A new protocol for the synthesis of new thioaryl-porphyrins derived from 5,10,15,20-tetrakis(pentafluorophenyl)porphyrin: Photophysical evaluation and DNA-binding interactive studies

Article abstract of DOI:10.3390/molecules23102588

A new protocol for the preparation of thioaryl-porphyrins is described. The compounds were prepared from different disulfides employing NaBH₄ as a reducing agent. The methodology allowed the preparation of four different thioaryl-porphyrins in very-good to excellent yields under soft conditions, such as short reaction times and smooth heating. Additionally, the photophysical properties of new compounds were determined and experimental and theoretical DNA interactions were assessed.

Full text of DOI:10.3390/molecules23102588

molecules
Article
A New Protocol for the Synthesis of New
Thioaryl-Porphyrins Derived from
5,10,15,20-Tetrakis(pentafluorophenyl)porphyrin:
Photophysical Evaluation and DNA-Binding
Interactive Studies
Patrícia Foletto 1, Fabiula Correa 1, Luciano Dornelles 1, Bernardo A. Iglesias 2,
* ,
Carolina H. da Silveira 2, Pablo A. Nogara 3, João B. T. da Rocha 3, Maria A. F. Faustino 4
and Oscar E. D. Rodrigues 1,
*
1
Departamento de Química, Universidade Federal de Santa Maria, Santa Maria-RS 97105-900, Brazil;
patriciafoletto@hotmail.com (P.F.); fabiulacorrea11@gmail.com (F.C.); ldornel@gmail.com (L.D.)
Laboratório de Bioinorgânica e Materiais Porfirínicos, Departamento de Química, Universidade Federal de
Santa Maria–UFSM, Santa Maria–RS 97105-900, Brazil; carolinahahndasilveira@gmail.com
Laboratório de Bioquímica Toxicológica, Departamento de Bioquímica e Biologia Molecular,
Univerisidade Federal de Santa Maria, Santa Maria–RS 97105-900, Brazil;
2
3
pbnogara@gmail.com (P.A.N.); jbtrocha@yahoo.com.br (J.B.T.d.R.)
4
QOPNA and Department of Chemistry, University of Aveiro, Aveiro 3810-193, Portugal; faustino@ua.pt
Correspondence: bernardopgq@gmail.com (B.A.I.); rodriguesoed@smail.ufsm.br (O.E.D.R.);
Tel.: +55-55-3220-8761 (B.A.I. & O.E.D.R.)
*
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
Academic Editors: M. Graça P. M. S. Neves, M. Amparo F. Faustino and Nuno M. M. Moura
Received: 12 September 2018; Accepted: 7 October 2018; Published: 10 October 2018
ꢀꢁꢂꢃꢄꢅꢆ
Abstract: A new protocol for the preparation of thioaryl-porphyrins is described. The compounds
were prepared from different disulfides employing NaBH4 as a reducing agent. The methodology
allowed the preparation of four different thioaryl-porphyrins in very-good to excellent yields under
soft conditions, such as short reaction times and smooth heating. Additionally, the photophysical
properties of new compounds were determined and experimental and theoretical DNA interactions
were assessed.
Keywords: thioaryl-porphyrins; disulfides; DNA interaction; photophysical characterization
1. Introduction
Porphyrins are a useful class of aromatic macrocycles. These compounds have diverse applications,
including medicinal [1], electronic devices [2], energy conversion [3], catalysis [4], and others [5–7].
The range of applications for porphyrins can be attributed to some features observed in these molecules,
including invariable planar shapes, effective absorption and emission, and high stability under
different hazardous conditions [
in biomedical devices can be highlighted as one of their most prominent features. Porphyrins show
photoactivity in some neoplastic diseases [12 17] and can be used as antimicrobial agents [18 21].
8–11]. Despite the numerous applications for porphyrins, their use
–
–
The most notable behavior observed in porphyrins to achieve these applications is their ability
to generate singlet oxygen species (1O2) [22]. This process initially involves porphyrin energy
absorption and formation of a triplet-excited state. Following this, a transfer of energy from the
1
excited porphyrin to molecular oxygen affords the cytotoxic O2 species [23
–
28]. In this context,
modulating physicochemical parameters in porphyrins to make them more tunable for specific
applications is an exciting and promising field of study. In this context, thioaryl-porphyrins derived
Molecules 2018, 23, 2588; doi:10.3390/molecules23102588
www.mdpi.com/journal/molecules

