Fluorinated maleimide-substituted porphyrins and chlorins: Synthesis and characterization

Article abstract of DOI:10.3762/bjoc.15.263

Maleimide-containing fluorinated porphyrins and chlorins were prepared based on the reaction of Zn(II) or Ni(II) complexes of 5,10,15,20-tetrakis(4-amino-2,3,5,6-tetrafluorophenyl)porphyrin and chlorin with maleic anhydride. Porphyrin maleimide derivative

Full text of DOI:10.3762/bjoc.15.263

Fluorinated maleimide-substituted porphyrins and chlorins:
synthesis and characterization
Valentina A. Ol’shevskaya*, Elena G. Kononova and Andrei V. Zaitsev
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2019, 15, 2704–2709.
A. N. Nesmeyanov Institute of Organoelement Compounds of
Russian Academy of Sciences, 119991, Vavilova St. 28, Moscow,
Russian Federation
doi:10.3762/bjoc.15.263
Received: 16 July 2019
Accepted: 29 October 2019
Published: 13 November 2019
Email:
Valentina A. Ol’shevskaya* - olshevsk@ineos.ac.ru
Associate Editor: J. A. Murphy
* Corresponding author
© 2019 Ol’shevskaya et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
chlorin; maleimide; porphyrin; spectral characteristics; synthesis
Abstract
Maleimide-containing fluorinated porphyrins and chlorins were prepared based on the reaction of Zn(II) or Ni(II) complexes of
5,10,15,20-tetrakis(4-amino-2,3,5,6-tetrafluorophenyl)porphyrin and chlorin with maleic anhydride. Porphyrin maleimide deriva-
tives were also prepared by the reaction of 5,10,15,20-tetrakis(4-azido-2,3,5,6-tetrafluorophenyl)porphyrinato Zn(II) or Ni(II) with
N-propargylmaleimide via the CuAAC click reaction to afford fluorinated porphyrin–triazole–maleimide conjugates. New male-
imide derivatives were isolated in reasonable yields and identified by UV–vis, 1H NMR, 19F NMR spectroscopy and mass-spec-
trometry.
Introduction
Porphyrins belong to a broad class of the natural and synthetic photosensitizers should have for such applications are their
macroheterocyclic compounds with unique properties. They photo and thermal stability, and an ability to selectively accu-
play an important role in photosynthesis [1], catalysis [2,3], mulate in the target tissue, the absence of toxicity, toxic byprod-
nonlinear optics [4,5], polymer synthesis [6] and energy conver- ucts and mutagenic effects, and an opportunity for medical
sions [7]. Porphyrins have been extensively studied as potential administration. An additional advantage of porphyrins is the
photosensitizers in a photodynamic therapy (PDT) [8,9], a possibility of functionalization of the macrocycle periphery
promising treatment modality for several cancer and infectious with various substituents and thus to affect the photophysical,
diseases. In PDT, light, O2, and a photosensitizing drug are photochemical and tumor-specific properties of the porphyrin
combined to produce a selective therapeutic effect via the gen- system. Such an approach provides a platform to new photosen-
eration of active oxygen forms (1O2, HO−, НО2−˙and O2−˙) sitizers with optimized characteristics useful for biomedical ap-
upon excitation with monochromatic light which causes the plications including PDT. Currently a number of investigations
death of the tumor [10-14]. Some other important features, that directed for the preparation of tumor-targeted photosensitizers
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have been explored aiming to improve their tumor-specificity tics and dependence of their biological properties on the struc-
[15,16].
ture of peripheral substituents, we developed a simple synthetic
approach for new maleimide derivatives of the fluorinated
To continue our ongoing efforts on the preparation of porphy- porphyrins and chlorins. We also believe the synthetic potential
rin-based photosensitizers [17-20], we present herein the syn- of maleimide units in these new conjugates allows versatile
thesis of maleimide-subtituted porphyrins and chlorins based on ways to obtain a series of new photosensitizers for medical ap-
5,10,15,20-tetrakis(pentafluorophenyl)porphyrin (1) as the plications.
starting compound. The presence of fluorine atoms on the four
phenyl rings at the meso-positions of the porphyrin structure
Results and Discussion
Synthesis of maleimide-substituted
can make a strong influence on the hydrophobic interactions
and lipophilicity, metabolic stability, thus modulating the bio-
logical efficiency of the photosensitizing agents [21,22]. At the
same time fluorinated porphyrins are well known for their
photostability and efficiency in generating long-lived triplet
excited states through intersystem crossing (ISC) with minimal
energy loss from excited states, and are widely used to generate
singlet oxygen for PDT applications [9,23]. We intend here to
combine within one molecule the structural specificity of a
meso-fuorinated porphyrin/chlorin macrocycle and maleimide
units to develop novel multifunctional compounds with im-
proved properties for various applications. Maleimides are
considered as a biologically important scaffold that possess
almost all types of biological activities including antibacterial
and antifungal activity [24], anticancer activity [25], cox-2 in-
hibitor and anti-inflammatory, antidiabetic activity [26] and
photodynamic activity [27]. Attaching of the maleimide group
with its rich biological activity to the tetrapyrrole macrocycles
with their unique photophysical properties may result in new
conjugates with improved chemical, biological and anticancer
characteristics [28]. Moreover, maleimide is a stable function-
ality that rapidly and covalently conjugates thiol groups of
cysteine residues in proteins or peptides by the thio-Michael ad-
dition to the double bond of the maleimide to form a corre-
sponding succinimidyl thioether. Conjugation of the cysteine
sulfhydryl group with maleimide moieties allows us to prepare
the bioconjugates selectively, covalently in high yields with no
