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. 2020 Sep 10;11(10):2041–2047. doi: 10.1021/acsmedchemlett.0c00266

meso-Thiophenium Porphyrins and Their Zn(II) Complexes: A New Category of Cationic Photosensitizers

Zeaul Hoque Mazumdar †, Debdulal Sharma †, Avinaba Mukherjee ‡, Samita Basu §, Pradeep Kumar Shukla ∥, Tarun Jha ⊥, Devashish Sengupta †,*
PMCID: PMC7549270  PMID: 33062190

Abstract

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A new category of cationic meso-thiophenium porphyrins are introduced as possible alternatives to the popular meso-pyridinium porphyrins. Combinations of cationic porphyrins bearing meso-2-methylthiophenium and meso-4-hydroxyphenyl moieties T2(OH)2M (A2B2 type) and T(OH)3M (AB3 type) along with their zinc(II) complexes T2(OH)2MZn and T(OH)3MZn, are reported. The increase in the number of thienyl groups attached to the meso-positions of the porphyrin derivatives (A2B2 frame) has been shown to impart longer fluorescence lifetimes and stronger photocytotoxicity toward A549 lung cancer cells, as evident with T2(OH)2M and its corresponding diamagnetic metal complex T2(OH)2MZn. The photoactivated T2(OH)2MZn imparts an early stage reactive oxygen species (ROS) upregulation and antioxidant depletion in A549 cells and contributes to the strongest oxidative stress-induced cell death mechanism in the series. The DFT calculations of the singlet–triplet energy gap (ΔE) of all the four hydrophilic thiophenium porphyrin derivatives establish the potential applicability of these cationic photosensitizers as PDT agents.

Keywords: meso-Thiophenium porphyrins, anticancer photodynamic therapy, Zn-porphyrins, cationic porphyrins, reactive oxygen species (ROS)

The role of cationic porphyrin photosensitizers (PSs) has been long popularized due to their versatile applications in photobiology and photophysics. Designing of metal-free and metalated porphyrin macrocycles bearing pyridinium groups at meso-positions of porphyrins offers scope for exploring multifunctional therapeutics with ubiquitous involvement as agents in both anticancer and antimicrobial photodynamic therapy (PDT),1−7 along with their usage as reversible proteasominhibitors,8 immunosuppressives,4 anti-HIV agents,9 nonlinear optical imaging agents,10 magnetic resonance imaging agents,11 and other applications.12−14 Functionalization with combinations of pyridyl groups at meso-positions that are alkylated to afford water-soluble cations has been reported extensively and their photocytotoxicities studied.1,4,9,15 Nitronium porphyrin derivatives are known for their excellent membrane permeability and lysosomal accumulation in cells with high selectivity toward carcinomas.16Though the reports are few, phosphonium bearing cationic porphyrins also contribute as PDT agents through selective accumulation in mitochondria of cancer cells.4,17 Cationic porphyrins serve as subcellular organelle-targeted photosensitizers that can localize in the cancer cell mitochondria or endoplasmic reticulum (ER) and promote PDT induced apoptosis leading to a range of inflammatory and immune responses generated by ROS that damage the microvasculature and tumor cells.4,18 In the pursuit to develop new cationic PSs, an alternative approach to introduce substituents analogous to pyridinium ions at the meso-positions can be achieved by the incorporation of thienyl groups that can be further alkylated to generate the corresponding sulphonium or thiophenium ions. Though the photochemistry of meso-thienyl substituted porphyrins has been explored in the literature19−24 there are no reports of PSs bearing meso-thiophenium cations being applied in photobiological studies. Triebs et al. first reported the synthesis of a meso-thienylporphyrin.24 Thienyl bearing porphyrins show remarkable photophysical and electrochemical properties that have been explored to develop light-harvesting systems and photovoltaics.19,21−24 This paper reports a simple approach toward the synthesis of A2B2 and AB3 types of combinations of meso-2-thiophenium and meso-4-hydroxyphenyl porphyrin derivatives in order to introduce hydrophilicity in the otherwise hydrophobic meso-thienyl porphyrin derivatives. The molecular geometries, total energies, and singlet–triplet energy gap of all the water-soluble target PSs were determined using density functional theory (DFT) calculations. It is known that only half of the cationic porphyrin molecules can influence interactions with biological systems such as DNA.25,26 The proposed cationic thiophenium porphyrins are expected to exhibit interesting photobiological outcomes comparable with their pyridinium, and phosphonium counterparts.

