4.7 Article

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

Journal

CRYSTENGCOMM
Volume 24, Issue 48, Pages 8372-8389

Publisher

ROYAL SOC CHEMISTRY
DOI: 10.1039/d2ce01231f

Keywords

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Funding

  1. Slovak Scientific Grant Agency VEGA [1/0139/20]
  2. Slovak Science and Technology Assistance Agency [APVV-20-0213]
  3. Ministry of Science and Higher Education (Poland) [26230120002]
  4. Slovak Infrastructure of High Performance Computing [DIR/WK/2018/06]

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In this study, a series of cyclopropyl-containing peptide-derived compounds were synthesized and their crystal structures were determined. The self-assembly mechanism and potential biological activity of these compounds were investigated. This research provides a basis and guidance for further applications of cyclopropyl-containing peptide-derived compounds.
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-bcyclopropyl-(R,S)-Ala-OH], 2-(cyclopropylmethyl)-2-acetamidopropanedioic acid hydrate (3), 2-acetamido-3cyclopropylpropanoic 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 pi-stacking interactions. Quantum-chemical computational studies revealed that the cyclopropyl ring is capable of pi((C=O)) (center dot center dot center dot sigma*) ((cyclopropyl)), pi((arom))center dot center dot center dot sigma*((cyclopropyl)), (pi*arom ()center dot center dot center dot sigma*cyclopropyl) and (pi*((arom))center dot center dot center dot sigma((cyclopropyl)) interactions. The molecular docking study delineated the C-H center dot center dot center dot C-(cyclopropyl) and C-H-(cyclopropyl)center dot center dot center dot pi 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.

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