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from 5,10,15,20-tetrakis(pentafluorophenyl)porphyrin (TPPF20) are a class of extensively documented
porphyrins that have sulfur atoms in their structures. Generally, they are obtained via thiols with
high yields and require either long reaction periods, high temperatures or react only with porphyrin
complexed with certain metals, such as Zn(II) and Mn(III) [10,29–31].
Based on this, this study aims to describe a new methodology to prepare thioaryl-porphyrins via
a reductive cleavage of disulfides in the presence of TPPF20. For this new class of thioaryl-porphyrins,
the photophysical parameters were evaluated as well as the ct-DNA interactions by spectroscopic
methods (Scheme 1).
Scheme 1. Synthesis of thioaryl-porphyrins 3a–d.
2. Results and Discussion
Diphenyl disulfide and TPPF20 were used as standard to prepare compound 3a and to optimize
the reactional conditions. Initially, TPPF20 (10
µmol; 10 mg), diphenyl disulfide (80
µmol; 17.4 mg),
THF (7 mL), EtO◦H (3 mL), and NaBH4 (180
µmol; 6.8 mg) were added to a reaction flask. The system
was stirred at 50 C and the reaction monitored by thin layer chromatography (TLC) for 15 min. In this
case, the respective thioaryl-porphyrin 3a was obtained in 84% yield. In order to find the best reactional
condition, disulfide variation was evaluated, while keeping the reaction times. When we reduced the
amount of diphenyl disulfide to 40 µmol (8.7 mg), the respective compound 3a was obtained in 70%
yield. Additionally, the effect of time was studied. In this case, when the reaction was carried out in
one hour, it afforded thioaryl-porphyrin 3a in 77% yield. Moreover, decreasing the reaction time to five
minutes allowed the preparation of compound 3a in 53% yield. After optimization, the best reaction
was achieved by using 80 µmol of diphenyl disulfide for 15 min at 50 ◦C.
With the optimal reactional condition established, the versatility of the protocol was explored
using different diaryldisulfides, containing either activating or deactivating groups attached to the
aromatic ring (Table 1).
The compounds were obtained in very-good to excellent yields for all disulfides used (Table 1).
Despite this, the activating groups attached to the aromatic ring in the disulfide portion afforded better
yields compared to the deactivating ones. For instance, the activating methyl and amine groups in
compounds 3b and 3d (Table 1, Entries
respectively. The presence of a chlorine group attached to the aromatic ring decreased the yield to 82%
(Entry ). This behavior may be explained by the higher nucleophilicity of the thiolates with activating,
instead of deactivating, groups attached to the aromatic ring in the disulfides moieties.
2 and 4) afforded thioaryl-porphyrins with 92 and 93% yields,
3

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Table 1. Preparation of thioaryl-porphyrin 3a–d.
Entry
Product
Yield (%) a
1
84
3a
2
92
3b
3
82
3c
4
93
3d
a
Yields are related to isolated and purified products.

