2. Academic Validation
  3. Design, synthesis and characterization of aryl bis-guanyl hydrazones as RNA binders of C9orf72 G4C2 extended repeats

Design, synthesis and characterization of aryl bis-guanyl hydrazones as RNA binders of C9orf72 G4C2 extended repeats

  • Eur J Med Chem. 2025 May 7:293:117736. doi: 10.1016/j.ejmech.2025.117736.
Alice Maiocchi 1,  Martina Pedrini 1,  Veronica Ferrari 2,  Agata Sofia Assunçao Carreira 3,  Vincenzo Maria D'Amore 4,  Federica Santoro 4,  Anna Di Porzio 4,  Maddalena Bosetti 3,  Riccardo Cristofani 2,  Alessandra Silvani 1,  Diego Brancaccio 4,  Luciana Marinelli 4,  Francesco Saverio Di Leva 5,  Alessandro Provenzani 6,  Angelo Poletti 7,  Pierfausto Seneci 8
Affiliations

Affiliations

  • 1 Chemistry Department, Università degli Studi di Milano, Via Golgi 19, 20133, Milan, Italy.
  • 2 Dipartimento di Scienze Farmacologiche e Biomolecolari (DisFeB) "Rodolfo Paoletti", Università degli Studi di Milano, Via Balzaretti 9, 20133, Milan, Italy.
  • 3 Laboratory of Genomic Screening, Department of Cellular, Computational and Integrative Biology, University of Trento, Via Sommarive 9, Povo, 38123, (TN), Italy.
  • 4 Department of Pharmacy, Università degli Studi di Napoli Federico II, via D. Montesano 49, 80131, Napoli, Italy.
  • 5 Department of Pharmacy, Università degli Studi di Napoli Federico II, via D. Montesano 49, 80131, Napoli, Italy. Electronic address: francesco.dileva@unina.it.
  • 6 Laboratory of Genomic Screening, Department of Cellular, Computational and Integrative Biology, University of Trento, Via Sommarive 9, Povo, 38123, (TN), Italy. Electronic address: alessandro.provenzani@unitn.it.
  • 7 Dipartimento di Scienze Farmacologiche e Biomolecolari (DisFeB) "Rodolfo Paoletti", Università degli Studi di Milano, Via Balzaretti 9, 20133, Milan, Italy. Electronic address: angelo.poletti@unimi.it.
  • 8 Chemistry Department, Università degli Studi di Milano, Via Golgi 19, 20133, Milan, Italy. Electronic address: pierfausto.seneci@unimi.it.
PMID: 40349639 DOI: 10.1016/j.ejmech.2025.117736
Abstract

Expanded G4C2 repeats derived from mutations of the C9orf72 gene are causative factors in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) patients, leading to multiple pathological events. Bis thiophene para dinicotinimidamide 2a was reported to preferentially stabilize G-quadruplex G4C2 RNA structures at sub-micromolar concentrations. We replaced its amidine groups with BBB-compliant guanyl hydrazones, and carried out scaffold variations to improve water solubility. An eight-membered array was built around bis-thiophene- (4b-6a), bis-oxazole- (7b), diphenylurea diamide- (8b) and phenyldioxy ditriazolephenyl scaffolds (9a,b). Biological profiling of the array identified 4b as a promising, drug-like hit, active in cellular assays on ALS patient-derived cells.

Keywords

ALS; C9orf72 gene; Expanded G(4)C(2) repeats; Guanyl hydrazones; NMR binding studies; RNA transcripts; RNA-Small molecule modeling.

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