Supramolecular synthon hierarchy in cyclopropyl-containing peptide-derived compounds

Joanna Bojarska; Martin Breza; Milan Remko; Paweł Borowiecki; Andrzej Fruziński; Izabela D. Madura; Krzysztof Kaczmarek; Zbigniew Leśnikowski; Agata Kraj; Piotr Zielenkiewicz; Wojciech M. Wolf

doi:10.1039/D2CE01231F

Supramolecular synthon hierarchy in cyclopropyl-containing peptide-derived compounds†

Joanna Bojarska,

*^a Martin Breza,

^b Milan Remko,^c Paweł Borowiecki,

^d Andrzej Fruziński,^a Izabela D. Madura,

^e Krzysztof Kaczmarek,^f Zbigniew Leśnikowski,^gh Agata Kraj,^h Piotr Zielenkiewicz^ij and Wojciech M. Wolf^a

Author affiliations

* Corresponding authors

^a Chemistry Department, Institute of Ecological and Inorganic Chemistry, Technical University of Lodz, 116 Zeromskiego St., 90-924 Lodz, Poland
E-mail: joanna.bojarska@p.lodz.pl

^b Department of Physical Chemistry, Slovak Technical University, Radlinskeho 9, SK-81237 Bratislava, Slovakia

^c Remedika, Luzna 9, Bratislava, Slovakia

^d Laboratory of Biocatalysis and Biotransformation, Department of Drugs Technology and Biotechnology, Faculty of Chemistry, Warsaw University of Technology, 75 Koszykowa St., 00-662 Warsaw, Poland

^e Faculty of Chemistry, Warsaw University of Technology, 3 Noakowskiego St., 00-664 Warsaw, Poland

^f Institute of Organic Chemistry, Faculty of Chemistry, Lodz University of Technology, 116 Zeromskiego St., 90-924 Lodz, Poland

^g Institute of Medical Biology, Polish Academy of Sciences, Laboratory of Medicinal Chemistry, 106 Lodowa St., 92-232 Lodz, Poland

^h Institute of Medical Biology, Polish Academy of Sciences, National Library of Chemical Compounds POL-OPENSCREEN, 106 Lodowa St., 92-232 Lodz, Poland

ⁱ Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Pawinskiego 5a, 02-106 Warsaw, Poland

^j Department of Systems Biology, Institute of Experimental Plant Biology and Biotechnology, University of Warsaw, Miecznikowa 1, 02-096 Warsaw, Poland

Abstract

Considering the increasing importance of cyclopropyl-containing peptide-derived compounds in the pharmaceutical industry, herein, we report the crystal engineering of a series of novel derivatives, i.e., diethyl 2-acetamido-2-(cyclopropylmethyl)malonate (1), 2-(cyclopropylmethyl)-2-acetamidopropanedioic acid (2) [Ac-b-cyclopropyl-(R,S)-Ala-OH], 2-(cyclopropylmethyl)-2-acetamidopropanedioic acid hydrate (3), 2-acetamido-3-cyclopropylpropanoic acid (4), and (2S)-2-[cyclopropyl(9H-fluoren-9-ylmethoxycarbonyl)amino]propanoic acid (5) [Fmoc-b-cyclopropyl-(S)-Ala-OH]. Although several cyclopropyl-based peptide-derived structures have been reported in the literature, to the best of our knowledge, studies on the synthon hierarchy in this class of structures are limited. Thus, to address this gap, herein, we report a multidisciplinary study to shed light on the role of cyclopropyl synthons in (bio)supramolecular assemblies, opening a new vista for the further applications of this unique scaffold. The synthesis was achieved via a multi-step protocol in good yield and the structures were determined by single-crystal X-ray diffraction. The diverse supramolecular synthons responsible for the arrangement of molecules in the crystal lattice of either new compounds or all cyclopropyl-containing peptide-derived solids deposited in the CSD thus far were specified and summarized, building a library. The self-assembly is directed by the cooperative interplay of H-bonds and π-stacking interactions. Quantum-chemical computational studies revealed that the cyclopropyl ring is capable of Image ID:d2ce01231f-t1.gif , Image ID:d2ce01231f-t2.gif , Image ID:d2ce01231f-t3.gif and Image ID:d2ce01231f-t4.gif interactions. The molecular docking study delineated the C–H⋯C_{(cyclopropyl)} and C–H_{(cyclopropyl)}⋯π interactions of the cyclopropyl moiety with the essential amino acid residues inside the active pocket of the human androgen receptor, highlighting the vital role of cyclopropyl in the supramolecular landscape of the bio-complex. Indeed, 2 shows a significant docking score with effective binding affinity, and thus is a promising candidate for prostate cancer prevention or management.