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2.1. General Absorption and Emission Properties of Thioaryl-Porphyrins 3a–d
Porphyrins 3a
at about 417 nm and four vibronic Q band transitions at 508–652 nm (Figure 1). All porphyrins had
about the same molar absorptivity (log ; Table 2), which is in agreement with the molecular structures.
–
d
in chloroform solution show a Soret band transition (π → π* macrocycle ring)
ε
Moreover, it seems that the aryl-sulfur electron-withdrawing or -donating moiety does not change the
band position or peak magnitude, and therefore, it is very likely that it was overlapped by the Soret
band intensity.
Figure 1. Normalized UV-vis absorption spectra of thioaryl-porphyrins 3a–d containing different
substituent groups in CHCl3 solutions.
The emission spectra analysis of thioaryl-porphyrins 3a
–d dissolved in dry chloroform solution
(λ
exc
= 418 nm) are shown in Figure 2 and Table 2. The fluorescence emission quantum yields (Φf)
for sulfur-derivatives were estimated from the reference 5,10,15,20-tetraphenylporphyrin (TPP) by
comparative method. The fluorescence quantum yield of molecules indicates the capacity of an
excited compound (in the first excited state) to return to the electronic ground state by photon
emission. This process depends on the electronic molecular structure, solvent interaction type,
and stereochemistry. The values of fluorescence quantum yields were determined at an optical density
(OD) in the range 0.01–0.03. By inserting the aryl-sulfur units with different electronic groups at the
para-position of the meso-aryl moieties, the fluorescence quantum yield decreased when compared
to the TPP standard. This may be explained by the presence of the halogen atoms in the meso-aryl
moieties [32]. Moreover, the spin-orbit coupling factor of the halogen atoms decreased radiative
channels and increased non-radiative channel processes [32–34].
Figure 2. Emission spectra of porphyrin derivatives (excitation at
λ
exc
= 418 nm) in argon saturated
CHCl3 solutions.

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Table 2. Absorption and emission data of porphyrin derivatives 3a–d.
−1
a
c
Emission (nm) b
Porphyrin
nm, λ (log ε; M−1cm
)
Φf
3a
3b
3c
3d
417 (5.00), 509 (3.81), 542 (3.00), 585 (3.30), 648 (2.60)
417 (5.04), 509 (3.85), 540 (3.04), 585 (3.34), 647 (2.65)
418 (5.02), 508 (3.86), 542 (3.08), 585 (3.36), 652 (2.62)
418 (5.07), 509 (3.96), 543 (3.30), 584 (3.52), 646 (2.69)
648, 710
648, 710
652, 710
649, 710
0.03
0.01
0.02
0.01
a
Measured in chloroform ([ ] = 10−5 M range); b Measured in dry chloroform solution ([ ] = 2.0
×
10−7 M) at 298 K
(λexc = 418 nm); c TPP in DCM as standard (Φf = 0.15) [35].
2.2. Singlet Oxygen Generation (1O2) Experiments
The ability of porphyrins 3a–d
to produce 1O2 was monitored using 1,3-diphenylisobenzofuran
(DPBF) in aprotic solvent (DMF) [36]. The DPBF photo-oxidation method has been widely used to
quantitatively analyze singlet oxygen production because the reaction product (1,2-dibenzoylbenzene)
does not absorb in the visible region. In this assay, changes in DPBF absorbance are directly related to
the amount of 1O2 generated [37]. This can be observed in Figure 3, in which the first-order kinetic
profile of DPBF photo-oxidation in the presence of thioaryl-porphyrin 3a was monitored at 415 nm
during irradiation with a red-light LED array system (
important parameters in which to evaluate the photodynamic potential of a photosensitizer is the
production of singlet oxygen, ( ∆), which is one of the most important reactive oxygen species (ROS)
in photophysical and photochemical processes [38]. In this study, the singlet oxygen quantum yield
of porphyrins 3a was determined, and the values are presented in Table 3. As observed in Table 3,
the ∆ found for compound 3a is close to the standard TPP and porphyrin in several solvents [39 41].
In the case of porphyrins 3b , which have S-aryl units with different substituents ( :4-CH3, :4-Cl,
:2-NH2), the observed values are smaller than TPP (Φs∆td = 0.66) [38
42], although they still displayed
λ = 635 nm) in DMF solution. One of the
Φ
–
d
Φ
1
–
–
d
b
c
d
,
an ability to generate singlet oxygen. This behavior could be attributed to electronic deactivation
pathways of the excited state due to the presence of the substituents on the thioaryl moieties. Although
the ability of sulfur-porphyrin derivatives to generate 1O2 is, in general, lower than the TPP or the
starting porphyrin 1, all the thioaryl derivatives, after being exposed to red light in the presence of
oxygen, demonstrate potential for photodynamic therapy (PDT) applications.
Figure 3. First-order kinetic graphical profile of photodegradation of 1,3-diphenylisobenzofuran (DPBF)
by irradiation with LED array system (λ = 635 nm) in the presence of thioaryl-porphyrin 3a.
Table 3. Singlet oxygen quantum yields of thioaryl-porphyrins 3a–d.
Porphyrin
Φ∆
3a
3b
3c
0.67
0.10
0.11
3d
TPP *
1
0.14
0.66
0.70 a [39]; 0.80 b [40], 0.60 c [41]
b
* As standard in DMF solution.; a in benzene. in dichloromethane; c in toluene.

