Photo induced anti-inflammatory activities of a Thiophene substituted subphthalocyanine derivative
Graphical abstract
Photo induction increased the anti-inflammatory activity of Thiophene SubPc. Thiophene’s substation to SubPc will enable more controlled and localized activation of the compound to prevent its possible side effects during the treatment of inflammatory disorders.
Introduction
Thiophene and its derivatives have been long known for their anti-inflammatory, anti-microbial and anti-cancer properties. It was first discovered in coal tar and its derivatives are also found in petroleum [1,2]. This heterocyclic compound is more biologically active than benzene due to its pie electron cloud and its activation should be well monitored to prevent the side effects [3,4].
Similar to most of the biologically active drug substances, the usage of Thiophene also leads to unwanted side effects that can debilitate the patient’s condition. In humans, it has the following side effects: skin irritation, induction of sensitization responses, nausea, jaundice and itching [[5], [6], [7]]. Modulating the electronic properties of porphyrinoids from the violet to the infrared regions of the electromagnetic spectrum [8,9], has led to decreased vitamin C levels in the metabolism, necrosis of granular cells of the cerebellum, mitochondrial aberrations and inflammatory responses in lung [10].
Controlled activation, targeted delivery and activation, localized activity, effective dose control are necessary parameters to circumvent the side effects of Thiophene. Photodynamic therapy and photo-induction of the active ingredients of the drug candidates enable localized and controlled activation of the compounds [11]. This enables the activity of the compound at the target and minimizes the side effects that are associated with it [12]. In order to generate a Thiophene derivative that can be activated by photo-induction, a Thiophene SubPc derivative was synthesized. Subphthalocyanines (SubPcs) are the member of the porphyrinoid family, consist of three isoindole units and boron atom in the center of macrocycle [13]. SubPcs are aromatic molecules with 14 π-electrons but unlike other porpyronids compounds possess a peculiar conical structure [14]. The peculiar geometric structure provides them high solubility high solubility in common organic solvents and low tendency to aggregate which are main requirement for many optoelectronic applications [15]. Apart from these exceptional features, SubPc also have strong absorption in the visible spectral range (550−650 nm) and exhibit less intensity of absorption in the UV region (<400 nm) [13]. These outstanding optical features strongly related to chemical molecular structures of SubPc which can be simply tuned by introduction of some pertinent functional groups to the the axial or peripheral position of the macrocycle. Therefore, SubPcs have found both potential and practical application in many distinct fields of biology, chemistry and advanced technology [13].
In this study, we are presenting photo-activated anti-inflammatory effects of Thiophene substituted SubPc derivative. Thiophene SubPc caused a significant and substantial decrease in the extracellular levels of inflammatory cytokines by the mammalian macrophages as well as the gene expression levels of those cytokines. Light based control over the activity of the compound will enable its targeted and localized activation and will minimize its unwanted side effects during the treatment (Fig. 1).
Section snippets
Cell culture and growth
In this study macrophage cell line, RAW 264.7, with ATCC origin was grown in RPMI 1640 that was upgraded with 10 % of fetal bovine serum, 1% of antibiotics (100 μg/ml penicillin and 100 μg/ml streptomycin) and sodium pyruvate. Cell incubations were conducted in an incubator that was set to 37 ⁰C 5 % CO2 [16].
Stimulation of macrophages with Thiophene SubPc and Lipopolysachharide (LPS) with or without light exposure
106 macrophages/well were put in 1 mL into 24 well plates. After resting the cells 12 h in 37 ⁰C 5% CO2 incubator, 50 and 100 ug/mL of Thiophene SubPc and in control wells the same volume
Thiophene SubPc did not have any cytotoxic or immunostimulatory effect on the macrophages
In order to assess cytotoxic potential as well as immunostimulatory activity of Thiophene SubPc, macrophages were incubated with 50 and 100 ug/mL of SubPc in the absence of LPS. As a positive control only LPS stimulated cells were used. Based on Trypan blue counting, there was no change in the cell viability after Thiophene SubPc treatment (Fig. 2). This situation did not change by light exposure as well. Thiophene SubPc did not lead to TNFα, IL6 and IL12p40 production in the absence of LPS (
Discussion
Thiophene derivatives have been generated and tested for their various biological activities. There have been studies showing that Thiophene derivatives have anti-cancer, anti-inflammatory and anti-microbial activities [2,18]. These derivatives are substrates of cytochrome P450 which converts them into metabolically toxic molecules. Cytochrome P450 enzymes, normally, play roles in the production of steroid hormones, cholesterol, bile acids, and certain fatty acids [20].
Metabolic processing of
Author contributions
The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. All authors contributed equally.
Funding sources
No funding to declare.
Declaration of Competing Interest
None of the authors have any financial or nonfinancial conflict of interest.
Acknowledgment
We would like to sincerely thank Dr. Juan Anguita from CICBiogune, Spain for his guidance and support.
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