Imide Condensation as a Strategy for the Synthesis of Core‐Diversified G‐Quadruplex Ligands with Anticancer and Antiparasitic Activity**
| Autor: | Michael P. O'Hagan, M. Carmen Galan, Juan Carlos Morales, Gregory Hollingworth, Steven T. G. Street, Pablo Peñalver |
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| Přispěvatelé: | University of Bristol, Ministerio de Ciencia, Innovación y Universidades (España), European Commission |
| Rok vydání: | 2021 |
| Předmět: |
Antiprotozoal agents
Stereochemistry Antiparasitic medicine.drug_class anti cancer drugs Imides Ligands 010402 general chemistry G-quadruplex 01 natural sciences Drug design Catalysis BCS and TECS CDTs Aggregation chemistry.chemical_compound medicine heterocyclic compounds Imide Antiparasitic Agents Full Paper ligand design approach 010405 organic chemistry European research Organic Chemistry DNA Amphiphiles General Chemistry Telomere Full Papers G-quadruplexes 0104 chemical sciences 3. Good health chemistry Anti cancer drugs anti parasitic drugs |
| Zdroj: | Digital.CSIC: Repositorio Institucional del CSIC Consejo Superior de Investigaciones Científicas (CSIC) Street, S, Peñalver, P, O'Hagan, M, Hollingworth, G, Morales, J C & Galan, M C 2021, ' Imide Condensation as a Strategy for the Synthesis of Core-diversified G-quadruplex Ligands with Anti-cancer and Anti-parasitic Activity ', Chemistry-A European Journal, vol. 27, no. 28, pp. 7712-7721 . https://doi.org/10.1002/chem.202100040 Chemistry (Weinheim an Der Bergstrasse, Germany) Digital.CSIC. Repositorio Institucional del CSIC instname |
| ISSN: | 1521-3765 0947-6539 |
| DOI: | 10.1002/chem.202100040 |
| Popis: | A facile imide coupling strategy for the one‐step preparation of G‐quadruplex ligands with varied core chemistries is described. The G‐quadruplex stabilization of a library of nine compounds was examined using FRET melting experiments, and CD, UV‐Vis, fluorescence and NMR titrations, identifying several compounds that were capable of stabilizing G‐quadruplex DNA with interesting selectivity profiles. The best G4 ligand was identified as compound 3, which was based on a perylene scaffold and exhibited 40‐fold selectivity for a telomeric G‐quadruplex over duplex DNA. Surprisingly, a tetra‐substituted flexible core, compound 11, also exhibited selective stabilization of G4 DNA over duplex DNA. The anticancer and antiparasitic activity of the library was also examined, with the lead compound 3 exhibiting nanomolar inhibition of Trypanosoma brucei with 78‐fold selectivity over MRC5 cells. The cellular localization of this compound was also studied via fluorescence microscopy. We found that uptake was time dependant, with localization outside the nucleus and kinetoplast that could be due to strong fluorescence quenching in the presence of small amounts of DNA. The rigid rules of G‐quadruplex stabilization: A library of amphiphiles has been synthesized in one step, using a simple imide condensation reaction. The G‐quadruplex stabilization, anti‐cancer and anti‐parasitic activity of the library has been investigated, uncovering the important factors that govern G‐quadruplex binding and selectivity, yielding a promising new core‐motif and a compound with potent trypanosomacidal activity. |
| Databáze: | OpenAIRE |
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