The porphyrins T2(Et)2 and T(Et)3 were synthesized by a one-pot, three-component microwave irradiation method (Scheme 1). Pyrrole (4 equiv), 4-hydroxybenzaldehyde (2 equiv), and thiophene-2-carboxaldehyde (2 equiv) were condensed together in a mixture of 150 mL propionic acid and 50 mL propionic anhydride, at 135 °C, for 8 min under an irradiation power of 800 W, in a microwave synthesizer. The compound T2(Et)2 (Yield = 10%) was formed. A slight modification in the stoichiometry (pyrrole (4 equiv), 4-hydroxybenzaldehyde (3 equiv), and thiophene-2-carboxaldehyde (1 equiv)) of the starting materials led to the formation of compound T(Et)3 (Yield 11%). The compounds were purified through column chromatography. In comparison, Alder’s method27 gave yields of 3% and 7% for compounds T2(Et)2 and T(Et)3, respectively. The porphyrins T2(Et)2 and T(Et)3 were hydrolyzed by treating them with an excess of NaOH in N,N-dimethylformamide (DMF) and H2O to obtain T2(OH)2 and T(OH)3. Metalation and subsequent alkylation of the metalloporphyrins and their free base precursors were carried out employing previously published protocols9,15 to obtain the Zn-porphyrins T2(OH)2Zn and T(OH)3Zn and the water-soluble compounds T2(OH)2M, T(OH)3M, T2(OH)2MZn, and T(OH)3MZn. The compounds were successfully characterized by various spectroscopic techniques. The 1H NMR splitting pattern and the high-resolution mass spectra (ESI-HRMS) (Figures in the SI) confirmed the purity of the reported target compounds and their precursors. Apart from the thiophenium and β-pyrrolic proton peaks, the 1H NMR spectra of the four PSs T2(OH)2M, T(OH)3M, T2(OH)2MZn, and T(OH)3MZn also displayed a singlet between 4 and 5 ppm which was indicative of successful methylation of the thienyl S atom whereas the disappearance of the proton signals of the highly shielded NH group indicated successful metalation. Subtle changes in the absorption and emission spectral profile as expected for metalated species were observed.5,9,28−30

Scheme 1. Schematic Representation of the Synthesis of meso-Substituted Water-Soluble Porphyrins Containing Combinations of Thiophenium and Hydroxyphenyl Moieties and Their Corresponding Zn(II) Complexes.

Scheme 1

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The absorption spectra of the synthesized cationic thiophenium porphyrins T2(OH)2M, T(OH)3M, T2(OH)2MZn, and T(OH)3MZn, recorded in H2O at 10 μM concentration, are shown in Figure 1. The free base compounds T2(OH)2M and T(OH)3M exhibit typical porphyrinoid spectra with a strong Soret band between 421 and 430 nm and four weak Q-band absorptions between 516 and 658 nm. The presence of the meso thienyl groups induced a slight red shift in the Soret and Q-band region. The red shift becomes more apparent, with an increase in the number of meso thienyl groups. The red shifts of the Soret band and Q-band have been observed for cationic thiophenium compound T2(OH)2M (430, 516, 565, 612, 653) and compound T(OH)3M (426, 518, 562, 604, 653) as well as for their corresponding Zn(II) complexes, compound T2(OH)2MZn (434, 563, 614) and compound T(OH)3MZn (431, 548, 608), respectively.

Figure 1.

Figure 1

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Absorption spectra of compounds T2(OH)2M, T(OH)3M, T2(OH)2MZn, and T(OH)3MZn in H2O at 10 μM concentration.

The fluorescence emission spectra of compounds T2(OH)2M, T(OH)3M, T2(OH)2MZn, and T(OH)3MZn are shown in Figure 2. The emission spectral data were recorded through excitation of 10 μM solution of the individual water-soluble target compounds in H2O at a wavelength corresponding to λmax of their Soret band. The fluorescence spectrum of the free-base cationic compound T2(OH)2M depicts twin peaks at 665 and 724 nm whereas compound T(OH)3M has fluorescence emission peaks at 664 and 725 nm (Figure 2).

