Synthesis and characterization of new porphyrin/4-quinolone conjugates

Article abstract of DOI:10.1016/j.tet.2011.07.025

New porphyrin/4-quinolone conjugates were synthesized from the Suzuki-Miyaura coupling reaction of a β-borylated porphyrin with bromo-4-quinolones containing N-ethyl and N-d-ribofuranosyl substituents. The use of electrospray ionization tandem mass spectrometry showed important information about the fragmentation pathways of the new compounds. It was possible to distinguish between those compounds with the porphyrin moiety linked at the 6-position of the quinolone unit from their 7-substituted isomers. The new compounds showed to be good singlet oxygen generators.

Full text of DOI:10.1016/j.tet.2011.07.025

Tetrahedron 67 (2011) 7336e7342
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis and characterization of new porphyrin/4-quinolone conjugates
a
b
a
a,
*
ꢀ
Ana T.P.C. Gomes , Anna C. Cunha , Maria do Rosario M. Domingues , Maria G.P.M.S. Neves
,
ꢀ a
a
b
b
b
Augusto C. Tome , Artur M.S. Silva , Fernanda da C. Santos , Maria C.B.V. Souza , Vitor F. Ferreira ,
a,
*
ꢀ
Jose A.S. Cavaleiro
a University of Aveiro, Department of Chemistry and QOPNA, 3810-193 Aveiro, Portugal
ˇ
b
ꢀ
Universidade Federal Fluminense, Departamento de Química Organica, 24020-141 Niteroi, RJ, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 25 May 2011
Received in revised form 8 July 2011
Accepted 12 July 2011
Available online 20 July 2011
New porphyrin/4-quinolone conjugates were synthesized from the SuzukieMiyaura coupling reaction of
a
b-borylated porphyrin with bromo-4-quinolones containing N-ethyl and N-D-ribofuranosyl sub-
stituents. The use of electrospray ionization tandem mass spectrometry showed important information
about the fragmentation pathways of the new compounds. It was possible to distinguish between those
compounds with the porphyrin moiety linked at the 6-position of the quinolone unit from their 7-
substituted isomers. The new compounds showed to be good singlet oxygen generators.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Porphyrin
Quinolones
SuzukieMiyaura coupling
Singlet oxygen
Photosensitizers
1. Introduction
photosensitizer must give rise in high yield to such reactive oxygen
species.
Since a few decades ago several research groups have been
concerned with the establishment of new synthetic methodologies
leading to new porphyrin macrocycles.1 When envisaging synthetic
and reactivity studies to be carried out, chemists might have in
mind potential applications for the new products, mainly in the
biomedical area. Porphyrin derivatives have demonstrated signifi-
cant properties by acting as photosensitizers against cancer cells
and in the treatment of the age-related macular degeneration. Al-
though a few formulations are approved, it is known that new and
better derivatives should become available by synthesis. Structural
requirements of a new potential photosensitizer have to be con-
sidered in a synthetic plan. It is also required for a new synthesized
derivative that it should have adequate photophysical properties to
be used in photodynamic therapy of cancer cells.2,3 This therapy
combines the use of a photosensitizing drug, oxygen and visible
light to produce lethal cytotoxic agents like singlet oxygen (1O2)
and/or other reactive oxygen species, which are responsible for the
destruction of the malignant tissues.4e7 In such way a potential
It is well-known that coupling molecules with well-established
pharmacological activities might be a good strategy to develop new
significant products. In this context, porphyrins linked to other
biologically active molecules, like, e.g., quinolones, can give rise to
new derivatives with potential biological applications. Quinolone
derivatives can themselves act as antimicrobial8,9 and antitumour
agents.10,11 Establishment of synthetic methodologies leading to
porphyrin/quinolone conjugates can then be considered an im-
portant synthetic target. Our group has already reported two dif-
ferent procedures for the functionalization of porphyrins with that
kind of molecules.12,13
This publication reports a new and efficient approach for the
synthesis of novel porphyrin/quinolone conjugates through
a SuzukieMiyaura coupling reaction involving a b-borylated por-
phyrin and four bromo-4-quinolones. The structural characteriza-
tion of the new derivatives has included the use of electrospray
ionization tandem mass spectrometry (ESI-MS/MS). This is a tech-
nique, which can give significant structural information about
porphyrinic compounds;14e17 having in mind the possibility of bi-
ological significance for the new derivatives18 such technique also
allows the monitoring of a drug-related material being used.
* Corresponding authors. Tel.: þ351 234 370 717; fax: þ351 234 370 084; e-mail
addresses: gneves@ua.pt (M.G.P.M.S. Neves), jcavaleiro@ua.pt (J.A.S. Cavaleiro).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.07.025

A.T.P.C. Gomes et al. / Tetrahedron 67 (2011) 7336e7342
7337
The rate of the singlet oxygen (1O2) production by the new
deprotected and demetallated porphyrin/quinolone conjugates
was also evaluated.
The b-bromoporphyrin required for the synthesis of 3 was pre-
pared in good yield by reaction of meso-tetraphenylporphyrin (TPP)
with N-bromosuccinimide in chloroform.22
The SuzukieMiyaura coupling reaction of the b-borylated por-
phyrin 3 with bromo-4-quinolones 2aed was carried out in
a mixture of toluene/DMF using Pd(PPh3)4 as the catalyst and
Cs2CO3 as the base. The reactions were carried out in Schlenk tubes
at 80 ꢀC for 16 h. The workup involved the treatment of the reaction
mixture with an aqueous solution of NaCl, extraction with
dichloromethane, evaporation of the solvent and purification of the
crude residue by column chromatography. The desired products
4aed were obtained in moderate to excellent (50e89%) yields.
Quinolone derivatives 2a and 2b showed to be more reactive
than the ribonucleosides 2c and 2d providing the corresponding
porphyrin/quinolone conjugates 4a and 4b in 89% and 82% yields,
respectively. The conjugates 4c and 4d were isolated in lower yields
(w50%) but nearly 50% of the starting porphyrin 3 was recovered in
both cases. Attempts to improve the outcome of the coupling
process between 3 and 2c or 2d were not successful (e.g., by in-
creasing the reaction times and by increasing the number of
equivalents of the bromoquinolones); this fact might be due to
steric effects caused by the ribofuranosyl group.