requirement for prior activation of reactants [29] and thus
strengthen the association of a drug molecule with the cell sur-
face. It is important to mention that Kitagishi and co-workers
[30] showed that the maleimide-appended porphyrin/cyclodex-
trine complex was conjugated to a cystein residue of serum
albumin via a Michael addition reaction. At the same time, it is
well known that 5,10,15,20-tetrakis(pentafluorophenyl)porphy-
rin and its chlorin derivatives generate singlet oxygen by the
light irradiation under atmospheric oxygen [31]. These tetrapyr-
role macrocycles and their metal complexes are considered to
be efficient precursors for design and selection of new PDT
agents, since their reactivity toward various nucleophiles
provides a simple, selective and general access to the functio-
nalized derivatives [32-34]. Considering the promise of
porphyrins and chlorins for the development of PDT therapeu-
porphyrins
In this work for the preparation of porphyrins functionalized
with maleimde moieties commercially available 5,10,15,20-
tetrakis(pentafluorophenyl)porphyrin (1) [35] was used as
starting compound. The synthesis includes the metallation of
the free base porphyrin 1 with an excess of zinc acetate or
nickel acetate resulting in the corresponding porphyrin Zn(II)
and Ni(II) complexes 2a [36] and 2b [37], respectively. Com-
plexes 2a and 2b readily reacted with the excess of NaN3 in
DMF/DMSO to afford porphyrins 3a and 3b in high yields via
the selective substitution of fluorine atoms in the para-position
of the pentafluorophenyl substituents with four azide functions.
The subsequent reduction of para-tetraazidoporphyrinato Zn(II)
3a with SnCl2 in MeOH [38] at ambient temperature smoothly
provided the corresponding tetraamino-substituted porphyrin 4a
in 91% yield. (Scheme 1). The free amino groups of porphyrin
4a are useful and reactive functionalities for further modifica-
tions. It was shown that the interaction of porphyrin 4a with
maleic anhydride by analogy with a well-known standard pro-
cedure [39,40] provided the target maleimide-substituted por-
phyrin 5a in 42% yield, which contains four maleimide
moieties in the structure. Treatment of porphyrin 5a with tri-
fluoroacetic acid in CHCl3 resulted in the removal of zinc from
the coordination sphere of the porphyrin macrocycle and gave
the free base maleimide porphyrin 6 in a quantitative yield. A
successful formation of the fluorinated porphyrin azides 3a and
3b allowed their utility as intermediates in the further porphy-
rin core functionalisation especially with 1,2,3-triazole hetero-
cycles via the copper-catalyzed azide–alkyne cycloaddition
reaction (CuAAC) between alkynes and azides, developed inde-
pendently by Sharpless [41] and Meldal [42]. In addition to the
applications of triazoles as pharmacophores in the potential bio-
logically active molecules, these heterocycles have also been
used as linkers and for labeling biomolecules in chemical
biology [43]. Moreover, this synthetic approach provides high
yields, selectivity, mild reaction conditions and simple purifica-
tion methods. It was demonstrated that the CuAAC reaction of
porphyrins 3a and 3b with N-propargylmaleimide [44] was
carried out successfully in CH2Cl2 and the fluorinated porphy-
rin–triazole–maleimide conjugates 7a and 7b were obtained in
54–58% yield. In these conjugates the tetrafluorophenyl units of
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Scheme 1: Synthesis of fluorinated maleimide-substituted porphyrins 5a, 6, 7a, 7b, and 8.
the porphyrin macrocycle where separated from maleimides ylide, generated in situ from sarcosine and paraformaldehyde.
with 1,2,3-triazole spacer groups. Removal of zinc in porphyrin The reaction of chlorin 9 with the excess of NaN3 in DMF/
7a under the action of CF3COOH in CHCl3 resulted in porphy- DMSO resulted in tetraazide chlorin 10 in 85% yield after the
rin 8 in a quantitative yield (Scheme 1).
purification. The reduction of azide groups in chlorin 10 with
SnCl2 in MeOH gave tetraamino-substituted chlorin 11 which
was transformed into the corresponding maleimide 12 in 25%
Synthesis of maleimide-substituted chlorins
Following the developed procedure, maleimide-substituted yield on the reaction with maleic anhydride according to the
chlorins were also prepared. Chlorins reveal a number of appli- standard procedure. Chlorin 12 was metalated with Zn(OAc)2/
cations in the photobiological processes demonstrating suitable CHCl3/MeOH giving chlorin 13 in 92% yield. (Scheme 2).
properties for PDT [45-47]. In this context the synthesis of new
chlorins is one of the most important possibilities for the pro- All prepared compounds have been structurally identified by
duction of new efficient photosensitizers. The reason for this is 1H, 19F NMR, IR and UV–vis absorption spectra (see Support-
that chlorins absorb light intensely at wavelengths where the ing Information File 1).
human tissues are the most transparent [48]. Based upon our
previous successful results with porphyrins we studied the pos- Conclusion
sibility to obtain maleimide derivatives of 5,10,15,20- In this work, we developed a facile protocol for the preparation
tetrakis(pentafluorophenyl)-17,18-N-methylpyrrolidine chlorin of new porphyrin and chlorin conjugates with maleimide enti-
9 [49] prepared by the reaction of porphyrin 1 with azomethine ties which were synthesized in reasonable isolated yields and
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Beilstein J. Org. Chem. 2019, 15, 2704–2709.
Scheme 2: Synthesis of fluorinated maleimide-substituted chlorins 12,13.
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ORCID® iDs
Valentina A. Ol’shevskaya - https://orcid.org/0000-0002-0199-5172
Elena G. Kononova - https://orcid.org/0000-0002-9602-0158
Andrei V. Zaitsev - https://orcid.org/0000-0001-6448-2561
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