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2.3. Biomolecule Interactive Studies
2.3.1. DNA-Binding Assays by Absorption and Emission Analysis
The interaction of thioaryl-porphyrins 3a–d with ct-DNA has also been studied by UV-vis
absorption spectroscopy at the 300–800 nm range in DMSO (1%)/Tris-HCl buffer solution mixture at
pH 7.4. Thioaryl-porphyrin derivatives interact with DNA and decrease the transition band at a visible
range (Soret band). The effect of different ct-DNA concentrations on the Soret and Q-band transitions
in the absorption spectrum of compound 3a (as an example) is presented in Figure 4.
Figure 4. UV-vis titration absorption spectra of thioaryl-porphyrin 3a in a DMSO/Tris-HCl buffer
(pH 7.4) mixture. The ct-DNA concentration ranged from 0 to 100 µM. The insert graph shows the plot
of [DNA]/(ε − ε ) versus [DNA].
a
f
In general, upon interaction with the ct-DNA concentration, porphyrin derivatives 3a
distinctive changes (slight hypochromicity; H%) in the UV-vis absorption electronic spectra (Table 4).
The addition of various ct-DNA concentrations (0–100 M) decreased Soret band intensity. No red
–d revealed
µ
shift was observed in any case, which may indicate the non-observed electrostatic interaction of the
porphyrin molecules and nucleic acids (Figure 4; Table 4). Furthermore, the changes in intensity of
the π→π* Soret transition may be due to the interaction of the aromatic structure of the tetrapyrrolic
derivatives, peripheral groups, or both, which is likely because of H-bonding interactions with the
DNA nucleobases. This effect is probably caused by the presence of the π-density macrocycle moiety
in the structure that may interact with DNA via hydrophobic interactions, as previously reported for
some cases of porphyrin derivatives, and possibly by H-bonding interactions [32,43].
Table 4. DNA-binding data of thioaryl-porphyrin derivatives 3a–d.
Absorption
∆λ (nm) b
Emission
Porphyrin
H(%) a
Kb (M
)
KSV (M
−1
c
−1
)
e
−1
f
Q(%) d
kq (s−1M
)
2.08 × 106
1.27 × 106
0.76 × 106
2.86 × 106
4.92 × 103
3.30 × 102
2.66 × 102
6.57 × 103
2.14 × 1012
1.43 × 1011
1.15 × 1012
2.85 × 1012
3a
3b
3c
7.65
4.72
3.22
6.31
0.0
0.0
0.0
0.0
32.58
3.60
21.28
39.56
3d
a
H(%) = (Absinitial
−
Absfinal)/(Absinitial
)
×
100 (at Soret band); b ∆λ(nm) = λfinal
–
λinitial (at Soret band); c Binding
constant by UV-vis ct-DNA analysis; d Q(%) = (Emissioninitial
−
Emissionfinal)/(Emissioninitial
)
×
100; e Stern-Volmer
quenching ethidium bromide-DNA (EB-DNA) constant by emission spectra; f Stern-Volmer rate quenching EB-DNA
constant by emission analysis.

