An octabrominated Sn(IV) tetraisopropylporphyrin as a photosensitizer dye for singlet oxygen biomedical applications

Balaji Babu, John Mack* and Tebello Nyokong*
Institute for Nanotechnology Innovation, Department of Chemistry, Rhodes University, Makhanda 6140, South Africa. E-mail:;

Received 28th May 2020 , Accepted 18th June 2020

First published on 18th June 2020

Two novel Sn(IV) tetraisopropylphenylporphyrins have been synthesized to explore the effect of octabromination at the β-pyrrole positions on their photophysical properties and photodynamic activity. The lower energy Q band of an octabrominated complex lies at 675 nm well within the therapeutic window. The octabrominated dye has a relatively high singlet oxygen quantum yield of 0.78 in DMF and exhibits favorable photodynamic activity against MCF-7 cells with an IC50 value of 10.7 μM and a 5.74 log reduction value (5 μM) towards S. aureus under illumination at 660 nm for 60 min with a Thorlabs M660L3 LED (280 mW cm−2).


Porphyrin-based photosensitizers have been proposed as promising candidates for photodynamic therapy (PDT).1 Several porphyrin derivates are in clinical trials and some, such as Photofrin®, Foscan®, and Purlytin®, are currently used in the PDT treatment of various cancers.2 During PDT, a photosensitizer dye is excited by incident light of appropriate wavelength and rapidly undergoes intersystem crossing (ISC) to a long lived triplet state (T1), which transfer its energy by a Type-II mechanism to ground state molecular dioxygen to form the highly reactive 1O2 species,3 which is the cytotoxic species believed to be mainly responsible for PDT activity. The development of new photosensitizer dyes with enhanced properties is an important research goal. Incorporation of heavy atoms, such as Br and I, on the porphyrin core and coordination of heavy metals (Sn, In, Zn, Pt, Pd) are strategies that can be used to increase the efficiency of triplet state formation,4–7 since this enhances rate of ISC and the singlet oxygen quantum yield. Ideally, a photosensitizer dye should absorb above 650 nm where tissue penetration of light is deeper.2 Substitution of the porphyrin core with bromines is known to shift the absorption wavelength of the porphyrin Q band to longer wavelength.8

Sn(IV) porphyrins are known to have favorable photophysical and photocytotoxic properties.4 Sn(IV) ethyl etiopurpurin (Purlytin™) is a well-established second-generation photosensitizer which is under clinical II trials.2c We recently reported that a readily synthesized Sn(IV) tetrathien-2-ylporphyrin complex exhibits favorable photodynamic activity, since axial ligation limits the extent of aggregation.4d Since the lowest energy Q band of this complex lies at 613 nm, the goal of this study was to explore the use of bromination of the porphyrin ligand to shift the Q band further into the therapeutic window (620–1000 nm). Sn(IV)porphyrins tetrabrominated at the 2,3,12,13-β-pyrrole positions were recently reported to produce singlet oxygen on irradiation with white light but no in vitro cell studies were carried out.4e Although transition metal octabromoporphyrin complexes have been reported to have interesting photophysical and catalytic properties,9a–i Sn(IV) octabromoporphyrins have only very rarely been reported. The synthetic and catalytic properties of [Sn(IV)(Br8TPP)(OH)2] and [Sn(IV)(Br8TPP)(OTf)2] have been reported in the literature,9j,k but the potential utility of main group octabromoporphyrin complexes for singlet oxygen biomedical applications has not previously been explored.

In this study, we synthesized dihydroxy[2,3,7,8,12,13,17,18-octabromo-5,10,15,20-tetra(4-isopropyl)phenylporphyrinate] Sn(IV) (SnBr, 2) (Fig. 1) along with its non-brominated analogue (SnH, 1) as a negative control complex, so that its in vitro photodynamic efficacy for PDT could be studied against MCF-7 cells and for photodynamic antimicrobial chemotherapy (PACT) against S. aureus.

image file: d0dt01915a-f1.tif
Fig. 1 A schematic representation of (a) SnH and (b) SnBr. (c) UV-visible absorption and (d) emission spectra of the Sn(IV) porphyrins in DMF (λex was set at the B band maxima).

Results and discussion

SnH and SnBr were synthesized by following previously reported procedures.4a,9j The structures of these compounds were confirmed by 1H NMR spectroscopy and mass spectrometry. The β-pyrrole protons of SnH resonate at 9.19 ppm, while no β-pyrrole proton peak was observed for SnBr indicating complete substitution by bromine atoms (Fig. S1 and 2, see the ESI). The anticipated parent peaks are observed in the MALDI-TOF data and the calculated isotopic distribution patterns match the observed patterns (Fig. S3–6, see the ESI).

