Octaalkynyltetra[6,7]quinoxalinoporphyrazines: A new class of photosensitisers with potential for photodynamic therapy

Article abstract of DOI:10.1039/b109742n

Acetylene-substituted tetra[6,7]quinoxalinoporphyrazines, obtained in two steps from dialkynyl-1,2-diones and 1,2-diamino-4,5-dicyanobenzene, show intense absorptions in the near infrared and have photooxidising properties that make them promising candida

Full text of DOI:10.1039/b109742n

Octaalkynyltetra[6,7]quinoxalinoporphyrazines: a new class of
photosensitisers with potential for photodynamic therapy
Frieder Mitzel,a Simon FitzGerald,b Andrew Beebyb and Rüdiger Faust*a
a Department of Chemistry, University College London, 20 Gordon Street, London, UK WC1H OAJ.
E-mail: r.faust@ucl.ac.uk
b Department of Chemistry, University of Durham, South Road, Durham, UK DH1 3LE
Received (in Cambridge, UK) 24th October 2001, Accepted 30th October 2001
First published as an Advance Article on the web 23rd November 2001
Acetylene-substituted tetra[6,7]quinoxalinoporphyrazines,
obtained in two steps from dialkynyl-1,2-diones and 1,2-dia-
mino-4,5-dicyanobenzene, show intense absorptions in the
near infrared and have photooxidising properties that make
them promising candidates as agents active in photo-
dynamic therapy.
Photodynamic therapy (PDT) is an increasingly valuable
method for the treatment of a variety of conditions, among them
various forms of cancer, age-related macular degeneration, and,
most recently, atherosclerosis.1–4 At the core of PDT lies the
generation of reactive oxygen species by energy transfer from a
photosensitiser embedded in the malignant tissue which is
irradiated with external light of appropriate wavelength. The
reactive oxygen species in turn cause significant cellular
damage and thereby ultimately lead to the eradication of the
pathogenic tissue. Sensitisers suitable for biomedical applica-
tions of this type must meet the minimum requirements of
accessibility by light in a biological matrix and of efficient
induction of photooxidation. These requirements lead to the
definition of a therapeutic window of ca. 650–800 nm in the
absorption of practical PDT agents. Current applications largely
exploit the photosensitising action of functionalised porphyrins
such as a mixture of haematoporphyrin derivatives HpD, which
is marketed under the tradename Photofrin®.5 Despite the
success of this drug in PDT, efforts are continuing to devise
photosensitisers with an improved photochemical profile with
respect to that of Photofrin®,6 whose role in PDT is somewhat
limited, among other things, by its low-intensity absorption
around 630 nm.
We wish to present here octaalkynyltetra[6,7]quinoxalino-
porphyrazines 1a–c as a new class of photosensitisers which, by
virtue of their concise and flexible synthesis and their
(photo)chemical properties, are promising candidates as effec-
tive PDT agents. As such, 1a–c represent viable alternatives to
some of the phthalo- and naphthalocyanines that are currently
being investigated as second generation sensitisers for PDT6,7
and are a significant advancement over the corresponding
octaalkynylphthalocyanines8,9 and tetrapyrazinoporphyrazines
previously reported.10
spectra of the tetra[6,7]quinoxalinoporphyrazines is quite
remarkable. Whereas non-acetylenic 1d shows a B-band at 364
nm (e = 132 000 M21 cm21) and a Q-band at 735 nm (e =
431 000 M21 cm21), the corresponding maxima of acetylenic
compound 1a (M = Mg, B-band: 388 nm, e = 288 000
M21 cm21; Q-band at 770 nm, e = 512 000 M21 cm21) are
significantly batho- and hyperchromically shifted. This in-
dicates that the p-system of the main chromophore of 1a
extends beyond the periphery of the polyazamacrocycle and
includes the acetylene substituents. However, an extension of
the p-system of 1a by the appendage of terminal aryl groups to
the acetylene units as, for example, in 1b (B-band: 394 nm, e =
306 000 M21 cm21; Q-band: 770 nm, e = 517 000 M21 cm21
,
THF) does not result in a further bathochromic shift of the Q-
band. In comparison to octaalkynyltetrapyrazinoporphyra-
zines10 and 2phthalocyanines,8,9 whose Q-band absorption
The syntheses of the quinoxalinoporphyrazines 1 are sum-
marised in Scheme 1 and follow a route similar to the one
outlined for the related octaalkynyltetrapyrazinoporphyra-
zines.10 Key step in the preparation of the new acetylenic
chromophores is the condensation of the dialkynyl-1,2-diones
4a–c11 with 1,2-diamino-4,5-dicyanobenzene 3 followed by a
base-induced cyclotetramerisation of the intermediate quinoxa-
lines to the porphyrazine framework. The alkyl-substituted
derivative was prepared for comparison.† The new chromo-
phores are deep blue (1a, 1d) or green (1b, 1c) solids that show
good solubility in common organic solvents (CH2Cl2, THF).
The electron absorption spectra of compounds 1a–d in THF
are dominated by two transitions, namely the higher-energy B-
band and the lower-energy Q-band, that in case of 1a–c
stretches into the near infrared (Fig. 1). The influence of
peripheral substituents on the appearance of the UV–Vis–NIR
Scheme 1 Reagents and conditions: i, CuCN, DMF, 140 °C, 15 h, 25%; ii,
AcOH, rt., 20 min, 66–80%; iii, Mg(OBu)2, BuOH, reflux, 1 h, 22–41%; iv,
LiOPent, PentOH, reflux, 1 h, then Zn(OAc)2, PentOH, reflux, 3 h, 44%.
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Chem. Commun., 2001, 2596–2597
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b109742n

