Abstract
The search to replace conventional cancer treatment therapies, such as chemotherapy, radiotherapy and surgery has led over the last ten years, to a substantial effort in the development of several classes of photodynamic therapy photosensitizers with desired photophysicochemical and photobiological properties. Herein we report the synthesis of 6-iodoquinoline- and benzothiazole-based unsymmetrical squaraine cyanine dyes functionalized with amine groups located in the four-membered central ring. Their photodegradation and singlet oxygen production ability, as well as their in vitro photocytotoxicity against Caco-2 and HepG2 cell lines using a 630.8 ± 0.8 nm centered light-emitting diode system, were also investigated. All photosensitizer candidates displayed strong absorption within the tissue transparency spectral region (650–850 nm). The synthesized dyes were found to have moderate light stability. The potential of these compounds is evidenced by their cytotoxic activity against both tumor cell lines, highlighting the zwitterionic unsubstituted dye, which showed more intense photodynamic activity. Although the singlet oxygen quantum yields of these iodinated derivatives are considered low, it could be concluded that their introduction into the quinoline heterocycle was highly advantageous as it played a role in increasing selective cytotoxicity in the presence of light. Thus, the novel synthesized dyes present photophysicochemical and in vitro photobiological properties that make them excellent photosensitizer candidates for photodynamic therapy.
Highlights
Since squaric acid (3,4-dihydroxy-1,2-dioxocyclobut-3-ene) was first reported in 1959 by Cohen et al [1], and later by other studies, as a rigid structure [2] with high chemical reactivity [3], its condensation with electron-rich precursors has been extensively studied [4,5,6] aiming to find products with potential applicability in several technological and biomedical areas [7,8,9]
The initial goal of this work was the synthesis of novel unsymmetrical squaraine cyanine dyes that exhibit properties inherent to those of an ideal photosensitizer molecule, aiming at the discovery of new photosensitizing potential molecules to be applied in cancer photodynamic therapy (PDT)
The design of the molecules intended to be synthesized was based on the photophysical and photochemical studies already described in the literature, which reported that quinoline-based squaraines displayed higher wavelength absorption capacity than their benzothiazole- and benzoselenazole-based analogs, a photophysical property considered advantageous since, it allows greater therapeutic efficacy, as these molecules may be distributed to deeper tissue zones as they will be able to absorb and be stimulated by radiation of higher wavelength [5,53]
Summary
Since squaric acid (3,4-dihydroxy-1,2-dioxocyclobut-3-ene) was first reported in 1959 by Cohen et al [1], and later by other studies, as a rigid structure [2] with high chemical reactivity [3], its condensation with electron-rich precursors has been extensively studied [4,5,6] aiming to find products with potential applicability in several technological and biomedical areas [7,8,9]. PDT is a minimally invasive therapeutic strategy with reduced side effects that involve the death of target tissue cells by the combined action of adequate light, a photoactive molecule and molecular oxygen, which results in the production of reactive oxygen species (ROS) that promote cell structural and functional failure [30,31] This therapeutic modality has progressed over the last few years [32,33], to study its potential use for the treatment of cancer, and for dermatological [34] and ophthalmic conditions [35], such as psoriasis [36,37] and age-related macular degeneration [38], respectively. Several research studies have recently reported the discovery of new compounds, such as cyanines [40], squaraines [24], chlorins [41] or phthalocyanines [42] which, by appropriate structural modifications, can ideally override the gaps of first-generation photosensitizers [43]
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