2. Results and discussion
2.1. Synthesis of
derivatives
b-substituted porphyrin/quinolone
The required bromo-4-quinolones 2aed were conveniently pre-
pared according to the synthetic strategy shown in Scheme 1. The
reaction of meta- and para-bromoanilines with diethyl ethox-
ymethylenemalonate afforded, after cyclization, the corresponding
derivatives 1a,b.19 Then, treatment of these intermediates with ethyl
bromide in the presence of K2CO3 in DMF provided the N-protected
ethyl 1,4-dihydro-1-ethyl-4-oxoquinoline-3-carboxylates 2a and
2b.20 The synthesis of the protected ribonucleosides ethyl 1,4-
dihydro-1-(2,3,5-tri-O-benzoyl-b-D-ribofuranosyl)-4-oxoquinoline-
3-carboxylates 2c and 2d required the previous silylation of the ap-
propriate bromoquinolones 1a,b with N,O-bis(trimethylsilyl)tri-
fluoroacetamide (BSTFA) containing 1% of trimethylchorosilane
(TMCS), followed by the condensation with 1-O-acetyl-2,3,5-tri-O-
Basic hydrolysis of the ester groups of conjugates 4aed followed
by the demetallation of the porphyrin nucleus under acidic con-
benzoyl-b-D-ribofuranose in acetonitrile using trimethylsilyltri-
fluoromethanesulfonate (TMSOTf) as catalyst.19
Scheme 1. Synthesis of the bromo-4-quinolones 2aed.
The synthesis of the novel porphyrin/quinolone conjugates 4aed
ditions afforded efficiently conjugates 5aed (Scheme 3). The hy-
drolysis of the ester group in 4a and 4b was performed by heating
each compound with a methanolic solution of potassium hydroxide
at 80 ꢀC for 1 h. Using similar reaction conditions, but extending the
is outlined in Scheme 2. The key
b-borylated porphyrin 3 was
obtained by reaction of 2-bromo-5,10,15,20-tetraphenylporphyr-
inatozinc(II) with pinacol borane in the presence of Pd(PPh3)2Cl2.21
Scheme 2. Synthesis of porphyrin 3 and its transformation into products 4aed.

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A.T.P.C. Gomes et al. / Tetrahedron 67 (2011) 7336e7342
Scheme 3. Deprotection and demetallation of porphyrin/quinolone conjugates 4aed.
reaction time to 24 h, allowed the simultaneous hydrolysis of the
ethyl ester groups and the removal of the protecting benzoyl groups
of the ribose moieties in the porphyrin/quinolones 4c and 4d. In all
cases, the reaction mixtures were neutralized with an aqueous
solution of citric acid and extracted with dichloromethane. After
the usual workup, the residues were taken into chloroform and
trifluoroacetic acid (10:1) and, after stirring for 2 min at room
temperature, the resulting green reaction mixtures were neutral-
ized with sodium carbonate. After the workup, pure porphyrin/
quinolone conjugates 5a and 5b were obtained in 99% and 98%
yields, respectively, directly by crystallization while compounds 5c
and 5d (obtained in 88% and 89% yields, respectively) required
purification by preparative TLC using a mixture of CHCl3/MeOH
(1%) as the eluent.
8.70 ppm (J¼2.1 Hz) due to H-50 correlates with the double doublet
at 7.55 ppm (J¼2.1 Hz and J¼8.6 Hz) and consequently it was at-
tributed to the resonance of H-70. Also the correlation of H-70 with
the doublet at 7.08 ppm (J¼8.6 Hz) allowed to assign this signal to
H-80. The singlet at 8.52 ppm was identified as being due to the
resonance of H-20.
A careful analysis of the HMBC spectrum of 4a allowed the
unequivocal assignment of the carbonyl carbon resonances. The
resonance of H-20 correlates with both carbonyl signals at 166.3 and
174.2 ppm. However, the resonance of protons H-50 only correlates
with the signal at 174.2 ppm allowing obviously its assignment to
the C-40 resonance; the other one at 166.3 ppm was assigned to the
ester carbonyl group. The correlation observed between the quartet
at 4.42 ppm and the signal at 166.3 ppm confirms the assignment
of this quartet to the methylene protons resonance of the ester
group.
2.2. Structural characterization
As referred previously, the main difference between 4a and 4b is
given by the resonances of the quinolone moiety. In the case of 4b,
the COSY analysis shows that the doublet at 7.57 ppm (J¼8.1 Hz),
assigned to the resonance of H-60, correlates with the signal of H-50,
that appears under the multiplet at 8.24e8.20 ppm, due to the H-
ortho protons of the 5,10,15-phenyl groups. The resonance of H-80
appears as a singlet at 7.29 ppm and, as in the case of derivative 4a,
the singlet at 8.48 ppm was assigned to the resonance of H-20.
In the case of the porphyrin/ribonucleoside conjugates 4c and
4d, the m/z values 1336.3452 and 1336.3468 [MþH]þ observed for
both isomers in the HRMS-ESIþ spectra confirmed their molecular
formulae. The 1H NMR spectra of these compounds show a more
complex pattern due to presence of the protected ribose unit.
The structures of the new products 4aed and 5aed were
assigned on the basis of their 1H and 13C NMR spectra and their
molecular formulae were confirmed by HRMS. 2D NMR spectra
(COSY, HMBC and HSQC) were also obtained in order to un-
equivocally identify the protons and carbons resonances.
The HRMS-ESIþ of the isomeric porphyrin/quinole conjugates
4a and 4b show molecular ions at the m/z values 920.2574 and
920.2559 [(MþH)þ], confirming the success of the SuzukieMiyaura
coupling of porphyrin 3 with the bromo-4-quinolones 2a and 2b.
The 1H NMR spectra of the two isomers show the same type of
profile, the principal difference being the signals due to the reso-
nances of H-50, H-60/H-70 and H-80 of the quinolone moiety.
In the 1H NMR spectrum of the porphyrin/quinolone conjugate
4a it is possible to identify the two AB spin systems related to the
However, the resonances due to the H-b, meso-phenyl and quino-
lone protons show similar features to the ones observed for the
corresponding porphyrin/quinolone conjugates 4a and 4b. The
COSY spectra were fundamental for the unequivocal assignment of
all sugar protons and of their protecting groups. For instance, for
compound 4c a careful analysis of the COSY correlations allowed t0o0
assign the doublet at 6.39 ppm (J¼5.4 Hz) to the resonance of H-1 ,
the triplets at 6.07 ppm (J¼5.4 Hz) and 5.93 ppm (J¼5.4 Hz) to H-200
and H-300, respectively, and the multiplet at 4.94e4.75 ppm to the
resonance of H-400 and H-500. Considering the proton resonances of
the benzoyl groups, the protons H-2000 appear as two double dou-
blets at 8.11 and 7.97 ppm (J¼1.4 and 7.8 Hz) and a multiplet at
7.15e6.90 ppm, while one H-4000 appears as a triple triplet at
7.56 ppm (J¼1.4 and 6.1 Hz); the others H-4000 and H-3000 appear as
resonances of four b-pyrrolic protons: one at 8.95 and 8.93 ppm
(J¼4.7 Hz) due to H-7 and H-8 and the other at 8.85 and 8.76 ppm
(J¼4.7 Hz) assigned to H-17 and H-18. The two singlets at 8.93 and
8.91 ppm are due to the resonances of the H-12,13 and H-3, re-
spectively. The protons of the meso-phenyl groups appear as two
multiplets, one at 8.23e8.21 ppm due to ortho-protons and the
other at 7.78e7.72 ppm due to the meta- and para-protons. The
protons of the phenyl group nearby the quinolone unit appear as
multiplets at 8.02e7.86 ppm (H-ortho), 7.49e7.48 ppm (H-meta)
and at 7.11e7.09 ppm (H-para).
