Porphyrins are tetrapyrrole macrocycles that can coordinate transition metal ions such as iron, cobalt and magnesium and are able to perform a diversity of functions and applications. In biological systems, these molecules are associated with proteins involved in photosynthesis, cell respiration, cell death, antioxidant defence, among others. The stability and versatile applications of porphyrins inspired the synthesis of derivatives including 5,10,15,20-tetrakis(N-methyl pyridinium-4-yl)porphyrin (TMPyP) that is the object of the present chapter. In synthetic porphyrins such as TMPyP, the catalytic and photochemical properties can be achieved by the coordination with a diversity of central metal ions. In photodynamic therapy (PDT), TMPyP and other porphyrins act as photosensitizers. The photochemical properties of TMPyP and other porphyrins are also useful for the fabrication of solar cells. The catalytic properties require the presence of a central metal. The MnTMPyP have antioxidant activity that is influenced the capacity of membrane binding, substituents, and meso substituents. Manipulation of the interfacial confinement properties is one of the newest application areas of porphyrins. The association of porphyrins with different surfaces modulates the electronic and physicochemical properties of these molecules. All of these properties are the object of experimental and theoretical studies discussed in the present chapter.
- antioxidant activity
- photodynamic therapy
Porphyrins constitute a group of aromatic organic molecules, composed of four pyrrole rings linked by methene (═CH─) bridges (5, 10, 15 and 20), that are the
In biological systems, the porphyrins are associated with proteins involved in important cellular processes such as photosynthesis, molecular oxygen transport, cell respiration, cell death, the combat of the oxidative stress, biological synthesis, fat acid oxidation and others [1, 3–5]. The iron protoporphyrin IX (known as heme group) is the biological metalloporphyrin present in almost all biological processes. Heme is the prosthetic group of myoglobin, hemoglobin and a diversity of enzymes such as peroxidases, cytochromes, NO• synthase and others. Besides iron ion, other metals are found in biological porphyrins, the magnesium ion in chlorophyll, and the cobalt ion in vitamin B 12 . Biological and synthetic porphyrins and metalloporphyrins have been extensively investigated and applied in medicine, chemistry, sensing and other technological devices due to their catalytic, photochemical and photophysical properties [6, 7]. In biological systems, free-base porphyrins are largely used as photosensitizer (PS) in photodynamic therapy (PDT) [2, 5, 8, 9]. Otherwise, metalloporphyrins have been used for mimicking the function of hemeproteins such as cytochrome P-450 in oxidative catalysis and superoxide dismutase SOD against oxidative stress. Porphyrins are also used as building blocks and in transport chains of molecular devices [4, 9–11].
Porphyrins are versatile catalytic and therapeutic agents. The properties of porphyrins can be modulated by changing the central metal, substituents at the
2. Biological applications of porphyrins
2.1. Porphyrins in photodynamic therapy (PDT)
2.1.1. A brief historical of PDT
The term PDT—photodynamic therapy—is recent. However, the heliotherapy—the therapeutic exposure to sunlight—was already used more than 4000 years ago by Egyptians, Greeks, and Indians as a treatment for several skin disorders, like psoriasis, vitiligo, cancer and even psychosis [21–29]. Heliotherapy, recently known as phototherapy, employs either UV and visible light with/without an exogenous photosensitizer. The photosensitizer is a molecule which when exposed to light absorbs determined wavelength becomes electronically excited and starts photochemical reactions that can produce a desirable beneficial effect, as in the case of vitamin D synthesis or damage and death, as in the case of tumor and infections treatment [2, 30]. Phototherapy without an exogenous photosensitizer is used in dermatology to treat vitiligo, eczema, neonatal jaundice and vitamin D deficiency, and even some cancer types [30–33]. During 18th and 19th centuries, phototherapy without exogenous photosensitizer was used in France in the treatment of many diseases, including tuberculosis, rheumatism, edema, rickets and paralysis [28, 34]. When an exogenous photosensitizer is used in tandem with the sunlight, this therapy is called photochemotherapy. An example of the exogenous photosensitizer is the psoralen series (Figure 3). These molecules are used as active treatments of HIV-associated dermatoses, seborrheic dermatitis, mycosis fungoids, prurigo, palmar and plantar pustulosis, among other diseases [30, 35]. The use of psoralens and ultraviolet light—UV (300–400 nm) was used by ancient Egyptians to treat vitiligo in the past and has been accepted for the treatment of psoriasis (PUVA) and in immunotherapy throughout the world [22, 27, 30, 35, 36].