The electronic absorption spectrum of SnH has a narrow and intense B (or Soret) band at 429 nm and two Q bands at 564 and 605 nm (Fig. 1), while that of SnBr has broader B and Q bands at 478 and 675 nm, respectively. It is noteworthy that the molar extinction coefficients for the Q bands of SnBr are significantly more intense than those of SnH.8,9 Bromination of the porphyrin core has previously been reported to result in a red shift of the main absorption bands.8 The large red shift of the lower energy Q band to 675 nm makes SnBr suitable for PDT applications since this falls deep within the therapeutic window (620–800 nm).3 SnH has two emission bands at 614 and 665 nm (Fig. 1) and a fluorescence quantum yield (ΦF) < 0.01, Table 1, while SnBr is non-emissive due to the combined heavy atom effects of the Sn(IV) ion and the bromine atoms that increase the rate of ISC to the triplet state.4e,10

Table 1 Selected physicochemical properties of SnH and SnBr in DMF
  SnH SnBr
a Excited at the B (or Soret) band maxima.b N2 purged.
λmax/nm (log[thin space (1/6-em)]ε) 429 (5.16), 564 (4.32), 605 (4.30) 378 (4.92), 478 (5.05), 608 (4.54), 675 (4.72)
λem[thin space (1/6-em)]a/nm 614, 665
ΦF <0.01
τT[thin space (1/6-em)]b (μs) 94.7 0.74
ΦΔ 0.64 0.78

DFT geometry optimizations were carried out for SnH and SnBr by using the B3LYP functional of the Gaussian 09 software package11 with 6-31G(d) basis sets (Fig. 2). The Sn(IV) ion lies in the central cavity of the porphyrin core and has trans-hydroxy axial ligands. The presence of the bromine atoms causes steric hindrance with the meso-aryl rings that forces SnBr into a saddle-shaped conformation (Fig. 2). In contrast, the porphyrin core of SnH is almost perfectly planar. The non-planarity lowers the HOMO–LUMO energy gap of SnBr causing a significant red-shift of the Q and B bands (Fig. 2 and S7, see the ESI).8b This can be readily rationalized through a consideration of the effect of bromination on the relative energies of the a, s, -a and -s MOs of Michl's perimeter model (Fig. 2),12 which give rise to allowed and forbidden B and Q transitions of Gouterman's 4-orbital model (Fig. S8 and Table S1, see the ESI) that have ΔML = ±1 and ±9 properties, respectively.13 The nomenclature used depends on whether a nodal plane (a, -a) or MO coefficients (s, -s) are aligned with the y-axis (Fig. 2).12 There is a marked stabilization of the π-MOs of SnBr through an inductive effect due to the electron withdrawing properties of the bromines (Fig. 2). The saddling of the ligand enables the meso-aryl rings to rotate into the plane of the porphyrin π-system (Fig. 2b) resulting in a larger destabilizing mesomeric interaction in the s MO (Fig. 2d), which has large MO coefficients on the meso-carbons (Fig. 2c). The larger splitting of the a and s MOs of SnBr is expected to result in a slight intensification of the Q band (Table 1), due to a mixing of the allowed and forbidden properties of the Q and B bands that occurs when the orbital degeneracies of the frontier π-MOs are lifted.12,13

image file: d0dt01915a-f2.tif
Fig. 2 B3LYP optimized geometries showing top and side views of (a) SnH and (b) SnBr with hydrogens omitted for clarity. (c) The angular nodal patterns and energies of the a, s, -s and -s MOs of Michl's perimeter model at an isosurface of 0.02 a.u.12 (d) MO energies for SnH and SnBr at the CAM-B3LYP/6-31G(d) level of theory. The a, s, -s and -s MOs of Michl's perimeter model12 are highlighted with thicker black lines. HOMO−LUMO gap values are highlighted with red diamonds and are plotted against a secondary axis.

The triplet state of Sn(IV) porphyrins was studied by laser flash photolysis. The transient absorption spectra of SnH and SnBr in N2 saturated DMF are provided in Fig. 3a and b. Singlet depletion is observed at the Q and B band wavelengths and triplet–triplet absorption bands are observed from 450–550 and 500–600 nm for SnH and SnBr, respectively.4d,e The transient intermediates of SnH and SnBr undergo a first-order decay process (Fig. 3a and b insets) to give triplet state lifetimes of 94.7 and 0.74 μs, respectively, Table 1. The singlet oxygen generation ability of SnH and SnBr was determined by measuring the phosphorescence of 1O2 at 1270 nm in air-saturated DMF solutions.14 Following excitation at the B band maxima (420 nm for SnH, 485 nm for SnBr) the characteristic signal of 1O2 phosphorescence was observed (Fig. 3). When the solutions were purged with N2 prior to measurement, the signals were quenched. The singlet oxygen quantum yield (ΦΔ) value was evaluated by using a standard dye (zinc tetraphenylporphyrin, ΦΔ = 0.53 in DMF).15 As anticipated, the ΦΔ value of SnBr (ΦΔ = 0.78) is higher than that of SnH (ΦΔ = 0.65) due to the presence of the eight bromine atoms, Table 1. Assuming that there is efficient energy transfer from the triplet state to 3O2, non-radiative decay is likely to be the other significant relaxation mechanism to the ground state.