The unequivocal assignments of the quinolone proton reso-
nances were based on COSY correlations. Therefore, the doublet at

A.T.P.C. Gomes et al. / Tetrahedron 67 (2011) 7336e7342
7339
a multiplet at 7.43e7.34 ppm together with the resonances of H-70
and H-80 of the quinolone moiety. The correlation of these signals
with the triple triplet at 7.56 ppm (J¼1.2, 1.4 and 6.1 Hz) and with
the multiplet at 7.43e7.34 ppm allowed to assign these signals to
the resonances of, respectively, two and four H-3000. Finally the
signals of the three H-400 appear also in the multiplet at
7.43e7.34 ppm together with the resonance of H-70 and H-80 of the
quinolone moiety.
In the case of compounds 4a and 4b the MS/MS spectra (Table 1
and Fig. S1) show that the major product ion (100% relative abun-
dance) is due to the loss of CH3CH2OH (ꢁ46 Da) from the ethox-
ycarbonyl group. Minor ions formed by loss of CH2]CH2 at m/z
892.4 and by the combined loss of CH2]CH2 and CH3CH2OH, at m/z
846.4, are also detected for both isomers. But in case of 4a the
combined loss of CH2]CH2 and CH3CH2CO2H is responsible for
a minor product ion at m/z 818.4 (the proposed structures of mo-
lecular ions [MþH]þ and main fragmentation ions of compounds 4a
and 4b are shown in Scheme S1, SD).
Based on the heteronuclear (1He13C) HSQC and HMBC spectra it
was possible to identify the resonances of the carbonyl and aliphatic
carbons. For example, for compound 4c the carbonyl carbons were
identified as the signals at 174.3 (C-40),166.0 (C]O of the ethyl ester
group) and 165.1, 165.0 and 164.6 ppm (carbonyl carbon of the
benzoyl groups). In the aliphatic region of this spectrum the carbon
resonances of C-100 (91.2 ppm); C-200 (74.3 ppm), C-300 (70.3 ppm), C-
400 and C-500 (80.3 and 63.0 ppm) as well the carbon resonances of the
ethyl group (60.4 and 14.3 ppm) can be found. It is important to note
that HMBC correlations allow us to confirm the structure of the
compound 4c, showing correlations between all the subunits of this
molecule (Fig. 1). The resonance of H-100 of the ribose moiety cor-
relates with C-20 of the quinolone unit at 131.9 ppm and that due to
H-200 correlates with the carbonyl group of the benzoyl group at
165.1 ppm. The resonance of H-50 of the quinolone unit correlates
with the C-2 of the porphyrin moiety at 135.5 ppm.
Table 1
Main fragment ions observed in the ESI-MS/MS spectra of the [MþH]þ ions of
porphyrin/quinolone conjugates 4aed and their relative abundances (RA%)
Compound
4a
4b
4c
4d
[MþH]þ
920.5
920.5
1336.3
d
1336.3
d
eCH2]CH2
892.4 (<5)
874.4 (100)
846.4 (20)
892.4 (<5)
874.4 (100)
846.2 (<5)
eHOCH2CH3
eCH2]CH2 and
eCH3CH2OH
eCH3CH2CO2H and
eCH2]CH2
d
d
d
d
818.4 (<5)
d
d
d
e(SugareH)
eC56H37N5O3Zn
892.4 (10)
445.2 (100)
892.5 (<5)
445.2 (100)
Interestingly, in the case of porphyrin/ribonucleoside de-
rivatives 4c and 4d the major fragmentation pathway is due to the
loss of the subunits porphyrin/quinolone (ꢁ890 Da, loss of
C56H37N5O3Zn) with the formation of abundant product ions at m/z
445.2 (the proposed structures of molecular ions [MþH]þ and main
fragmentation ions of compounds 4c and 4d are shown in Scheme
S2, SD). In this case, the charge is retained in the sugar unit. The
complementary cleavage of the N-sugar bond [loss of the ribose
moiety (ꢁ444 Da, C26H20O7) and the charge retained in the por-
phyrinic unit] is responsible for the minor ions detected at m/z
892.5 for both isomers.
Although the fragmentation pathways for each pair of isomeric
porphyrin/quinolone conjugates 4a/4b and 4c/4d are similar, the
relative abundance of certain minor fragment ions is different and
this suggests that the position of the linkage porphyrin/quinolone
affects the stability of the product ions. For instance, for derivatives
4a/4b the combined loss of CH2]CH2 and CH3CH2OH (m/z 846.4)
occurs with higher relative abundance for derivative 4a (porphyrin
moiety linked at C-6 position of the quinolone unit) than for 4b
(analogue linkage at C-7) as indicated in Table 1. A similar situation
occurs when compounds 4c and 4d are compared; the relative
abundance of the minor fragment due to the loss of the sugar unit
(m/z 892.4) is higher for 4c than for 4d.
Considering now the results obtained for the deprotected and
demetallated porphyrin/quinolone conjugates 5aed, shown in
Table 2 and Fig. S2, it is possible to observe a facile decarboxylation
of the quinolone moiety for all the compounds. In fact, all spectra
show that the major product ion is due to the loss of CO2 (ꢁ44 Da).
This fragmentation pathway is typical of compounds with a car-
boxylic group, as observed for porphyrin/amino acid conjugates.15
Minor ions due to the loss of the quinolone unit (C12H10NO3) and
to the combined loss of CO2 with CH2]CH2 are detected, re-
spectively, at m/z 615.3 and at m/z 758.4 for compound 5a (the
proposed structures of molecular ions [MþH]þ and main frag-
mentation ions of compounds 5a and 5b are shown in SD, Scheme
S3-A). For compound 5b only a minor ion at m/z 812.5 due to the
loss of H2O is detected. Again, for derivatives 5a and 5b the position
of the linkage porphyrin/quinolone seems to affect slightly the
fragmentation pattern and the stability of the minor product ions
formed.
Fig. 1. Main HMBC correlations of compound 4c.
For the conjugate 4d the chemical shifts of the protons and
carbons of the ribonucleoside unit are similar to the ones described
for 4c. Presumably due to an aggregation effect, the corresponding
spectrum does not show the same resolution as it was observed for
compound 4c, even when other deuterated solvents (DMF, THF,
DMSO, TFA) and also different temperatures were tested.