Photodynamic therapy (PDT) is a non-invasive treatment method that uses light, photosensitizer and molecular oxygen for the treatments of cancer, inflammation, immunological diseases and bacterial infections [8, 37–41]. In ancient times, phototherapy was used based on the observation of positive results without a mechanistic knowledge. People using and advocating phototherapy did know the key role of the photosensitizer in this type of treatment. In that times, the photosensitizer role was played by an endogenous biomolecule absorbing sunlight. The domain of the PDT mechanism initiated with the isolation of hematoporphyrin (Hp) (Figure 4) [28, 42]. From dried blood cells by Scherer in 1841 followed by the discovery of its fluorescence properties in 1871 . In 1911 and 1913, the side effects of sun exposure after the administration of hematoporphyrin were described by Hausmann and Friedrich Meyer-Bertz. The latter scientist tested on himself the effect of Hp and sun and provided the first scientific communication of human photosensitization . Besides, the powerful cytotoxic effect of phototherapy, another significant finding favoring the consolidation of this type of treatment, was the report of Auler and Banzer showing the affinity of Hp for cancer cells in 1942 . In the following, several other studies led to the development of new range of porphyrinic photosensitizers [28, 43, 46–51].
2.1.2. The PDT mechanism
The Jablonski diagram , first proposed by Professor Alexander Jablonski in 1935, has been used to describe the photodynamic processes of photosensitizer molecules used in PDT. The PDT principles are based on the presence of an endogenous or exogenous photosensitizer in the target tissue that can absorb red light to be promoted to a long-lived electronic excited state. In the electronic excited state, the photosensitizer triggers photooxidative events directly or more commonly via energy transfer to molecular oxygen. The quantum yield triplet state generation depends on the molecular structure, and the energy transfer to molecular oxygen competes with other deactivating routes for the excited state .
According to Figure 5, Jablonski diagram shows that the ground state photosensitizer (S0) can absorb a photon and be converted to the short-lived excited singlet state (Sn) at different vibrational sublevels (Sn’). The Sn state, if n > 1 can lose energy
In PDT, singlet oxygen is the principal reactive species. However, as well as others ROS, singlet oxygen has the capacity of damage limited due to its short lifetime (~100 ns in lipid regions of membranes and 250 ns in the cytoplasm) [30, 49, 55], and a diffusion range of approximately 45 nm in the cellular medium [28, 56–58]. The PDT has amino acid residues in proteins, unsaturated lipids, and DNA as the targets for oxidation leading to cell damage [59–61].
2.1.3. Porphyrin as photosensitizers
An ideal photosensitizer needs to have the following characteristics: (1) chemical purity; (2) high yield of singlet oxygen production; (3) high absorption coefficient in the red region of the visible spectrum (680–800 nm). Wavelengths longer than 900 nm should be avoided due to their insufficient energy to excite a dye photosensitizer to the triplet state; (4) efficient accumulation in tumor tissue associated with a rapid clearance in healthy organs; (5) low toxicity in the dark extensive to their metabolites; and (6) small aggregation [8, 30, 49, 62–64].