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The constant binding values (Kb) of the thioaryl-porphyrins were calculated using Equation (2)
(see ESI) (Table 4). In this study, porphyrin derivatives containing S-aryl units demonstrated stronger
binding to ct-DNA (Kb ~106 M−1), following the increasing order of Kb data: 3c
<
3b
< 3a < 3d.
All DNA UV-vis titration spectra of thioaryl-porphyrins 3b–d are listed in the supporting information
(Figures S9–S11).
Competitive-binding assays using the well-known quenching fluorescence method experiment to
determine the displacement of the intercalating ethidium bromide (EB) from ct-DNA may provide
further confirmation of the binding affinity of the compounds. Emission fluorescence spectra were
monitored as increasing concentrations of porphyrins were added by titration to a fixed ct-DA
concentration pre-treated with EB (Figure 5).
Figure 5. Emission fluorescence spectra of ethidium bromide (EB) bound to ct-DNA in the presence of
porphyrin 3d in a DMSO/Tris-HCl buffer mixture at
λ
exc
= 510 nm. The arrow indicates the changes in
fluorescence intensities at increasing sample concentrations. The insert graph shows the plot of F0/F
versus [ct-DNA].
When thioaryl-porphyrin derivatives were added to the DNA pre-treated with EB, the DNA-induced
emission intensity of EB decreased (Figure 5). The EB-DNA interaction with porphyrin 3d showed strong
emission at λem = 644 nm, and, when excited, at λexc = 510 nm, in addition to also depicting the emission
spectra of EB bound to ct-DNA in both the absence and presence of the porphyrin.
These results demonstrate a quenching of the fluorescence intensity of the EB-DNA adduct
following the addition of increasing concentrations of porphyrin compounds (Figure 5). This spectral
behavior may be attributed to the competition of the porphyrin moiety with the EB intercalator over
binding to the DNA structure. In this context, the KSV values suggest the competition mode of
EB-binding. Moreover, the higher values observed for the quenching constant rate (kq) indicated a
static interaction between the porphyrins and DNA (Table 4).
The inset graphs in Figure 5 show the Stern-Volmer plot, which was obtained as the relationship
between F0/F and ct-DNA concentrations. The quenching Stern-Volmer constant (KSV) and quenching
constant rate (kq) values are presented in Table 4. Moreover, EB-DNA emission spectra of derivatives
3a–c are listed in the supporting information section (Figures S12–S14).
2.3.2. DNA Molecular Docking with Thioaryl-Porphyrins 3a–d
A molecular docking simulation was carried out in order to better understand the interactions of
compounds 3a–d with DNA. The molecular docking with DNA showed that thioaryl-porphyrin
derivatives interact in the minor groove region with a very similar binding pose (Figure 6).
All molecules bind in the region between the nucleoside residues deoxyadenosine-7 (dG-7),
deoxythymidine-8 (dT-8), deoxycytidine-9 (dC-9) from the DNA chain A, deoxyadenosine-20 (dG-20),