image file: d0dt01915a-f3.tif
Fig. 3 Transient absorption spectra for (a) SnH and (b) SnBr excited at 500 nm in N2 purged DMF (insets: triplet absorption decay curves). Singlet oxygen phosphorescence generated by (c) SnH and (d) SnBr in air saturated and N2 purged DMF.

The photophysical and photochemical results demonstrate that SnH and SnBr merit study for PDT applications. The uptake of the Sn(IV) porphyrins in MCF-7 cells was evaluated at different incubation times (6, 12, 24, and 48 h) by measuring the absorbance of internalized Sn(IV) porphyrin (Fig. 4a and see the ESI). The results show that SnH and SnBr were quickly internalized within 6 h of incubation and that their concentration reaches a maximum at 24 h. The cytotoxicity of SnH and SnBr towards MCF-7 cells both in the dark and upon irradiation at 660 nm (Thorlabs M660L3 LED, 30 min) was investigated by MTT assay (Fig. 4b and see the ESI).16 A photosensitizer dye that is suitable for application in PDT should exhibit negligible dark cytotoxicity but significant photocytotoxicity upon light irradiation. MCF-7 cells were seeded in 96 well plates and incubated with SnH and SnBr over a range of different concentrations (0–50 μM) in Dulbecco's modified Eagle's medium (DMEM) for 24 h. DMSO was used to solubilize the Sn(IV) porphyrins but even at 50 μM was diluted to <1% during the PDT activity experiments. Cells were exposed to 660 nm light (280 mW cm−2) for 30 min and incubated for a further 24 h and the cell viability was determined by MTT assay. A separate set of plates with cells treated with SnH and SnBr in the same manner but with no light exposure were also prepared as a control. The dose-dependent response curves for the Sn(IV) porphyrins are shown in Fig. 4b. The calculated IC50 values (concentration required to inhibit cell growth by 50%) are provided in Table 2. A comparison is made with analogues of SnH axially ligated with 3-pyridyl (3PyO) groups that have meso-thien-2-yl (TTP) and meso-phenyl (TPP) rings and with Photofrin®. Both SnH and SnBr exhibited no toxicity to MCF-7 cells in the dark with IC50 values of >50 μM, Table 2. In contrast, upon light exposure, SnBr showed a significant reduction in cell viability with an IC50 value 10.7 μM. Thus, SnBr is potentially useful for PDT applications.

image file: d0dt01915a-f4.tif
Fig. 4 (a) Time-dependent relative cellular uptake of 10 μM SnH and SnBr in DMEM solution by MCF-7 cells measured by absorption spectroscopy of the lysed cells. (b) Cytotoxicity of SnH and SnBr against MCF-7 cells after 24 h incubation in the dark followed by photoirradiation for 30 min with a Thorlabs M660L3 LED (280 mW cm−2) as determined with the MTT assay. (c) The DCFDA assay for ROS detection in MCF-7 cancer cells in 10 μM SnH and SnBr DMEM solution in the dark and upon illumination (NAC is a ROS quencher, H2O2 is a positive control). (d) Logarithmic reduction of S. aureus treated with 5 μM of SnH and SnBr after irradiation with a Thorlabs M660L3 LED (280 mW cm−2). Error bars represent the mean standard deviation.
Table 2 IC50 values of SnH and SnBr against MCF-7 cells
  IC50 (μM)
Darka Lightb
a 24 h incubation in the dark.b 24 h incubation in the dark followed by exposure to a Thorlabs M660L3 LED (504 J cm−2) for 30 min.c IC50 values are taken from ref. 4d (photoexposure to a 625 nm Thorlabs M625L3 LED (240 mW cm−2 for 20 min).d The dark IC50 value for Photofrin® was determined for HeLa cells and is taken from ref. 20.e The light IC50 value for Photofrin® (2 h exposure; white bulb; fluence rate: 5.5 × 10–2 mW cm−2) is taken from ref. 16b.
SnH >50 38.9 (±1.1)
SnBr >50 10.7 (±1.1)
[Sn(IV)TTP(3PyO)2]c >50 5.6 (±1.1)
[Sn(IV)TPP(3PyO)2]c >50 18.7 (±1.1)
Photofrin® >41d 2.0 (±0.2)e