Porphyrins satisfy most of the desirable properties of photosensitizers, such as high efficiency of singlet oxygen generation, absorption of the higher wavelengths of the electromagnetic spectrum and a relatively higher affinity for malignant cells. Porphyrins have 18π electrons on the aromatic macrocycle that responds for the “
In the early twentieth century, data of literature described experiments that demonstrated the potential role of Hp in the detection and treatment of cancers; however, one of the major drawbacks was the large doses required to achieve consistent photosensitizer uptake in tumors, which led to inappropriate phototoxicity [45, 69–71]. In 1955, Schwartz et al.  demonstrated Hp to be impure and attributed selective fluorescence of malignant tissue after in vivo administration of Hp to a mixture of porphyrins with different properties. Subsequent studies led to the development of a derivative of hematoporphyrin (HpD) by the treatment of crude Hp with acetic and sulfuric acids, which enhanced tumor accumulation. The ability to accumulate selectively in neoplastic tissue using lower doses of HpD than Hp was reported by Lipson and coworkers [73–77]. In 1972, Diamond et al. demonstrated the destructive potential of HpD irradiated with white light on glioma in rats . Six years later, Dougherty et al. reported the partial and complete response of many tumors, including malignant melanomas and carcinomas of the colon, breast, and prostate, treated by photodynamic therapy using HpD as a photosensitizer . In the following, HpD compounds were purified, many of the less active monomers were removed, and the most efficient HpD derivatives were used to produce Photofrin (Figure 7).
Among a diversity of porphyrinic photosensitizers,
Regarding TMPyP, the focus of the present study, its efficiency as a photosensitizer is related to its topology. A study comparing photodamage in a mitochondrial membrane model modulated by the topology of TPPS4 and 5,10,15,20-tetrakis(N-methyl pyridinium L)porphyrin (TMPyP)  shows that in L-α-phosphatidylcholine/cardiolipin (PC/CL)liposomes (mitochondrial membrane model) both porphyrin can damage the membrane
2.2. Porphyrins in chemical therapy
The synthetic analogs of porphyrins are widely used in therapy of diseases connected to oxidative stress processes. A quantitative structure-activity relationship (QSAR) studies have been performed to identify the optimal active molecule within a series of analog structure characteristics to diversify the biological action of the compound. The QSAR studies can correlate the physicochemical characteristics that affect the compound’s activity in biological systems. These studies assumed that the binding affinity of the compound to the target receptor could determinate the biological activity . The biological effects of two meso-tetrakis porphyrins, TPPS4 (anionic) and TMPyP (cationic) demonstrated that the cationic porphyrin has affinity to the inner mitochondrial membrane . Therefore, in mitochondria, Mn3+TMPyP has been used as an antioxidant against superoxide ions. The replacement of manganese by an iron ion in TMPyP makes this porphyrin a prooxidant agent . Au-porphyrins have been reported as excellent antiproliferative agents, showing cytotoxic effects on cancer cells. Regarding to the mimetic SOD activity of porphyrins, the correlation between the metal-centered reduction potential and the catalytic rate constant for the O2•− dismutation was found for Fe and Mn porphyrins. The structure-activity relationships have been established over the years by the rate-limiting step of metal reduction of this class of compounds . Modulation of SOD activity has been achieved by decreasing the electron density of the groups at the meso and β-pyrrile positions, thus increasing the Mn3+/Mn2+ potential and facilitating its reduction [118–120]. Either the mimetic SOD activity can occur when the O2·− is directed to the catalytic site by the metal-centered positive charges via electrostatic facilitation [118, 119]. The manganese (III) 5,10,15,20-tetrakis(N-ethylpyridinium-2-yl) porphyrin (Mn3+TE-2-PyP5+, E½ = +228 mV
In a cell redox balance, the association of Mn3+TMPyP to membrane lipid bilayers can be intrinsically related to the redox potential of the Mn2+/Mn3+ couple. In homogeneous systems, Batinić-Haberle et al.  had reported the effect of Mn3+TMPyP in a CL-containing inner mitochondrial membrane under pH 11 to 7.8 conditions. The potential values of Mn2+/Mn3+ redox process were found to be E1/2 =94 mV for
3. Technological applications
Porphyrins free base are extensively applied in solar cells and sensor due to their photophysical characteristics. The intense absorption bands covering a significant range of the visible region of the electromagnetic spectrum and due to the relatively low cost of these compounds as compared with inorganic semiconductors make these molecules appropriate for application in solar cells. These characteristics experimentally observed are consistent with the results obtained by density functional theory (DFT). Therefore, DFT/time-dependent (TD)DFT calculation is a useful strategy for the molecular design of porphyrins with the more appropriate characteristics for application is dye-sensitizer solar cells (DSSCs) [125–129]. As an example, Santhanamoorthi et al.  have presented the theoretical study of newly designed porphyrin dyes (1−5) for DSSC applications. In this study, the authors calculated seven different structures of porphyrins and found the best characteristics for use in solar cells for two calculated molecules that were named Dyes 2 and 4. Dyes 2 and 4 presented smaller HOMO-LUMO energy gaps and absorption in Q band significantly stronger. Equally, DFT/TDDFT can be used for conceiving porphyrin derivatives for a diversity of technological applications. Theoretical calculations allow the prediction of the best characteristics for porphyrins to be used in technological applications and optimize the subsequent efforts for the synthesis.