Molecules 2018, 23, 2588
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deoxycytidine-21 (dC-21) and deoxyguanosine-22 (dG-22) from DNA chain B (Figure 6, left side).
In fact, some studies have even indicated that thioaryl-porphyrin hybrids can bind to the minor groove
of DNA [44,45].
Figure 6. Overview of the interactions between DNA and compounds 3a–d. Both compounds
interact in the minor groove region of the DNA. The dotted lines represent the respective
interactions: green indicates H-bonds; orange represents the π-anion interactions; light blue indicates
carbon-hydrogen bonds. Rings in red, blue, pink, and green (in DNA) indicate deoxyadenosine (dG),
deoxythymidine (dT), deoxycytidine (dC), and deoxyguanosine (dG), respectively. The distances of the
interactions are in Å.
In general, the compounds showed electrostatic
groups (from DNA) and the pyrrolic and aryl ring from compounds 3a
π
-anion interactions between the phosphate
, in addition to H-bonds
–
d
between the fluorine group and an amino moiety from the DNA bases. These observations indicate that
the substituent groups do not significantly interfere in the interactions, despite compound 3d (which
possesses the ortho-amino group) presenting more H-bonds with the DNA. In addition, we observed
the importance of the carbon-hydrogen bond with the fluorine moiety (C-H· · · F-C) [46
an interaction that stabilizes the thioaryl-porphyrins-DNA adduct. The predicted theoretical
thermodynamic data ( Gbind) indicated that all the thioaryl-porphyrin derivatives present spontaneous
interaction with DNA fragments (3a 8.8 kcal/mol); 3b 9.3 kcal/mol); 3c 9.3 kcal/mol);
3d 8.8 kcal/mol)). This is probably due to the steric hindrance of the thioaryl-porphyrin derivatives
–49] as
∆
(
−
(
−
(
−
(
−
since they bind to the minor groove of DNA and do not intercalate [49].
3. Materials and Methods
Chemistry: Hydrogen nuclear magnetic resonance (1H-NMR) spectra were obtained on a Bruker
Avance III spectrometer, that operate on the frequency of 600 MHZ to hydrogen, at the Universidade
Federal de Santa Maria. Spectra were recorded in CDCl3 solutions. Chemical shifts are reported in
parts per million, referenced to the solvent peak of TMS. Data are reported as follows: chemical shift
(d), multiplicity (s = singlet, d = doublet, dd = double doublet, t = triplet, m = multiplet), and coupling
constant (J) in hertz and integrated intensity. Fluor-19 nuclear magnetic resonance (19F) spectra were
obtained at 565 MHz. Spectra were recorded in CDCl3 solutions and C6F6 as external reference.
High resolution mass spectra: Samples were diluted in methanol, containing 100 µL of 200 mM
NH4OH. Analyses were performed by infusion mode in an ACQUITYTMUPLC system from Waters
Corp. (Milford, MA, USA) equipped with sampler manager and quadrupole time of flight (Q-Tof) MS
detector. The Q-Tof Xevo G2 mass spectrometer was equipped with an electrospray ionization source
(ESI). Detections were performed in positive ion mode (ESI+) and resolution mode. Optimized MS

Molecules 2018, 23, 2588
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conditions were: capillary voltage 2.50 kV, cone volta◦ge 112 V, extractor cone 4.5 V, desolvation gas
◦
500 L/h, cone gas 10 L/h, desolvation temperature 400 C, and source temperature 150 C. Acquisition
mass range was monitored from 50 to 1800 Da. System control and data acquisition were performed
using MassLynx V 4.1 software.
General Procedure for the Synthesis 3a–d
In a Schlenk tube under an argon atmosphere, 0.08 mmol of the respective diaryldisulfide,
THF (7 mL), sodium borohydride (180
TPP-F20 (10
µ
mol; 6.8 mg), and ethanol (3 mL) were added. After 1 min,
◦
µ
mol; 10 mg) 1 was added, and the resulting mixture was stirred at 50 C for 15 min.
The reaction was quenched with 10 mL of water, and the aqueous layer was extracted with CH2Cl2.
The combined organic extracts were dried over MgSO4, filtered and evaporated to dryness. The crude
products were purified in a silica gel TLC for chromatographic purification, using hexane–ethylacetate
(70:20) as the eluent, affording the pure porphyrin 3a–d.
5,10,15,20-tetrakis[4-(phenylthio)-2,3,5,6-tetrafluorophenyl]porphyrin (3a). Physical state: purple solid.
Yield: 10.9 mg, 84%. 1H-NMR (600 MHz, CDCl3)
δ 8.91 (s, 8H), 7.70 (d, J = 6 Hz, 8H), 7.41–7.49
(m, 12H),
F ortho),
−
2.85 (s, 2H) ppm. 19F-NMR (565 MHz, CDCl3) δ −132.87 (dd, J1 = 22.6, J2 = 11.3 Hz,
−
136.29 (dd, J1 = 22.6, J2 = 11.3 Hz, F meta) ppm. HRMS-ESI: m/z calcd to to C68H30F16N4S4
[M + H]+; 1335.1176 found:1335.1223.
5,10,15,20-tetrakis[-(4-methylphenylthio)-2,3,5,6-tetrafluorophenyl]porphyrin (3b). Physical state: purple
solid. Yield: 12 mg, 92%. 1H-NMR (600 MHz, CDCl3)
δ 8.90 (s, 8H), 7.65 (d, J = 6 Hz, 8H), 7.29
(d, J = 6 Hz, 8H), 2.44 (s, 12H),
−
2.91 (s, 2H). 19F-NMR (565 MHz, CDCl3) δ −133.28 (dd, J1 = 28.2,
J2 = 11.3 Hz, F ortho),
−
136.49 (dd, J1 = 28.2, J2 = 11.3 Hz, F meta) ppm. HRMS-ESI: m/z calcd to
C72H38F16N4S4 [M + H]+; 1391.1802 found: 1391.1873.
5,10,15,20-tetrakis[4-(4-chlorophenylthio)-2,3,5,6-tetrafluorophenyl]porphyrin (3c). Physical state: purple
solid. Yield: 10.7 mg, 82%. 1H-NMR (600 MHz, CDCl3)
δ 8.90 (s, 8H), 7.66 (d, J = 6 Hz, 8H), 7.47
(d, J = 6 Hz, 8H),
−
2.89 (s, 1H). 19F-NMR (565 MHz, CDCl3) δ −132.80 (dd, J1 = 22.6, J2 = 11.3 Hz,
F ortho),
−
135.90 (dd, J1 = 22.6, J2 = 11.3 Hz, F meta) ppm. HRMS-ESI: m/z calcd to C68H26Cl4F16N4S4
[M + H]+; 1472.9588 found: 1472.9628.
5,10,15,20-tetrakis[4-(2-aminophenylthio)-2,3,5,6-tetrafluorophenyl]porphyrin (3d). Physical state: purple
1
solid. Yield: 12.9 mg, 93%. H-NMR (600 MHz, CDCl3)
δ 8.86 (s, 8H), 7.83–7.81 (m, 4H), 7.32–7.29
(m, 4H), 6.88–6.83 (m, 8H), 4.68 (s, 8H)
−
2.96 (s, 2H). 19F-NMR (565 MHz, CDCl3) δ −133.78 (dd,
J1 = 28.2, J2 = 11.3 Hz, F ortho),
−
136.53 (dd, J1 = 28.2, J2 = 11.3 Hz, F meta) ppm. HRMS-ESI: m/z calcd
to C68H34F16N8S4 [M + H]+; 1395.1612 found: 1395.1611.
4. Conclusions
The synthesis of thioaryl-porphyrins using a new synthetic protocol was disclosed.
The methodology enabled the preparation of four porphyrins in very-good to excellent yields under
soft conditions. The new compounds presented good photophysical properties to be considered as
photosensitizers for photodynamic therapy. Additionally, experimental and theoretical DNA interactive
assays were performed, showing an effective interaction between thioaryl-porphyrin hybrids and DNA.
Supplementary Materials: The following are available online. Experimental procedures, characterization of
compounds, DNA UV-vis absorption spectra, EB DNA emission fluorescence spectra.
Author Contributions: P.F., F.C., L.D., M.A.F.F. and O.E.D.R. designed and developed the synthesis of the
thioaryl-porphyrins. B.A.I. and C.H.d.S. performed the photophysical evaluations. P.A.N. and J.B.T.d.R. performed
the docking studies.

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Funding: The authors gratefully acknowledge CAPES, CNPq (Ed. Universal 400791/2016-1, Produtividade em
Pesquisa-303387/2015-7, Pesquisador visitante-401397/2014-9).
Acknowledgments: The authors gratefully acknowledge CAPES and CNPq. Thanks are also due to the University
of Aveiro, to FCT/MEC for the financial support of QOPNA research Unit (FCT UID/QUI/00062/2013), through
national funds and when applicable co-financed by the FEDER, within the PT2020 Partnership Agreement and
“Compete” 2020, and also to the Portuguese NMR Network.
Conflicts of Interest: The authors declare no conflict of interest.
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