The intracellular generation of reactive oxygen species (ROS) by SnH and SnBr was measured through the use of the 2′,7′-dichlorodihydro-fluorescein diacetate (DCFDA) assay (Fig. 4c and see the ESI).17 DCFDA is a cell permeable dye that undergoes hydrolysis by intracellular esterase to form non-fluorescent 2′,7′-dichlorodihydro-fluorescein (DCFH) dye. In the presence of ROS, DCFH is oxidized to a green fluorescent 2′,7′-dichlorofluorescein (DCF) dye which can be measured by microplate reader (λex = 485 nm, λem = 535 nm) and fluorescence microscopy (Fig. S9, see the ESI). Fig. 4c shows that negligible intracellular fluorescence was detected in the control cells and non-irradiated Sn(IV) porphyrin treated cells. Upon exposure to 660 nm light from a Thorlabs M660L3 LED, a dramatic increase in DCF green fluorescence was observed from MCF-7 cells treated with Sn(IV) porphyrins. When cells were pre-treated with N-acetyl cysteine (NAC) as a ROS scavenger prior to light exposure, the fluorescence intensity decreased significantly. Further fluorescence microscopic images of MCF-7 cells treated with SnBr were obtained after irradiating at 660 nm for 15–30 min (Fig. S9, see the ESI). Green fluorescent spots in the images correspond to DCF emission. Control cells and cells treated with SnBr in the dark exhibited no green fluorescence. The results confirm that SnBr generates intramolecular ROS upon light irradiation.

PACT is an effective mode of treatment for most types of bacterial infection including pathogens that have developed resistance against antibiotics.18 The mode of action of the photosensitizer dye is similar to that in PDT. The PACT activity of SnH and SnBr was studied against Gram-positive bacteria, S. aureus (Fig. 4d and see the ESI). A concentration of 5 μM was selected based on concentration optimization studies (Fig. S10, see the ESI). 5 μM of Sn(IV) porphyrin was incubated with S. aureus for 30 min and irradiated with a 660 nm Thorlabs LED for 60 min. Control studies showed that the incubation of S. aureus with Sn(IV) porphyrins (5 μM) for 60 min in the dark has no effect on cell survival (Fig. S11, see the ESI). As expected, SnBr showed more significant PACT activity than SnH when S. aureus was irradiated (Fig. 4d and S12, see the ESI). The results show that SnBr treated S. aureus exhibited only 1.9% cell survival with a 5.74 log reduction, Table 3. According to FDA regulations, any drug with a log reduction > 3 can be classified as a bactericidal agent.19

Table 3 Log reduction and percentage reduction (% cell survival) values for the photoinactivation effects of 5 μM solutions of SnH and SnBr on S. aureus after 60 min irradiation with a Thorlabs M660L3 LED (280 mW cm−2)
  Dark Light
Log reduction % cell survival Log reduction % cell survival
SnH (1) 0.15 88 0.85 83
SnBr (2) 0.31 81 5.74 1.9


In summary, a new promising high symmetry Sn(IV) porphyrin-based photosensitizer dye (SnBr) with facile synthesis suitable for scale up has been developed. The dye is octabrominated at the β-pyrrole positions of the porphyrin core and this results in a significant red shift of the Q and B bands, so that the lowest energy Q band of SnBr lies deep within the therapeutic window at 675 nm. The introduction of bromines as heavy atoms results in a relatively high ΦΔ value of 0.78. Cellular uptake and in vitro photocytotoxicity studies confirmed that the SnBr exhibited remarkable cellular uptake with an IC50 value of 10.7 μM. In addition, SnBr displayed significant PACT activity against S. aureus. The promising PDT and PACT activity of SnBr demonstrates its potential for these applications. Further studies on other structurally modified brominated Sn(IV) porphyrins are merited to explore strategies to improve their water solubility without sacrificing their photophysical properties.

Conflicts of interest

There are no conflicts to declare.


This work was supported by the Department of Science and Technology (DST) and National Research Foundation (NRF) of South Africa through DST/NRF South African Research Chairs Initiative for Professor of Medicinal Chemistry and Nanotechnology to TN (uid: 62620), and an ISRR grant (uid: 119259) from the NRF of South Africa to JM. Photophysical measurements were made possible by the Laser Rental Pool Programme of the Council for Scientific and Industrial Research (CSIR) of South Africa. Theoretical calculations were carried out at the Centre for High Performance Computing in Cape Town.


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Electronic supplementary information (ESI) available. See DOI: 10.1039/d0dt01915a

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