The most important features of the 1H NMR spectra of conju-
gates 5aed are the following: (i) the presence of characteristic
signals at
d
wꢁ2.50 due to the resonances of the inner NeH pro-
tons; (ii) the absence of the signals due to the resonances of the
CO2CH2CH3 group, and in the case of compounds 5c and 5d, the
absence of signals due to the benzoyl groups. These spectra confirm
the success of the demetallation and deprotection steps.
The HRMS-ESIþ spectra of the isomeric porphyrin/quinolone
conjugates 5a, 5b, 5c and 5d, with molecular ions [MþH]þ at m/z
830.3097, 830.3095, 934.3192 and 934.3206, respectively, are also
in agreement with the corresponding molecular formulae.
Considering the ESI-MS studies, the spectra of all studied por-
phyrin derivatives 4aed and 5aed, obtained in the positive mode,
show the corresponding protonated molecules [MþH]þ. The ESI-MS/
MSspectraof theseionsshowthatthefragmentationpatternissimilar
for each pair of isomers (Figs. S1 and S2 in Supplementary data).

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A.T.P.C. Gomes et al. / Tetrahedron 67 (2011) 7336e7342
Table 2
100
Main fragment ions observed in the ESI-MS/MS spectra of porphyrin/quinolone
conjugates 5aed and their relative intensities (RA%)
90
80
70
60
50
40
30
20
10
0
Compound
5a
5b
5c
5d
[MþH]þ
830.3
d
830.3
812.5 (<5)
934.3
d
934.3
d
TPP
5a
eH2O
eCO2
786.5 (100) 786.2 (100) 890.5 (100) 890.5 (100)
5b
5c
eCO2eR (CH2]CH2
or sugar)
758.4 (<5)
d
d
758.5 (70)
5d
eC12H10NO3 (quinolone) 615.3 (<5)
eH2O and esugar
d
d
d
d
d
784.4 (5)
784.4 (20)
Interestingly, in the case of porphyrin/ribonucleoside de-
rivatives 5c and 5d the difference between the relative abundance
(RA) of the less abundant fragment ions is considerable. In fact, the
combined loss of CO2 and the sugar unit for 5d is responsible for an
important fragment ion (RA 70%) at m/z 758.5, while for 5c this
fragment shows low relative abundance (<5% RA). The combined
loss of the sugar unit and H2O (ꢁ150 Da), responsible for the ions at
m/z 784.4, is observed for both isomers, but again it occurs with
a higher abundance (20%) than for derivative 5d (5%) (the proposed
structures of molecular ions [MþH]þ and main fragmentation ions
of compounds 5c and 5d, are shown in SD, Scheme S3-B).
0
2
4
6
8
10
12
14
Irradiation Time (min)
Fig. 2. Photodecomposition of DPiBF by singlet oxygen generated by TPP, 5a, 5b, 5c
and 5d after irradiation with white light filtered through a cut-off filter for wavelength
<550 nm (25 mW cmꢁ2).
affording novel porphyrin/quinolone conjugates 4aed. Also it is
possible to prepare b-substituted porphyrin/quinolone conjugates
5aed, in excellent yields, through alkaline hydrolysis of 4aed,
followed by demetallation. The new derivatives have been fully
characterized by NMR and mass spectrometry techniques. The
electrospray tandem mass spectrometry (MS/MS) of derivatives
4aed and 5aed shows several interesting features. Isomeric por-
phyrin/quinolone conjugates 4a,b and 5c,d, as well as their
deprotected forms 5a,b and 5c,d, give rise to similar fragmentation
pathways, confirming their analogous structures. Due to the RA of
some peaks it is possible to distinguish between derivatives with
the porphyrin moiety linked at C-6 of the quinolone unit (4a and
4c) from those derivatives having the porphyrin moiety linked to
the 7-position of the quinolone moiety (4b and 4d). This study gives
important information about the fragmentation pathways of these
derivatives, allowing the possibility of following the metabolic
degradation of a drug with the same structural features.
2.3. Singlet oxygen generation studies
Photodynamic activity is significantly related to the singlet ox-
ygen production (1O2).23 Photosensitizers that form singlet oxygen
are important for photoinduced reaction processes that are re-
sponsible for the destruction of tissues.23,24 In this context, we
decided to determine the photosensitizing properties of com-
pounds 5aed since that might be considered as an extra added-
value to the new products. The capacity to generate singlet oxy-
gen was then qualitatively evaluated by monitoring the photode-
composition of
a singlet oxygen quencher agent, the 1,3-
diphenylisobenzofuran (DPiBF). In this process 1O2 produced by
the photosensitizer reacts with the yellow DPiBF in a [4þ2] cyclo-
addition, affording the colourless ortho-dibenzoylbenzene. Since
DPiBF absorbs at 415 nm, it is possible to follow the capability of the
photosensitizer to generate 1O2 by measuring the absorption decay
at that wavelength.23,25
Singlet oxygen studies show that all the b-substituted porphy-
rin/quinolone conjugates 5aed are better singlet oxygen genera-
tors than TPP and that the efficiency of these compounds to
generate singlet oxygen is affected by the linkage position between
the porphyrin and the quinolone moieties, as well by the N-sub-
stituent of the quinolone group.
Hence, aerated solutions of the porphyrin/quinolone conjugates
5aed and DPiBF (100-fold molar excess) in DMF/H2O (9:1) were
exposed to filtered white light (cut-off <550 nm) while monitoring
the 415 nm absorption of DPBF.25 The results were compared with
those obtained using meso-tetraphenylporphyrin (TPP), a well-
known singlet oxygen generator.26 The obtained results are shown
in Fig. 2. The curves in the graphic represent the % of decay of ab-
sorption of DPiBF versus illumination time; a more pronounced
decay corresponds to a higher rate of singlet oxygen production.
It is evident from Fig. 2 that in all cases a significant photo-
degradation of DPiBF is observed. This indicates that all porphyrin/
quinolone conjugates 5aed demonstrate a photoxidising ability. It
is also evident that all conjugates 5aed are better singlet oxygen
generators than TPP. It is interesting to note that the best singlet
oxygen generators are compounds 5a and 5d. This indicates that
a direct relationship between the position of the porphyrin moiety
in the quinolone (positions 6 or 7) or the type of N-substituent, and
the ability of the conjugates to generate singlet oxygen cannot be
established.
In conclusion, the reaction of bromoquinolones with borylated
porphyrin 3 can be considered as a new synthetic methodology
leading to new porphyrin/quinolone conjugates.