Figure 2.

Figure 2

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Fluorescence emission spectra of compounds T2(OH)2M, T(OH)3M, T2(OH)2MZn, and T(OH)3MZn in H2O at 10 μM concentration. (λex = 428 nm for cationic ligands, and λex = 430 nm for cationic Zn(II) complexes.)

The Zn(II) complex T2(OH)2MZn exhibits the peaks at 620 and 625 nm while the Zn(II) complex T(OH)3MZn depicts the same at 619 and 624 nm (Figure 2). The fluorescence intensity of the Zn(II) complexes is quenched slightly with a significant broadening and blue shift of the bands compared to their parent complexes. The fluorescence quenching can be attributed to the “heavy atom effect”. The introduction of the heavy atom (Zn2+) in the porphyrin ring may enhance ISC to the triplet state thereby leading to a decrease in fluorescence.28−30 The Stokes shift calculated from the difference between the values of the emission band Q (0,0) and absorption band B (0,0) is listed in Table 1. The free-base porphyrins exhibit a larger Stokes shift as compared to their corresponding zinc incorporated derivatives suggesting structural reorganizations in the excited state.29,30

Table 1. Absorption and Emission Band Maxima (λmax (nm)), Relative Intensities, and Stokes Shift Values of the Various Ligands and Metalsa.

  Absorption
 Emission
  λmax (nm)
 λmax(nm)
 Stokes Shift
Code B(0,0) Qy(1,0) Qy(0,0) Qx(1,0) Qx(0,0) Q(0,0) Q(0,1) Q(0,0)-B(0,0)
T2(OH)2M 430 516 565 612 653 665 724 235
T(OH)3M 426 518 562 604 653 664 725 238
T2(OH)2MZn 434   563 614   620 665 186
T(OH)3MZn 431   548 608   619 664 188
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a

λex = 428 nm for cationic ligands, and λex = 430 nm for cationic Zn(II) complexes. Spectral data recorded with 10 μM solution of the compounds in H2O.

The fluorescence lifetimes of compounds T2(OH)2M, T(OH)3M, T2(OH)2MZn, and T(OH)3MZn were measured with the time-correlated single-photon counting technique, and the results are displayed in Figure 3. The samples, in H2O, were excited at their Soret band, and the fluorescence lifetimes were recorded at the maximum of the corresponding fluorescence Q (0,1) band. All the free-base fluorescence transients were fitted with a three-exponential decay function for better χ2 value. The average lifetime of the compound T2(OH)2M and T(OH)3M is found to be 8.20 and 6.51 ns, respectively. However, the decay curves of the corresponding Zn(II) complexes had to be fitted with a two-exponential decay function for better χ2 value, and the obtained lifetimes are 6.35 and 6.13 ns for the compounds T2(OH)2MZn and T(OH)3MZn, respectively.

Figure 3.

Figure 3

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Fluorescence emission decay profiles of T2(OH)2M, T(OH)3M, T2(OH)2MZn, and T(OH)3MZn at 10 μM in H2O (λex = 420 nm).

The in vitro photodynamic activity of the water-soluble cationic thiophenium porphyrin T2(OH)2M, T(OH)3M, and the corresponding Zn(II) complexes T2(OH)2MZn and T(OH)3MZn were investigated against human lung cancer cell line A549 under PDT and non-PDT conditions using the MTT assay, as shown in Figure 4. For the analysis, a stock solution of each sample was prepared in DMSO and diluted to appropriate concentrations with the culture medium. The cells, after being rinsed with phosphate-buffered saline (PBS), were incubated with different concentration of samples 2.5–20 μM in Dulbecco’s modified eagle medium (DMEM) solution for 24 h at 37 °C before being illuminated at ambient temperature. Percentages of cell viability and growth inhibition were determined by means of the colorimetric assay called the MTT assay. Approximately 1 × 104 cells were seeded in two 96 well cluster plates and allowed to reach the exponential phase of growth; thereafter, the samples were added and analyzed for cytotoxicity.

Figure 4.

