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905572.pdf (2.61 MB)

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2025-11-19

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Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/224875

Enhanced i-Motif Stability through Consecutive 2,2-Difluorocytidine Incorporation

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https://doi.org/10.1002/chem.202503008

Resum

Chemical modifications of nucleic acids are widely used to tune stability and functionality in therapeutic and nanotechnological applications. Among these, fluorinated cytidine derivatives such as 2-fluoro-arabinocytidine (2F-araC) and 2-fluoro-ribocytidine (2F-riboC) have been shown to influence i-motif structures differently, with 2F-araC strongly stabilizing and 2F-riboC exerting a mildly deleterious effect. In this study, we investigate the impact of gemcitabine (2-deoxy-2,2-difluorocytidine, dFdC) on i-motif stability. dFdC exhibits small effects in single or double substituted sequences, but a pronounced stabilization when multiple consecutive residues are incorporated. Thermal and pH-dependent analyses demonstrate that sequences containing fully substituted dFdC maintain i-motif folding at neutral pH and show enhanced thermal stability. Structural insights suggest that this stabilization arises from a combination of factors, such as hyperconjugative interactions, hydrogen bonding, and dipole alignment, while the adaptable sugar conformation mitigates destabilizing minor groove contacts observed in other more rigid modifications, such as 2-F-riboC. Cooperative interactions among adjacent dFdC residues and potential changes in hydration may play a key factor in reinforcing stability. These results highlight the unique capacity of dFdC to enhance i-motif robustness and suggest that strategically placed difluoro substitutions can be exploited to design i-motifs with improved stability, expanding their potential in biotechnology and therapeutic applications.

Matèries

Dicroisme circular, Estructura química, ADN

Matèries (anglès)

Circular dichroism, Chemical structure, DNA

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Articles publicats en revistes (Medicina)

Citació

DOMÍNGUEZ, Arnau, CABRERO, Cristina, GÓMEZ-PINTO, Irene, FÀBREGA, Carmen, GARGALLO GÓMEZ, Raimundo, ERITJA I CASADELLÀ, Ramon, GONZÁLEZ, Carlos, AVIÑÓ ANDRÉS, Anna. Enhanced i-Motif Stability through Consecutive 2,2-Difluorocytidine Incorporation. _Chemistry-A European Journal_. 2025. Vol. 0. [consulta: 2 de gener de 2026]. ISSN: 0947-6539. [Disponible a: https://hdl.handle.net/2445/224875]

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