4. Experimental
4.1. General
1H and 13C NMR spectra were recorded on Bruker Avance 300
(300 MHz for 1H and 75 MHz for 13C) and Bruker Avance 500
(500 MHz for 1H and 125 MHz for 13C) spectrometers. CDCl3, CDCl3/
CD3OD or DMSO-d6 were used as solvents and TMS as internal ref-
erence andthe chemical shifts areexpressed in d (ppm). Unequivocal
1H assignments were made using 2D COSY and NOESY experiments
(mixing time of 800 ms), while 13C assignments were made on the
basis of 2D HSQC and HMBC experiments (the delay for long-range
J C/H couplings were optimized for 7 Hz). HRMS were recorded on
a VG AutoSpec M mass spectrometer using CHCl3 as solvent and 3-
nitrobenzyl alcohol (NBA) as matrix. Positive ion ESI mass spectra
and tandem mass spectra were acquired using a Q-TOF 2 instrument
(Micromass, Manchester, UK). The samples for ESI analyses were
3. Conclusions
In this work it is shown that
several bromoquinolone derivatives in a SuzukieMiyaura reaction
b
-borylated porphyrin 3 reacts with
prepared by diluting 1
mL of the porphyrin solutions in chloroform
(w10ꢁ5 M) in 200
mL of methanol. Nitrogen was used as the

A.T.P.C. Gomes et al. / Tetrahedron 67 (2011) 7336e7342
7341
nebulizer gas and argon was used as the collision gas. Samples were
introduced into the mass spectrometer using a flow rate of 10 L/
(CHCl3): lmax (log
3
m
nm; HRMS (ESI) m/z calcd for C58H42N5O3Zn [MþH]þ 920.2579,
min, the needle voltage was set at 3000 V, with the ion source at
80 ꢀC and needle temperature at 150 ꢀC. Cone voltage was 30 V.
Collision-induced decomposition mass spectra (MS/MS) were ac-
quired by selecting the desired precursor ion with the quadrupole
section of the mass spectrometer and using collision energy of
25e40 eV. The UVevis spectra were recorded on an UV-2501 PC
Shimatzu spectrophotometer using CHCl3 as solvent. Flash chro-
matography was carried out using silica gel (230e400 mesh).
Preparative thin-layer chromatography was carried out on
20ꢂ20 cm glass plates coated with silica gel (1 mm thick). Analytical
TLC was carried out on precoated plastic sheets with silica gel
(Merck 60, 0.2 mm thick). Porphyrin 3, 2-(4,4,5,5-tetramethyl-1,3
,2-dioxaborolan-2-yl)-5,10,15,20-tetraphenylporphyrinatozinc(II),
was prepared according to the literature.27
found 920.2559.
4.2.3. 2-[3-Ethoxycarbonyl-1-(2,3,5-tri-O-benzoyl-
yl)-4-oxo-1,4-dihydroquinolin-6-yl]-5,10,15,20-tetraphenylporphyr-
inatozinc(II), 4c. Yield: 51%; 1H NMR (300 MHz, CDCl3)
8.94 and 8,83
(AB, 2H, J¼4.6 Hz, H-7 and H-8), 8.96 (s, 1H, H-3), 8.92 (s, 2H, H-12
and H-13), 8.86 (s,1H, H-20), 8.84 and 8.74 (AB, 2H, J¼4.7 Hz, H-17 and
H-18), 8.57 (d, 1H, J¼2.0 Hz, H-50), 8.26e8.16 (m, 6H, Ho-Ph-5,10,15),
8.11 (dd, 2H, J¼1.4 and 7.8 Hz, H-2000), 7.99e8.03 (m, 2H, Ho-Ph-20),
7.97 (dd, 2H, J¼1.4 and 7.8 Hz, H-2000), 7.77e7.74 (m, 12H, Hm,p-Ph-
5,10,15,20), 7.56 (tt, 2H, J¼1.4 and 6.1 Hz, H-4000), 7.43e7.34 (m, 9H, 6ꢂ
H-3000, H-4000, H-70 and H-80), 7.15e6.90 (m, 2H, H-2000), 6.39 (d, 1H,
J¼5.1 Hz, H-100), 6.07 (t, 1H, J¼5.1 Hz, H-200), 5.93 (t, 1H, J¼5.1 Hz, H-
300), 4.96e4.79 (m, 3H, H-400 and H-500), 4.33e4.14 (m, 1H,
CO2CH2CH3), 1.32 (t, 1H, J¼7.1 Hz, CO2CH2CH3) ppm. 13C NMR
4.2. Coupling reactions of porphyrin 3 with bromoquinolones
(75 MHz, CDCl3) d
174.3 (C-40), 166.0 (CO2CH2CH3), 165.1 (C]O Bz),
2aed. General procedure
165.0 (C]O Bz), 164.6 (C]O Bz), 150.9, 150.5, 150.4, 150.33, 150.30,
150.2, 147.5 (C-20), 146.1, 142.6, 141.1, 135.7, 135.5 (C-2), 134.4 (C-70),
134.1,133.8,133.6,132.6,132.19,132.12,131.9 (C-20),131.5,129.9,129.8,
129.7, 129.2, 128.9 (C-50), 128.7, 128.6, 128.5, 128.4, 128.3, 128.1, 127.5,
127.4, 126.9, 126.5, 121.9, 121.4, 121.0, 120.8, 113.5 (C-80), 91.2 (H-100),
80.3 (H-400 or H-500), 70.5, 70.4, 63.2 (H-400 or H-500), 62.8, 60.9, 29.7,
29.5 (CO2CH2CH3), 14.29 (CO2CH2CH3) ppm. UVevis (CHCl3): lmax
Porphyrin
(33.5 mol), Cs2CO3 (6.5 mg, 19.9
9.6 mol), DMF (0.5 mL) and toluene (1 mL) were brought together
3
(10.0 mg, 12.4
m
mol), bromoquinolones 2aed
m
mmol), Pd(PPh3)4 (11.0 mg,
m
in a 25 mL Schlenk tube. The solvent was degassed by repeated
sonication for 0.5e1 min under reduced pressure. The reaction
mixture was stirred for 16 h at 80 ꢀC, the mixture was quenched
with aq. NaCl and extracted with CH2Cl2. The organic layer was
washed with water, dried (Na2SO4) and concentrated. The residue
was purified by column chromatography using a mixture of tolu-
ene/ethyl acetate as the eluent.
