer F, Barthels F, Schirmeister T, Kloss F, Beemelmanns C, Org. Lett. 2020, 202, 22, 3744-3748, DOI: 10.1021/acs.orglett.0c00723
Biosynthesis, Synthesis, and Activities of Barnesin A, a NRPS-PKS Hybrid Produced by an Anaerobic Epsilonproteobacterium
Rischer M, Raguž L, Guo H, Keiff F, Diekert G, Goris T, Beemelmanns C, ACS Chem. Bio. 2028, 13, 1990-1995, DOI: 10.1021/acschembio.8b00445
Funding
- EX-SPHINGO (DFG)
- ERC (H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC))