In this paper, we explore the molecular basis of combining photodynamic therapy (PDT), a light-triggered targeted anticancer therapy, with the traditional chemotherapeutic properties of the well-known cytotoxic agent gemcitabine. A photosensitizer prerequisite is significant absorption of biocompatible light in the visible/near IR range, ideally between 600 and 1000 nm. We use highly accurate multiconfigurational CASSCF/MS-CASPT2/MM and TD-DFT methodologies to determine the absorption properties of a series of gemcitabine derivatives with the goal of red-shifting the UV absorption band toward the visible region and facilitating triplet state population. The choice of the substitutions and, thus, the rational design is based on important biochemical criteria and on derivatives whose synthesis is reported in the literature. The modifications tackled in this paper consist of: (i) substitution of the oxygen atom at O2 position with heavier atoms (O → S and O → Se) to red shift the absorption band and increase the spin–orbit coupling, (ii) addition of a lipophilic chain at the N7 position to enhance transport into cancer cells and slow down gemcitabine metabolism, and (iii) attachment of aromatic systems at C5 position to enhance red shift further. Results indicate that the combination of these three chemical modifications markedly shifts the absorption spectrum toward the 500 nm region and beyond and drastically increases spin–orbit coupling values, two key PDT requirements. The obtained theoretical predictions encourage biological studies to further develop this anticancer approach.
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14 December 2023
Research Article|
December 11 2023
Electronic spectroscopy of gemcitabine and derivatives for possible dual-action photodynamic therapy applications
Special Collection:
2023 JCP Emerging Investigators Special Collection
Abdelazim M. A. Abdelgawwad
;
Abdelazim M. A. Abdelgawwad
(Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Software, Supervision, Visualization, Writing – original draft, Writing – review & editing)
Institut de Ciència Molecular, Universitat de València
, 46071 València, Spain
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Daniel Roca-Sanjuán
;
Daniel Roca-Sanjuán
(Conceptualization, Data curation, Formal analysis, Investigation, Software, Validation, Visualization, Writing – original draft, Writing – review & editing)
Institut de Ciència Molecular, Universitat de València
, 46071 València, Spain
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Antonio Francés-Monerris
Antonio Francés-Monerris
a)
(Conceptualization, Data curation, Formal analysis, Funding acquisition, Methodology, Supervision, Validation, Writing – original draft, Writing – review & editing)
Institut de Ciència Molecular, Universitat de València
, 46071 València, Spain
a)Author to whom correspondence should be addressed: antonio.frances@uv.es
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a)Author to whom correspondence should be addressed: antonio.frances@uv.es
J. Chem. Phys. 159, 224106 (2023)
Article history
Received:
August 05 2023
Accepted:
November 12 2023
Citation
Abdelazim M. A. Abdelgawwad, Daniel Roca-Sanjuán, Antonio Francés-Monerris; Electronic spectroscopy of gemcitabine and derivatives for possible dual-action photodynamic therapy applications. J. Chem. Phys. 14 December 2023; 159 (22): 224106. https://doi.org/10.1063/5.0170949
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