(log
)¼428 (5.35), 558 (4.25), 598 (3.81), 673 (2.89) nm; HRMS (ESI)
4.2.4. 2-[3-Ethoxycarbonyl-1-(2,3,5-tri-O-benzoyl-
1-yl)-4-oxo-1,4-dihydroquinolin-7-yl]-5,10,15,20-tetraphenylporphy-
rinatozinc(II), 4d. Yield: 50%; 1H NMR (300 MHz, DMSO-d6):
8.92
(s, 1H, H-20), 8.81e8.76 (m, 4H,
-H), 8.69 (d, 1H, J¼4.6 Hz, H-17 or
H-18), 8.63e8.58 (m, 2H, -H), 8.23e8.08 (m, 8H, Ho-Ph-5,10,15),
b-D-ribofuranos-
d
4.2.1. 2-(3-Ethoxycarbonyl-1-ethyl-4-oxo-1,4-dihydroquinolin-6-yl)-
b
5,10,15,20-tetraphenylporphyrinatozinc(II), 4a. Yield: 89%; 1H NMR
b
(500 MHz, CDCl3)
d
8.95 and 8.93 (AB, 2H, J¼4.7 Hz, H-7 and H-8),
7.98e7.95 (m, 2H, H-2000), 7.81e7.79 (m, 9H, Hm,p-Ph-5,10,15,20),
7.72e7.70 (m, 2H, H-2000), 7.66e7.55 (m, 9H, 4ꢂ H-3000, 3ꢂ H-4000, H-50
and H-80), 7.40 (t, 2H, J¼7.7 Hz, H3000), 7.09 (t, 2H, J¼7.5 Hz, Hm-Ph-
20), 6.97e6.92 (m, 1H, H-200), 6.77 (br s, 2H, H-2000), 6.54e6.49 (m,
1H, H-100), 6.20e6.06 (m, 1H, Hp-Ph-20), 5.84e5.93 (m, 1H, H-300),
5.01e4.97 (m,1H, H-400), 4.82e4.79 (m, 3H, H-500), 4.19e4.05 (m, 2H,
CO2CH2CH3), 1.22 (t, 3H, J¼7.0 Hz, CO2CH2CH3) ppm. 13C RMN
(125 MHz, DMSO): 172.5 (C-40),165.5 (CO2CH2CH3),164.6 (C]O Bz),
164.2 (C]O Bz), 163.5 (C]O Bz), 149.5, 146.4 (C-20), 142.9, 142.5,
139.3, 134.1, 133.6, 131.6, 129.5, 129.3, 128.9, 128.7, 128.5, 128.1,
127.5, 126.7, 126.5, 120.1, 119.2, 111.5, 88.7, 80.8, 75.1, 70.6, 64.0, 59.8,
8.93 (s, 2H, H-12 and H13), 8.91 (s, 1H, H-3), 8.85 and 8.76 (AB, 2H,
J¼4.7 Hz, H-17 and H-18), 8.70 (d, 1H, J¼2.1 Hz, H-50), 8.52 (s, 1H, H-
20), 8.26e8.17 (m, 6H, Ho-Ph-5,10,15), 8.02e7.86 (m, 2H, Ho-Ph-20),
7.81e7.69 (m, 9H, Hm,p-Ph-5,10,15), 7.50 (dd, 1H, J¼2.1 and 8.6 Hz,
H-70), 7.11e7.06 (m, 2H, Hm-Ph-20), 7.49e7.48 (m, 1H, Hp-Ph-20),
7.08 (d, 1H, J¼8.6 Hz, H-80), 4.42 (q, 2H, J¼7.2 Hz, CO2CH2CH3),
4.28e4.27 (m, 2H, NCH2CH3),1.61 (t, 3H, J¼7.2 Hz, NCH2CH3),1.45 (t,
3H, J¼7.2 Hz, CO2CH2CH3) ppm. 13C NMR (75 MHz, CDCl3)
d 174.2
(C-40), 166.3 (CO2CH2CH3), 151.0, 150.5, 150.4, 150.3, 150.2, 148.3 (C-
20), 147.6, 145.2, 142.65, 142.65, 141.4, 137.0, 136.3, 135.7,134.8 (C-70),
134.4, 134.3, 132.5, 132.2, 132.1, 132.0, 131.5, 131.4, 128.6, 128.38 (C-
50), 128.34, 128.2, 127.5, 127.4, 126.6, 126.8, 126.6, 121.8, 121.7, 121.4,
121.0, 120.8, 114.3 (C-80), 110.9, 60.9 (NCH2CH3), 48.9 (CO2CH2CH3),
14.7 (NCH2CH3), 14.5 (CO2CH2CH3) ppm. UVevis (CHCl3): lmax
13.9 (CO2CH2CH3). UVevis (CHCl3): lmax (log
(4.07), 600 (3.63), 666 (3.18) nm; HRMS (ESI) m/z calcd for
3
C82H58N5O10Zn [MþH]þ 1336.3470, found 1336.3468.
(log
)¼423 (5.47), 511 (3.37), 550 (4.10), 587 (3.32) nm; HRMS (ESI)
4.3. Deprotection and demetallation of porphyrin/quinolone
conjugates 4aed. General procedure
4.2.2. 2-(3-Ethoxycarbonyl-1-ethyl-4-oxo-1,4-dihydroquinolin-7-
A
solution of the porphyrin/quinolone conjugate 4aed
mol) in 1.78 M methanolic potassium hydroxide solution
yl)-5,10,15,20-tetraphenylporphyrinatozinc(II), 4b. Yield: 82%; 1H
(7.5
m
NMR (500 MHz, CDCl3)
d
8.96 and 8.93 (AB, 2H, J¼4.6 Hz, H-7 and
(2.5 mL) and THF/Py (0.5 mL/50 m
L) was stirred at 80 ꢀC for 1 h
H-8), 8.94e8.93 (m, 3H, H-3, H-12 and H-13), 8.87 and 8.78 (AB, 2H,
J¼4.6 Hz, H-17 and H-18), 8.48 (s, 1H, H-20), 8.24e8.20 (m, 7H, Ho-
Ph-5,10,15 and H-50), 7.91e7.84 (m, 2H, Ho-Ph-20), 7.77e7.74 (m,
9H, Hm,p-Ph-5,10,15), 7.57 (d, 1H, J¼8.7 Hz, H-60), 7.29 (s, 1H, H-80),
7.17e6.94 (m, 3H, Hm,p-Ph-20), 4.41 (q, 2H, 7.2 Hz, CO2CH2CH3),
4.26e4.05 (m, 2H, NCH2CH3),1.45 (t, 3H, J¼7.1 Hz, NCH2CH3),1.40 (t,
(compounds 4a,b) or 24 h (compounds 4c,d) in a sealed tube.28 The
resulting solution was neutralized with aqueous solution of citric
acid. The mixture was extracted with chloroform and then the or-
ganic phase was washed with water and dried over Na2SO4. The
solvent was evaporated under reduced pressure to dryness. The
residue was dissolved in CHCl3 (1 mL) and neat TFA (0.1 mL) was
added. This mixture was stirred in the dark at room temperature for
2 min. Chloroform and water were then added and the mixture was
neutralized with aqueous sodium carbonate. The mixture was
extracted with chloroform, the organic phase was washed with
water, dried over Na2SO4 and the solvent was evaporated under
reduced pressure to dryness. Pure porphyrin/quinolone conjugates
3H, J¼7.1 Hz, CO2CH2CH3) ppm. 13C NMR (75 MHz, CDCl3)
d 174.3
(C-40), 166.3 (CO2CH2CH3), 151.0, 150.7, 150.57, 150.53, 150.4, 150.3,
150.2,148.4 (C-20), 147.2,145.1, 142.6, 142.5, 141.3,137.4,135.2,134.4,
134.3, 132.6, 132.3, 132.2, 131.7, 127.54, 127.49, 127.5, 127.2, 126.8,
126.6, 122.1, 121.7, 121.6, 121.2, 120.9, 117.2, 110.7, 60.9 (NCH2CH3),
48.4 (CO2CH2CH3), 14.6 (NCH2CH3), 14.4 (CO2CH2CH3) ppm. UVevis

7342
A.T.P.C. Gomes et al. / Tetrahedron 67 (2011) 7336e7342
5a,b were obtained directly by crystallization of the residue from
chloroform/hexane. The porphyrin/quinolone conjugates 5c,d were
first purified by preparative TLC using CHCl3/MeOH (1%) as the el-
uent and then were crystallized from chloroform/hexane.
compared with those obtained when using 0.5
tetraphenylporphyrin.
mM meso-
Acknowledgements
ˇ
4.3.1. 2-(3-Carboxy-1-ethyl-4-oxo-1,4-dihydroquinolin-6-yl)-
~
Thanks are due to Fundac¸ ao para a Ciencia e a Tecnologia (FCT,
Portugal) and FEDER for funding the Aveiro Organic Chemistry
Research Unit and the Portuguese National NMR network. Thanks
are also due to the collaborative research program FCT-CAPES
(Brazil) for funding this work. One of us (ATPC Gomes) thanks FCT
for her Ph.D. grant (SFRH/BD/38528/2007).
5,10,15,20-tetraphenylporphyrin, 5a. Yield: 99%; 1H NMR (300 MHz,
CDCl3)
d
15.14 (s, 1H, CO2H), 8.87 and 8.84 (AB, 2H, J¼4.7 Hz, H-7
and H-8), 8.83 (s, 1H, H-3), 8.82 (s, 2H, 12 and H-13), 8.80 (s, 1H, H-
20), 8.78 and 8.69 (AB, 2H, J¼4.8 Hz, H-17 and H-18), 8.67 (d,
J¼2.0 Hz, H-50), 8.25e8.20 (m, 6H, Ho-Ph-5,10,15), 7.94e7.92 (m,
2H, Ho-Ph-20), 7.78e7.69 (m, 9H, Hm,p-Ph-5,10,15), 7.55e7.54 (m,
1H, H-70), 7.21 (d, 1H, J¼8.8 Hz, H-80), 7.10e7.06 (m, 3H, Hm,p-Ph-
20), 4.37e4.35 (m, 2H, NCH2CH3), 1.63 (t, 3H, J¼7.1 Hz, NCH2CH3),
Supplementary data
-2.62 (s, 2H, NH) ppm. UVevis (DMF/H2O (9:1)): lmax (log
3
Supporting data associated with this article can be found in the
online version at doi:10.1016/j.tet.2011.07.025.
(5.07), 519 (5.06), 553 (3.86), 595 (3.74), 651(3.61) nm; HRMS (ESI)
m/z calcd for C56H40N5O3 [MþH]þ 830.3126, found 830.3097.
4.3.2. 2-(3-Carboxy-1-ethyl-4-oxo-1,4-dihydroquinolin-7-yl)-
References and notes
5,10,15,20-tetraphenylporphyrin, 5b. Yield: 98%; 1H NMR (300 MHz,
ꢀ
CDCl3)
d
15.15 (s, 1H, CO2H), 8.90 and 8.87 (AB, 2H, J¼4.7 Hz, H-7
1. Cavaleiro, J. A. S.; Tome, A. C.; Neves, M. G. P. M. S. In Handbook of Porphyrin
and H-8), 8.83e8.82 (m, 3H, H-3, H-12 and 13), 8.76 (s, 1H, H-20),
8.81 and 8.73 (AB, 2H, J¼4.9 Hz, H-17 and H-18), 8.34 (d, 1H,
J¼8.2 Hz, H-60), 8.26e8.20 (m, 6H, Ho-Ph-5,10,15),7.93e7.92 (m, 2H,
Ho-Ph-20), 7.82e7.71 (m, 9H, Hm,p-Ph-5,10,15), 7.40 (s, 1H, H-80),
7.16e7.07 (m, 3H, Hm,p-Ph-20), 4.27e4.24 (m, 2H, NCH2CH3), 1.44
(t, 3H, J¼7.1 Hz, NCH2CH3), -2.63 (s, 2H, NH) ppm. UVevis (DMF/
Science; Kadish, K., Smith, K. M., Guilard, R., Eds.; World Scientific Publishing
Company: Singapore, 2010; Vol. 2, pp 193e294.
2. (a) Cavaleiro, J. A. S.; Tome, J. P. C.; Faustino, M. A. F. Top. Heterocycl. Chem. 2007,
ꢀ
7, 179e248.
3. (a) Srivastava, B. K.; Solanki, M.; Mishra, B.; Soni, R.; Jayadev, S.; Valani, D.; Jain,
M.; Patel, P. R. Bioorg. Med. Chem. Lett. 2007, 17, 1924e1929; (b) Pandey, R. K.;
Zheng, G. In The Porphyrin Handbook, Applications: Past, Present and Future;
Kadish, K., Smith, K. M., Guilard, R., Eds.; Academic: San Diego, 2000; Vol. 6,
pp 157e230.
4. Bonnett, R. Chemical Aspects of Photodynamic Therapy; Gordon and Breach
Science: Amsterdam, 2000.
5. Kormeili, T.; Yamauchi, P. S.; Lowe, N. J. Br. J. Dermatol. 2004, 150, 1061e1069.
6. (a) Awan, M. A.; Tarin, S. A. Surgeon 2006, 4, 231e236; (b) Zheng, X.; Pandey, R.
K. Anti-Cancer Agents Med. Chem. 2008, 8, 241e268.
7. Obata, M.; Hirohara, S.; Sharyo, K.; Alitomo, H.; Kajiwara, K.; Ogata, S.; Tanihara,
M.; Ohtsuki, C.; Yano, S. Biochim. Biophys. Acta 2007, 1770, 1204e1211.
8. Oliphant, C.; Green, G. Am. Fam. Physician 2002, 65, 445e464.
9. Mugnaini, C.; Pasquini, S.; Corelil, F. Curr. Med. Chem. 2009, 16, 1746e1767.
10. Gasparotto, V.; Castagliuolo, I.; Ferlin, M. G. J. Med. Chem. 2007, 50, 5509e5513.
11. Xia, Y.; Yang, Z.; Xia, P.; Bastow, K. F.; Tachibana, Y.; Kuo, S.; Hamel, E.; Hackl, T.;
Lee, K. J. Med. Chem. 1998, 41, 1155e1162.
12. Santos, F. C.; Cunha, A. C.; de Souza, M. C. B. V.; Tome, A. C.; Neves, M. G. P. M. S.;
Ferreira, V. F.; Cavaleiro, J. A. S. Tetrahedron Lett. 2008, 49, 7268e7270.
13. Silva, A. M. G.; Castro, B.; Rangel, M.; Silva, A. M. S.; Brandao, P.; Felix, V.;
Cavaleiro, J. A. S. Synlett 2009, 1009e1013.
14. Silva, E. M. P.; Domingues, P.; Tome, J. P. C.; Faustino, M. A. F.; Neves, M. G. P. M.
S.; Tome, A. C.; Dauzone, D.; Silva, A. M. S.; Cavaleiro, J. A. S.; Correia, A. J. F.;
Domingues, M. R. M. Eur. J. Mass Spectrom. 2005, 14, 49e59.
15. Serra, V. V.; Domingues, M. R. M.; Faustino, M. A. F.; Domingues, P.; Tome, J. P.
C.; Neves, M. G. P. M. S.; Tome, A. C.; Cavaleiro, J. A. S.; Correia, A. J. F. Rapid
Commun. Mass Spectrom. 2005, 19, 1e12.
16. Domingues, M. R. M.; Domingues, P.; Neves, M. G. P. M. S.; Tome, A. C.; Cav-
H2O (9:1)): lmax (log
3
(3.47), 649 (3.40) nm; HRMS (ESI) m/z calcd for C56H40N5O3
[MþH]þ 830.3126, found 830.3095.
4.3.3. 2-[3-Carboxy-1-(
dihydroquinolin-6-yl]-5,10,15,20-tetraphenylporphyrin,
88%; 1H NMR (300 MHz, DMSO-d6)
15.19 (s, 1H, CO2H), 9.59 (s, 1H,
H-20), 8.87e8.70 (m, 7H, -H), 8.35e8.33 (m, 1H, H-50), 8.32e8.23
(m, 6H, Ho-Ph-5,10,15), 7.98e7.87 (m, 2H, Ho-Ph-20), 7.86e7.83 (m,
12H, Hm,p-Ph-5,10,15,20), 6.58e6.56 (m, 1H, H-100), 6.20e6.18 (m,
1H, H-200), 5.37e5.31 (m, 1H, H-300), 4.23e4.21 (m, 2H, H-500),
4.15e4.10 (m, 1H, H-400), -2.76 (s, 2H, NH) ppm. UVevis (DMF/H2O
b
-
D
-ribofuranos-1-yl)-4-oxo-1,4-
5c. Yield:
d
b
ꢀ
~
(9:1)): lmax (log
3
648 (2.72) nm; HRMS (ESI) m/z calcd for C59H44N5O7 [MþH]þ
ꢀ
ꢀ
934.3235, found 934.3192.
ꢀ
ꢀ
4.3.4. 2-[3-Carboxy-1-(
dihydroquinolin-7-yl]-5,10,15,20-tetraphenylporphyrin,
89%; 1H NMR (300 MHz, DMSO-d6) 9.06 (s, 1H, H-20), 8.98e8.42
(m, 7H,
b
-
D
-ribofuranos-1-yl)-4-oxo-1,4-
5d. Yield:
ꢀ
d
aleiro, J. A. S. J. Porphyrins Phthalocyanines 2009, 13, 525e527.
17. Quirke, J. M. E. In The Handbook of Porphyrins; Kadish, K., Smith, K. M., Guilard,
R., Eds.; Academic: San Diego, 2000; Vol. 7.
18. Prakash, C.; Shaffer, C. L.; Nedderman, A. Mass Spectrom. Rev. 2007, 26,
340e369.
19. Canuto, C. B. V. S.; Gomes, C. R. B.; Marques, I. P.; Faro, L. V.; Santos, F. C.;
Frugulhetti, I. C. P. P.; Souza, T. M. L.; Cunha, A. C.; Romeiro, J. A.; Ferreira, V. F.;
de Souza, M. C. B. V. Lett. Drug Des. Discovery 2007, 4, 404e409.
20. Ruxer, J. M.; Lachoux, C.; Ousset, J. B.; Torregrosa, J. L.; Mattioda, G. J. Heterocycl.
Chem. 1994, 31, 409e417.
b-H), 8.24e8.20 (m, 8H, Ho-Ph-5,10,15,20), 7.84e7.79 (m,
12H, Hm,p-Ph-5,10,15,20), 7.60e7.39 (m, 2H, H-50 and H-80),
7.22e6.94 (m, 1H, H-100), 6.95e6.75 (m, 1H, H-200), 6.58e6.50 (m,
1H, H-300), 6.50 (m, 1H, H-400), 6.04e6.00 (m, 2H, H-500), -2.62 (s, 2H,
NH) ppm. UVevis (DMF/H2O (9:1)): lmax (log
3
(3.48), 560 (3.45), 600 (3.23), 647 (3.06) nm; HRMS (ESI) m/z calcd
for C59H44N5O7 [MþH]þ 934.3235, found 934.3206.
21. Cunha, A. C.; Gomes, A. T. P. C.; Ferreira, V. F.; de Souza, M. C. B. V.; Neves, M. G.
P. M. S.; Tome, A. C.; Silva, A. M. S.; Cavaleiro, J. A. S. Synthesis 2010, 510e514.
22. (a) Callot, H. J. Tetrahedron Lett. 1973, 14, 498e4990; (b) Callot, H. J. Bull. Soc.
ꢀ
4.4. Singlet oxygen generation studies
Chim. Fr. 1974, 1492e1496.
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Stock solutions of the porphyrin/quinolone conjugates 5aed at
0.1 mM in DMSO and a stock solution of 1,3-diphenylisobenzofuran
(DPiBF) at 10 mM in DMSO were prepared. The reaction mixture of
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(b) Mitzel, F.; Fitzgerald, S.; Beeby, A.; Faust, R. Eur. J. Org. Chem. 2004,1136e1142.
50 mM of DPiBF and 0.5 mM of each porphyrin/quinolone derivative
ꢀ
26. (a) Moura, N. M. M.; Giuntini, F.; Faustino, M. A. F.; Neves, M. G. P. M. S.; Tome,
in DMF/H2O (9:1) in glass cells (2 mL) was irradiated with light
(550e800 nm) with a fluence rate of 25.0 mW cmꢁ2. The solutions
were stirred at room temperature while being irradiated. The
generation of singlet oxygen was followed by its reaction with
DPiBF. The breakdown of DPiBF was monitored by measuring the
decreasing of the absorbance at 415 nm. The obtained values were
€
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