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an effective and minimally invasive cancer therapy called
photodynamic therapy (PDT) (93,94). PDT uses a
photosensitizing drug, generally a porphyrin derivative, in
combination with visible light irradiation. In presence of
the oxygen accumulated in tumors, the photoactive
sensitizer triggers a series of photochemical processes that This strategy has been reported with conjugates such as
lead to direct cancer cell death and tumor microvascular
damage (95,96). PDT is clinically used for the treatment of
various types of malignant disorders such as bladder, lung
or esophageal cancer (97). A particular interest of the use
of these photosensitizers is their preferential accumulation
by malignant cells due to the presence of high amount of
collagen and lipids.
Strategies targeting photosensitizers covalently
attached to molecules have been reported lately with
different therapeutic approaches. The photosensitizer can
be combined with a carrier showing affinity for neoplasia
or to receptors expressed on specific tumors such as
monoclonal antibodies, antibody fragments, peptides,
proteins such as transferrin, epidermal growth factor and
insulin, low-density lipoproteins, various carbohydrates,
somatostatin, folic acid among others (98). Another
strategy will be the conjugation of a therapeutic agent to a tetraphenylporphyrin (TPP) was elected as photosensitizer
Figure 11. Photosensitizer/chromenopyrazoledione conjugate 14, and the chromenopyrazole 13 and the TPP derivative 12
involved in its synthesis.
The synthesis of the porphyrin-chromenopyrazodione
conjugate 14 was achieved from the porphyrin 12 and the
chromenopyrazole 13. TPP was regioselectively para-
mononitrated with sodium nitrate to 5-(p-nitrophenyl)-
10,15,20-triphenylporphyrin that was then reduced with tin
(II) chloride, and finally converted under diglycolic
anhydride treatment to the carboxylic porphyrin 12. The
NH-chromenopyrazoledione was first acylated using
174 @Real Academia Nacional de Farmacia. Spain
Paula Morales, Pilar Goya, Nadine Jagerovic
photosensitizer in view to obtain dual antitumor activity
and/or to use the photosensitizer as carrier due to their
ability to preferentially accumulate in cancer tissues (99).
temoporfin/ibuprofen as a non-steroidal anti-inflammatory
drug (100), tetraphenylporphyrin/trilobolide as a cytotoxic
agent (101), porphyrazine/doxorubicin (102).
Two studies on porphyrin/cannabinoid conjugates have
been reported so far (103,104). The first conjugate
involved a phthalocyanine named IR700DX-mbc94 with
the CB2R antagonist SR144528 (103). Phototherapy
treatment using this complex greatly inhibited the growth
of expressed CB2R tumors but not tumors that were not
expressing CB2R. Considering that the CB2R antagonist
does not have antitumor properties, the strategy used its
affinity for receptors expressed in tumors to increase the
accumulation of photosensitizer in the tumor.
Photosensitizer/chromenopyrazoledione conjugates
have been proposed recently (figure 11) in which meso-
and chromenopyrazoledione as antitumor agent (104).
bromoacetyl bromide, and then was allowed to react with
the carboxylic porphyrin 12 affording the conjugate 14. A
complete conformational analysis of this
chromenopyrazole conjugate performed using ab initio
calculations indicated that the global minimum energy
conformer adopts an expanded spatial conformation
whereas folded conformers, where the chromenopyrazole
and the porphyrin core lay paralleled, exert higher relative