Russian Chemical Bulletin, International Edition, Vol. 60, No. 4, pp. 719—728, April, 2011 719
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 4, pp. 704—713, April, 2011.
10665285/11/6004719 © 2011 Springer Science+Business Media, Inc.
Synthesis of potential antitumor agents, dimeric and trimeric chlorins,
from methylpheophorbide a
D. V. Belykh,
M. V. Mal´shakova,
Yu. A. Yudina,
K. A. Zavadskaya,
V. M. Khudyaev,
and A. V. Kuchin
Institute of Chemistry, Komi Research Center, Ural Branch of the Russian Academy of Sciences,
48 ul. Pervomaiskaya, 167982 Syktyvkar, Russian Federation.
Fax: +7 (821) 221 8477. Email: email@example.com
Syktyvkar State University,
55 Oktyabr´sky prosp., 167000 Syktyvkar, Russian Federation
A series of dimeric and trimeric chlorins were synthesized from methylpheophorbide a.
They are potential photosensitizers for photodynamic therapy in oncology. The macrocycles
were conjugated due to the formation of ester and amide bonds. The carboxy groups were
activated and catalytic transesterification was carried out to form the ester bond. The amide
bond was formed using carboxy group activation; in several cases, amidation of the ester group
in position 13(2) of the exocycle of methylpheophorbide а was carried out, which does not
Key words: methylpheophorbide a, dimers, trimers, chlorin е
Synthesis of potential photosensitizers (PS) for photo
dynamic therapy (PDT) in oncology is a topical direction
of the chemistry of tetrapyrrole macrocycles. The known
drug Photofrin II, which exerts a photocytotoxic effect on
cancer cells, is a mixture of porphyrin dimers and tri
It is reasonable to expect that natural dimeric and
trimeric porphyrins possess similar biological activity, and
the activity of oligoporphyrin can depend strongly on the
mode of conjugation of macrocycles. Dimeric porphyrins
are also used for modeling various biological processes.
In connection with the aforesaid, it seems interesting to
develop methods for synthesis of dimers and trimers from
chlorophyll derivatives. In the present work, we synthe
sized a series of chlorin dimers, whose macrocycles are
linked by bridges of various length. The macrocycles were
conjugated due to the formation of the amide or ester
bond. One of the variants of macrocycle conjugation modes
during preparation of dimers was used for the synthesis of
Results and Discussion
In Scheme 1, the synthesis based on methylpheophor
bide a (1) of analogs of chlorophyll a 2—6, 10, 11, and 13
containing carboxy, hydroxy, and amino groups is shown.
The latter were used for the preparation of ensembles con
taining two and three chlorin residues: dimeric and tri
meric chlorins. In the synthesis of dimers 14—17 (Scheme 2),
the macrocycles were conjugated by amide bond forma
tion due to the interaction of the amino group of one
chlorin with the activated carboxy group of another chlor
in (activation by formation of mixed anhydride).
In the synthesis of dimers 14—16, the methylpro
pionate substituent of methylpheophorbide а (1) was
hydrolyzed to form the carboxy group, and the correspond
ing pyro derivative 6 was obtained by reflux of pheophor
bide а 5 in collidine (see Scheme 1). In the synthesis of
dimer 17, more remote carboxy group was inserted by the
treatment of aminochlorin 3 with succinic anhydride. The
carboxy group of the synthesized chlorins was activated by
the addition of di(tertbutyl) dicarbonate.
Н NMR spectrum of dimer 15 contains signals
of two porphyrin macrocycles. In addition, it exhibits
a broadened multiplet corresponding to protons of two
amide groups, one of which was formed due to the inter
action of pyropheophorbide a (6) with 5,17dimethyl
13N(6aminohexyl)amide (4). Similar spe
cific features are observed in the spectra of dimers 14 and
16. The peaks of the corresponding molecular ions are
detected in the mass spectra of dimers 14—16.
The MALDI mass spectrum of dimer 17 exhibits peaks
attributed to its molecular ion, protonated molecular ion,
and the adduct of compound 17 with the sodium cation.
Н NMR spectrum of dimer 17, the signals of two
macrocycles in the molecule coincide due to symmetry of
In several cases, the amide bond was formed without
the use of activating agents. It is known that reflux of
methylpheophorbide а (1) with primary and secondary
aliphatic amines results in the amidation of the ester group