3.1. Porphyrins in solar cells
Solar energy is an important source of energy (~3 × 1024 J year−1) that sustains the life on the Earth [130–132], and it can be an alternative to using fossil fuels due to be a clean, inexhaustible and sustainable source of energy [133–139]. The utilization of solar energy as solar fuel or electricity is fundamental for the maintenance of development and live on Earth and has attracted the attention of various members of the scientific community.
O’Regan and Grätzel  have discussed dye-sensitized solar cells (DSSC), a viable and promising technology which have low-cost production and high power conversion efficiency [141–148]. To build an efficient system of the solar cell is necessary [149–152] three components: (1) dye (light-absorber); (2) a hole transport agent; and (3) an electron-transport agent. Figure 9 shows the schematic representation of components and representative operational principles of DSSC.
A typical DSSC device consists of a dye-sensitizer photoanode (TiO2, anode) and a platinum counter electrode (Pt-coated, cathode) sandwiching an electrolyte that contains a redox mediator (iodine-based or cobalt complexes, redox mediator). Upon light illumination, the photoexcited dye in the LUMO level of sensitizer injects an electron into a conduction band (CB) of TiO2, and then, the resultant oxidized dye is reduced by I− species (or Co2+ complex). The injected electrons move through an external circuit to the platinized counter electrode. Finally, the I− species (or Co2+ complex) is regenerated to produce the I3− species (or Co3+ complex) at the surface of the platinized counter electrode, and the circuit is completed . The efficiency of conversion of light to electric power (η) increases when a light-absorbing the dye, and therefore, the choice of a suitable dye is essential to a high η [127, 144, 153–156].
Despite to the intense absorption band, typical porphyrins have poor light-harvesting ability in the Q bands, being necessary the introduction of a push-pull structure [157–160] and the elongation of porphyrin π-conjugated system into
Porphyrin also can be used as a dye in thin layers on the porous TiO2 film. However, this system results in weak absorption of irradiated light, being essential the development of a way to strongly absorb the light in the dye layer. Gold layer can have been used in these systems due to its surface plasmon resonance (SPR) that offers an enhanced optical field with increased short-circuit current, which can be corroborated by theoretical calculations .
3.2. Porphyrins in catalysis and sensing
The application of metalloporphyrins in bioinorganic chemistry has attracted interest in catalytic reactions. Synthetic metalloporphyrins are mimetic models inspired two heme proteins: cytochrome P450 (biosynthesis and degradation of biomolecules) and peroxidases as lignin peroxidases (degrades the lignin-cell wall). In 1970, Groves et al.  designed the first-generation of metalloporphyrin chlorine (5,10,15,10-tetraphenyl-porphyrinato)iron(III), or [Fe3+TPPCl], activated by iodosylbenzene (PhIO) revealed a catalytic activity in the epoxidation of alkenes and the hydroxylation of alkanes. About 30 years ago, Traylor and Tsuchyia  presented the first synthesis of porphyrins with more stability and more efficient catalytic activity due to the introduction of electronegativity and/or bulky auxiliaries groups such as halogen, nitro or sulfonate at the
We are grateful to FAPESP (2015/17688-0; 2016/15465-7) for the financial support.