Electronic spectroscopy of gemcitabine and derivatives for possible dual-action photodynamic therapy applications

Abstract

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.

Chalcogen atom effect on the intersystem crossing kinetic constant of oxygen‐ and sulfur disubstituted heteroporphyrins

“…[22][23][24][25] The substitution of the pyrrole N atom by a heavier S, Se or Te atom, are expected to induce both a red shift of the absorption band and an enhancement of the spin-orbit coupling constants, being them essential requisites for their use in photodynamic therapy (PDT). [22][23][24][25] An analogue chalcogen effect was indeed demonstrated for a series of other photosensitizers, [26][27][28][29][30] and is considered a promising less-toxic way to induce the heavy atom effect on metal-free PS. From the other side, the radicals generated through Type II reactions may further react with oxygen to produce reactive oxygen species (ROS).…”