Omanische Heilpflanze im Fokus der Phytochemie IPB-Wissenschaftler und Partner aus Dhofar haben jüngst die omanische Heilpflanze Terminalia dhofarica unter die phytochemische Lupe genommen. Die Pflanze ist reich an…
Geschmack ist vorhersagbar: Mit FlavorMiner. FlavorMiner heißt das Tool, das IPB-Chemiker und Partner aus Kolumbien jüngst entwickelt haben. Das Programm kann, basierend auf maschinellem Lernen (KI), anhand der…
Ricardo, M. G.; Llanes, D.; Rennert, R.; Jänicke, P.; Rivera, D. G.; Wessjohann, L. A.;Improved access to potent anticancer tubulysins and linker‐functionalized payloads via an all‐on‐resin strategyChem.-Eur. J.30e202401943(2024)DOI: 10.1002/chem.202401943
Tubulysins are among the most recent antimitotic compounds to enter into antibody/peptide‐drug conjugate (ADC/PDC) development. Thus far, the design of the most promising tubulysin payloads relied on simplifying their structures, e.g., by using small tertiary amide N‐substituents (Me, Et, Pr) on tubuvaline residue. Cumbersome solution‐phase approaches are typically used for both syntheses and functionalization with cleavable linkers. p‐Aminobenzyl quaternary ammonium (PABQ) linkers were a remarkable advancement for targeted delivery, but the procedures to incorporate them into tubulysins are only of moderate efficiency. Here we describe a novel all‐on‐resin strategy permitting a loss‐free resin linkage and an improved access to super potent tubulysin analogs showing close resemblance to the natural compounds. For the first time, a protocol enables the integration of on‐resin tubulysin derivatization with, e.g., a maleimido‐Val‐Cit‐PABQ linker, which is a notable progress for the payload‐PABQ‐linker technology. The strategy also allows tubulysin diversification of the internal amide N‐substituent, thus enabling to screen a tubulysin library for the discovery of new potent analogs. This work provides ADC/PDC developers with new tools for both rapid access to new derivatives and easier linker‐attachment and functionalization.
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Ricardo, M. G.; Schwark, M.; Llanes, D.; Niedermeyer, T. H. J.; Westermann, B.;Total synthesis of Aetokthonotoxin, the cyanobacterial neurotoxin causing vacuolar myelinopathyChem.-Eur. J.2712032-12035(2021)DOI: 10.1002/chem.202101848
Aetokthonotoxin has recently been identified as the cyanobacterial neurotoxin causing Vacuolar Myelinopathy, a fatal neurologic disease, spreading through a trophic cascade and affecting birds of prey such as the bald eagle in the USA. Here, we describe the total synthesis of this specialized metabolite. The complex, highly brominated 1,2’-biindole could be synthesized via a Somei-type Michael reaction as key step. The optimised sequence yielded the natural product in five steps with an overall yield of 29 %.
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Holzmeyer, L.; Hartig, A.-K.; Franke, K.; Brandt, W.; Muellner-Riehl, A. N.; Wessjohann, L. A.; Schnitzler, J.;Evaluation of plant sources for antiinfective lead compound discovery by correlating phylogenetic, spatial, and bioactivity dataProc. Natl. Acad. Sci. U.S.A.11712444-12451(2020)DOI: 10.1073/pnas.1915277117
The continued high rates of using antibiotics in healthcare and livestock, without sufficient new compounds reaching the market, has led to a dramatic increase in antimicrobial resistance, with multidrug-resistant bacteria emerging as a major public health threat worldwide. Because the vast majority of antiinfectives are natural products or have originated from them, we assessed the predictive power of plant molecular phylogenies and species distribution modeling in the search for clades and areas which promise to provide a higher probability of delivering new antiinfective compound leads. Our approach enables taxonomically and spatially targeted bioprospecting and supports the battle against the global antimicrobial crisis.
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Serra, P.; Carbonell, A.; Navarro, B.; Gago-Zachert, S.; Li, S.; Di Serio, F.; Flores, R.;Symptomatic plant viroid infections in phytopathogenic fungi: A request for a critical reassessmentProc. Natl. Acad. Sci. U.S.A.11710126-10128(2020)DOI: 10.1073/pnas.1922249117