Table 1 Fluorescence lifetimes tf, fluorescence quantum yields Ff and
singlet oxygen quantum yields FD for selected tetra[6,7]quinoxalinopor-
phyrazinesa
c
Compound
tf/ns
Ffb
FD
1a (M = Mg)
1a (M = Zn)
1d (M = Mg)
4.3 0.1
2.4 0.1
5.3 0.1
0.46
0.25
0.59
0.19
0.56
0.15
a All measurements were performed in aerated THF at 298 K. b Absolute
values ( 10%) relative to cresyl violet in MeOH (Ff 0.54) and
=
disulfonated aluminium phthalocyanine in H2O (Ff = 0.40) standards.
c Obtained by time-resolved phosphorescence measurements using excita-
tion at lex = 355 nm. Values are relative to perinaphthenone (FD = 0.97)
and have an error of 10%.
(trace d, Fig. 2), clearly demonstrating the photooxidising
ability of the zinc quinoxalinoporphyrazine. The corresponding
magnesium derivative 1a (M = Mg) shows a markedly reduced
photosensitising effect.
Fig. 1 Electronic absorption spectra of 1a (a) and 1d (b) in THF at 298 K.
The inset shows the fluorescence spectrum of 1a in THF at 298K upon
irradiation at 388 nm.
As shown in Table 1, these qualitative findings are further
substantiated by the photophysical data obtained for compounds
1a (M = Mg, Zn) and 1d (M = Mg). Whereas the magnesium
porphyrazinato complexes are strong fluorophores with only
limited singlet oxygen producing capacity, the corresponding
zinc complex 1a (M = Zn) is a very efficient singlet oxygen
sensitiser with a singlet oxygen quantum yield of FD = 0.56. In
fact, this value is comparable with that determined for photofrin
(FD = 0.57 in benzene)1 and significantly exceeds that
maxima centre around 670 nm and 720 nm, respectively, the
significantly red-shifted absorption of 1a–c will allow the use of
more deeply penetrating light for the excitation of 1a–c in
biological tissue. In addition, the high molar extinction
coefficients associated with their NIR absorptions suggest a
more detailed exploration of their suitability for PDT applica-
tions. Furthermore, the photostability of the compounds is
satisfactory. Their aerated solutions in hexanol show very little
degradation upon irradiation with light at a fluence rate of 50
mW cm22 for several hours (e.g. 92% of the initial absorption
of 1a (M = Zn) at longest wavelength maximum still present
after 4h irradiation). In light of the fluorescence at 790 nm that
the alkynyl-substituted compounds 1a–c exhibit upon irradia-
tion at either their respective B- or Q-bands (Fig. 1), usage of
this class of compounds as fluorescent probes in biological
tissue or diagnostic tools in PDT can also be envisioned.
A qualitative evaluation of the photooxidising ability of 1a
(M = Zn) was performed using the singlet oxygen quencher
1,3-diphenylisobenzofuran (DPBF).12 Hence, an aerated solu-
tion of 1a (M = Zn) and DPBF (120-fold molar excess) in
hexan-1-ol was exposed to filtered light (cut-off < 550 nm) of
a slide projector lamp while monitoring the 413 nm absorption
of DPBF (Fig. 2). No or little photooxidation of DPBF is
observed in the absence of either light, 1a (M = Zn) or oxygen
(traces a–c, Fig. 2). However, significant photodegradation of
DPBF occured in the presence of 1a (M = Zn) and oxygen
determined for silicon naphthalocyanine (FD
= 0.35 in
benzene),1 an analogue of 1 that has been investigated in the
context of PDT applications.
The short and flexible synthesis of alkynyl-substituted
quinoxalinoporphyrazines coupled with their high intensity
absorption and their emission in the near infrared make them
interesting candidates for future PDT applications. While the
lipophilicity of the prototypical compounds presented here will
require an administration via, for example, liposomal formula-
tions, further adaptations of the chromophores to the require-
ments set by biological environments can be easily achieved by
exploiting, for example, the chemistry of the protected phenol
functionality in 1c. Work along these lines is currently under
way.
We wish to acknowledge University College London for the
provision of a Provost Studentship to F. M. and the EPSRC for
a studentship to S. F. We thank Dr A. J. MacRobert for helpful
discussions.
Notes and references
† All new compounds are fully characterised by spectroscopic and
analytical data. Detailed procedures for their syntheses will be reported
elsewhere.
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Fig. 2 Photooxidation of 1,3-diphenylisobenzofuran (DPBF) with 1a (M =
Zn) in hexanol at 298 K; co(DPBF) = 4.5 3 1025 mol l21, co (1a) = 4.0
3 1027 mol l21, light source: slide projector lamp (24 V, 250 W), cut-off
filter < 550 nm. The absorption at 413 nm was monitored in an aerated
solution of 1a (M = Zn) and DPBF upon irradiation (trace d); trace a, in the
absence of light; trace b, in the absence of 1a (M = Zn); trace c, in the
absence of oxygen.
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