Figure 4

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Percentage of cell inhibition by synthesized compounds at different doses (2.5–20 μM) against cell line A549, in the presence and absence of light. Data represented as mean ± SD, n = 4, *p ≤ 0.05 as compared to control of the respective groups (light/dark) was considered as statistically significant.

The photosensitizers T(OH)3MZn, T2(OH)2M and T(OH)3M showed 50% inhibitory activity on the survivability of A549 cells at 13.77 ± 0.82 μM, 12.93 ± 0.61 μM, and 14.54 ± 0.18 μM of dosimetry, respectively. However, none of the PSs showed inhibition in the absence of light. Among the four thiophenium porphyrins, T2(OH)2MZn has shown the highest efficacy of PDT in the series with an IC50 value of 7.05 ± 0.3 μM. However, in the absence of light exposure, this PS does not bear any significant cytotoxicity. All the other thiophenium bearing photosensitizers studied fail to show any significant cytotoxicity against normal lung cells L-132 and PBMC up to 100 μM of dosimetry. This indicates the target-specific photodynamic activity of the synthesized PSs.

To ascertain the probable reason for T2(OH)2MZn induced cytotoxicity in A549 cells, intracellular ROS activity was measured from fluorimetry data. T2(OH)2MZn produced intracellular ROS under PDT conditions. The fluorometric analysis revealed significant (p < 0.05) up-regulation of ROS level after induction of 7 μM of T2(OH)2MZn at an early hour (4, 6, 12, and 24 h) of exposure when compared to the untreated control in the presence of light (Figure 5). Besides this, the dark control groups showed no significant upregulation in ROS activity. Determination of intracellular GSH content revealed that T2(OH)2MZn in light treated cells was not able to deplete intracellular GSH level (Table 2) at an early hour of exposure, but at a late hour (12 h) significant GSH depletion was observed. GSH depletion was found to happen between 6 and 12 h postexposure.

Figure 5.

Figure 5

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Intracellular ROS activity analysis of A549 cells after induction of 7 μM of T2(OH)2MZn for 0, 4, 6, and 12 h in both the presence and absence of light. The values are represented as mean ± SD of three independent experiments. Statistical significance was considered as *P < 0.05.

Table 2. Intracellular GSH Content Analysis of A549 Cells after Induction of 7 μM of T2(OH)2MZn for 0, 4, 6, and 12 h in Both the Presence and Absence of Lighta.

  Time of Exposure
Control 0 h 4 h 6 h 12 h
Light 100 ± 0.01 99.4 ± 0.05 91.7 ± 0.2* 79.7 ± 0.01*
Dark 100 ± 0.02 99.7 ± 0.1 99.1 ± 0.03 98.9 ± 0.2
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a

The values represented in % of untreated control and as mean ± SD of three independent experiments. Statistical significance was considered as *P < 0.05.

The optimized molecular structures of the compounds T2(OH)2M, T(OH)3M, T2(OH)2MZn, and T(OH)3MZn are shown in Figure S1, and certain optimized bond lengths (Å) are listed in Table S1. The total energies and singlet–triplet energy gap of the compounds are listed in Table S2. The important bond lengths are found to be almost the same for both T2(OH)2MZn and T(OH)3MZn (Figure S1 and Table S1). This shows that the porphyrin ring geometry is not altered appreciably by an additional methylthiophenium moiety.

For all four water-soluble PSs, singlet state (1A) structures are found to be more stable than their triplet state (3A) counterparts (Table S2). This shows that all the compounds in their ground state will be in a singlet state (1A). From the point of view of photodynamic therapy (PDT), the singlet–triplet energy gap (ΔE) of compounds is an important parameter for determining their performance for PDT. It is reported that ΔE should be equal to or greater than 0.98 eV for optimal performance in PDT.31 The calculated ΔE for the PSs T2(OH)2MZn, T2(OH)2M, T(OH)3MZn, and T(OH)3M are found to be 1.234, 1.079, 1.082, and 1.003 eV, respectively (Table S2). As ΔE for all the PSs is greater than 0.98 eV, all four target PSs qualify as PDT agents. This agrees with the experimental findings.

