Small-ring cyclic â-amino acids as building blocks for neuropeptide Y analogs
Final Report Abstract
We feel that the three objectives of this project – (a) Synthesis of cyclobutylamino acids, (b) incorporation of these amino acids into NPY sequences and their evaluation for receptor subtype selectivity, (c) synthesizing carrier peptide / exo-methylene-g-butyrolactone hybrids as products, ultimately developing a carrier system based on NPY Y1 selective peptides, could be addressed. Our groups main expertise is centered on organic synthesis, from our point of view we made the biggest advances in this project in the synthesis of unnatural amino acids. Moreover, this project was the starting point for us to engage in visible light photocatalysis, a field in which we have now published (2013-2017) more than 20 publications and have established at the University of Regensburg the DFG Graduiertenkolleg 1626, with the application for an SFB. The synthesis of NPY analogs incorporating the unnatural amino acids synthesized by us as well as the ones we have received from the group of Prof. Aitken could also be convincingly carried out. Evaluation took place in collaboration with Prof. A. Buschauer (Institute of Pharmacy, University of Regensburg), the surprising switch from NPY Y1 to NPY Y4 subtype selectivity made the establishment of new binding and functional assays necessary which slowed down the overall progress of this part. We believe we could demonstrate in general the validity of our prodrug concept with exo-methylene-gbutyrolactones and also show that hybrids with carrier peptides can be synthesized, internalized and release their cytotoxic load. A more detailed pharmacological evaluation of the results with respect to time release window (our fastest compounds showed a half-life of approx. 8 hours, this might be too slow) and more potent drug molecules is necessary to move this project further to a therapeutical relevant system.
Publications
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Replacement of Thr32 and Gln34 in the C-Terminal Neuropeptide Y Fragment 25–36 by cis-Cyclobutane and cis-Cyclopentane β-Amino Acids Shifts Selectivity toward the Y4 Receptor. J. Med. Chem. 2013, 56, 8422-8431
L. Berlicki, M. Kaske, R. Gutiérrez-Abad, G. Bernhardt, O. Illa, R. M. Ortuño, C. Cabrele , A. Buschauer, O. Reiser
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High Affinity Agonists of the Neuropeptide Y (NPY) Y4 Receptor Derived from the C-Terminal Pentapeptide of Human Pancreatic Polypeptide (hPP): Synthesis, Stereochemical Discrimination, and Radiolabeling. J. Med. Chem. 2016, 59, 6049-6058
K. K. Kuhn, T. Ertl, S. Dukorn, M. Keller, G. Bernhardt, O. Reiser, A. Buschauer
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Enantioselective Three-Step Synthesis of Homo-b-proline: A Donor–Acceptor Cyclopropane as Key Intermediate. , Org. Lett. 2017, 19, 2754-2757
L. K. A. Pilsl, T. Ertl, O. Reiser
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Photosensitised Regio- and Stereoselective [2+2]-Cycloaddition of Cinnamates and related Alkenes. Chem. Commun. 2017
S. K. Pagire, A. Hossain, L. Traub, S. Kerres, O. Reiser
