Design, synthesis and characterization of aryl bis-guanyl hydrazones as RNA binders of C9orf72 G4C2 extended repeats
Expanded G<sub>4</sub>C<sub>2</sub> 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 G<sub>4</sub>C<sub>2</sub> 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.
Authors
- Luciana Marinelli (ORCID: https://orcid.org/0000-0002-4084-8044)
- Alice Maiocchi (ORCID: https://orcid.org/0000-0001-5499-4045)
- Vincenzo Maria D’Amore (ORCID: https://orcid.org/0000-0002-6460-3447)
- Anna Di Porzio (ORCID: https://orcid.org/0000-0002-4722-5691)
- Diego Brancaccio (ORCID: https://orcid.org/0000-0002-2256-5534)
- Alessandra Silvani (ORCID: https://orcid.org/0000-0002-0397-2636)
- Ágata Sofia Assunção Carreira (ORCID: https://orcid.org/0000-0002-0919-2542)
- Alessandro Provenzani (ORCID: https://orcid.org/0000-0003-1652-3415)
- Martina Pedrini (ORCID: https://orcid.org/0000-0003-4332-7241)
- Francesco Saverio Di Leva (ORCID: https://orcid.org/0000-0002-2294-0656)
- Angelo Poletti (ORCID: https://orcid.org/0000-0002-8883-0468)
- Veronica Ferrari (ORCID: https://orcid.org/0000-0003-2514-9445)
- Michela Bosetti (ORCID: https://orcid.org/0000-0002-3682-8702)
- Riccardo Cristofani (ORCID: https://orcid.org/0000-0003-2719-846X)
- Pierfausto Seneci (ORCID: https://orcid.org/0000-0001-9709-7344)
- Federica Santoro (ORCID: https://orcid.org/0000-0002-4048-1078)
Institutions
- University of Milan (IT)
- University of Trento (IT)
- University of Naples Federico II (IT)
Publication Details
- Journal
- European Journal of Medicinal Chemistry
- Published
- 2025-05-08
- DOI
- https://doi.org/10.1016/j.ejmech.2025.117736
- Citations
- 3
- Primary Topic
- Synthesis of heterocyclic compounds
- Type
- article
- Field-Weighted Citation Impact
- 2.81
Funders
- Fondazione Telethon