The stability of any PS when kept in dark and its ability to resist degradation when exposed to radiation is a marker of its photostability.32−34 The synthesized target sensitizers are photostable. The photophysical and photobiological studies were completed over a period of 4–6 months with the same set of solutions of the compounds in an appropriate solvent (H2O, in this particular case). Absorption spectra recorded before each set of the experiment did not show any difference in absorption behavior; neither was any variation in intensity noticed. In order to further ascertain the photostability of the photosensitizers, a 10 μM solution (in water) of each compound was prepared. The solutions were purged with nitrogen and then exposed to radiation from a Philips Essential Master PL-L 36W/865/4P linear compact fluorescent lamp for a period of 24 h. Postexposure, the solutions were kept in the dark for a period of 90 days. Absorption spectra recorded before and after the experiment did not show any significant deviation (Figure S2–3), save for the very slight change in the Soret band. The Q-band showed the same level of absorbance throughout. Agglomeration, sedimentation, or aggregation was not noticed either.

In conclusion, a new type of hydrophilic cationic porphyrin is introduced. Unlike pyridyl groups, thienyls are not readily alkylated.5,35 In this report, a simple solvent driven process has afforded the desired alkylated thiophenium cation. A clear indication of stronger photocytotoxicity, toward A549 lung cancer cell lines, is apparent in the presence of a higher number of the cationic meso-4-methylthiophenium groups in the reported porphyrins. Among the four water-soluble PSs, T2(OH)2MZn has the strongest cytotoxicity (IC50 value = 7.05 ± 0.3 μM) under photodynamic conditions. Besides this, all the porphyrins including T2(OH)2MZn are photodynamically active toward A549, but sparing the normal lung cells L-132 and PBMC which signifies the synthesized photosensitizers as target-specific entities. The strongest photocytotoxicity of the PS T2(OH)2MZn was probably a result of significant upregulation of intracellular ROS levels by the PSs. At an early hour (4–12 h) of T2(OH)2MZn exposure (at a concentration of 7 μM) significant upregulation of the ROS level was found to be happening in A549 cells. On the other hand, T2(OH)2MZn at around 6–12 h of exposure significantly depleted the intracellular GSH content and the downregulation was significantly more in the light treated control compared to the dark control ones. This shows that the synthesized drug exerts its apoptotic efficacy against A549 cell by upregulating the ROS level and also by downregulating the antioxidant level. Thiophenium bearing porphyrins offer the promise of target specific PDT and can be developed further to explore the photochemistry and photobiology of sulphonium ions as possible alternatives to nitronium ions. The experimental findings complement DFT studies.

Acknowledgments

The suggestions received from K. K. Mahalanabis (Retd.) (Jadavpur University, India) are acknowledged along with the help received from Ajoy Das, (SINP, Kolkata, India) in carrying out the fluorescence lifetime measurements.

Glossary

Abbreviations

T2(OH)2M

(cis-5,10-bis(4-hydroxyphenyl)-15,20-bis(2-methylthiophenium)porphyrin)

T(OH)3M

(5,10,15-tris(4-hydroxyphenyl)-20-mono-(2-methylthiophenium)porphyrin)

T2(OH)2MZn

(cis-5,10-bis(4-hydroxyphenyl)-15,20-bis(2-methylthiophenium)-21,23-Zn(II)-porphine)

T(OH)3MZn

(5,10,15-tris(4-hydroxyphenyl)-20-mono-(2-methylthiophenium)-21,23-Zn(II)-porphine)

PSs

photosensitizers

PDT

photodynamic therapy

ROS

reactive oxygen species

DFT

density functional theory

DMF

N,N-dimethylformamide

DMEM

Dulbecco’s modified eagle medium

MTT

3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsmedchemlett.0c00266.

  • Experimental details: synthetic methods, details of photobiological assays employed, DFT study protocol; characterization data: 1H NMR and mass spectral data; DFT results: optimized bond length, structures and singlet triplet energy gap of target photosensitizers, etc. (PDF)

Author Contributions

∇ Z.H.M. and D.S. contributed equally. The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

The support by DBT (Nanobiotechnology) Project Reg. No: BT/PR3184/NNT/28/554/2011 granted to Devashish Sengupta from the Government of India, Ministry of Science and Technology; Department of Biotechnology is acknowledged.

The authors declare no competing financial interest.

Supplementary Material

ml0c00266_si_001.pdf (1.9MB, pdf)

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