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…
Seit Februar 2021 bietet Wolfgang Brandt, ehemaliger Leiter der Arbeitsgruppe Computerchemie am IPB, sein Citizen Science-Projekt zur Pilzbestimmung an. Dafür hat er in regelmäßigen Abständen öffentliche Vorträge zur Vielfalt…
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.
Publikation
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 %.
Publikation
Hussain, H.; Ziegler, J.; Mrestani, Y.; Neubert, R. H. H.;Studies of the Corneocytary Pathway Across the Stratum Corneum. Part I: Diffusion of Amino Acids Into the Isolated CorneocytesPharmazie74340-344(2019)DOI: 10.1691/ph.2019.8098
Amino acids (AAs), important constituents of natural moisturizing factors (NMFs) of the skin are decreased in diseased conditions such as psoriasis and atopic dermatitis. No study so far investigated the uptake of AAs into isolated corneocytes (COR). The present study was performed using 19 AAs, including taurine (TAU), to measure their amount diffused into the COR and binding of these AAs to keratin. Incubation of alanine, aspartic acid, asparagine, glutamine, glutamic acid, histidine, proline, serine and TAU with the isolated COR showed uptake after 24 h of 51.6, 95.4, 98.6, 94.1, 95.6, 90.1, 94.6, 72.9 and 57.8 %, respectively, into the COR but no binding with keratin. Uptake of TAU was validated by time dependent in-vitro diffusion models 'without COR and 'with COR'. The time dependent curve fitting showed that in in-vitro diffusion model 'without COR' there was no change in the total concentration of TAU until 72 hours, while in diffusion model 'with COR' the total conc. decreased to 37.8 % after 72 hours. The Pearson's correlation coefficient 'r' between the conc. curves of both in-vitro diffusion models was -0.54 that was an evidence of significant amount of TAU uptake by the COR. AAs as part of the NMFs have a great potential to be diffused into the COR. This property of the AAs can be employed in further dermatological research on diseased or aged skin conditions with NMFs deficiency.
Publikation
Ricardo, M. G.; Marrero, J. F.; Valdés, O.; Rivera, D. G.; Wessjohann, L. A.;A Peptide Backbone Stapling Strategy Enabled by the Multicomponent Incorporation of Amide N‐SubstituentsChem.-Eur. J.25769-774(2019)DOI: 10.1002/chem.201805318
The multicomponent backbone N‐modification of peptides on solid‐phase is presented as a powerful and general method to enable peptide stapling at the backbone instead of the side chains. This work shows that a variety of functionalized N‐substituents suitable for backbone stapling can be readily introduced by means of on‐resin Ugi multicomponent reactions conducted during solid‐phase peptide synthesis. Diverse macrocyclization chemistries were implemented with such backbone N‐substituents, including the ring‐closing metathesis, lactamization, and thiol alkylation. The backbone N‐modification method was also applied to the synthesis of α‐helical peptides by linking N‐substituents to the peptide N‐terminus, thus featuring hydrogen‐bond surrogate structures. Overall, the strategy proves useful for peptide backbone macrocyclization approaches that show promise in peptide drug discovery.