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The porphyrin handbook - Kadish K.M.

Kadish K.M. The porphyrin handbook - Academic press, 2000. - 368 p.
Download (direct link): kadishsmishgulilard2000.djvu
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photosensitizing molecules that are manufactured outside the body and
then injected as preformed compounds. In contrast, endogenous
photosensitizers are synthesized within the body from nonphotosensitizing
precursors, the chemical conversion being carried out by normal metabolic
pathways. As shown in Scheme 89,331 in the biosynthesis of tetrapyrroles
in mammalian systems the production of heme is controlled by a feedback
mechanism in which the concentration of heme regulates the production of
<5-aminolevulinic acid (ALA) 438. However, if ALA is artificially added
to the system, the enzymes responsible for successive stages take over,
and along the way to heme, H2(Proto) is generated. Since the conversion
of H2(Proto)
into heme is relatively slow, certain types of cells tend to accumulate
photosensitizing concentrations of H2(Proto). Photosensitization can be
induced in cells of the epidermis and its appendages, but not in the
dermas. Moreover, since ALA passes readily through abnormal keratin but
not through normal keratin, the topical application of ALA induces
H2(Proto) photosensitization that is restricted primarily to the abnormal
epithelium. Subsequent exposure to light selectively destroys such
lesions.332
ALA also appears to have potential for clinical use as a
photodiagnostic or photodetection agent.333 Fluorescence visualized after
intravesical instillation of ALA shows some specificity for mucosal
lesions including cancer and dysplasias, although false positives caused
by inflammatory areas are also seen. However, it is the improvement in
sensitivity rather than in specificity that suggests that ALA
photodiagnosis could be a useful tool for guiding biopsies.
43/Porphyrins as Photosensitizers in Photodynamic Therapy
209
Scheme 71. Amide-linked chlorin dimer and trimer. OH
OH
341
OAc
342
A. CATIONIC PHOTOSENSITIZERS
Chen and coworkers74 demonstrated that carcinoma cells take up and retain
cationic dyes such as rhodamine-123 439 (Scheme 90), and such dyes showed
highly selective light-induced mitochondrial damage and cell killing.
Based on these findings, Oseroff et al. 334 developed some cationic dyes
for PDT. The most effective of these is N,N'-bis(2-ethyl-l,3-dioxolane)-
kryptocyanine 440 (EDKC). EDKC was found to be an efficient tumoricidal
agent when administered under hyperthermic conditions (42 C) together
with light.
It is of particular interest that such cationic dyes have preferential
affinity for enzymes of mitochondria of neoplastic cells. Consequently,
cationic dyes inhibit respiration and energy metabolism by inhibiting
cytochrome oxidase.335 However, the commonly used porphyrin-type
photosensitizers are spread over several cellular compartments. In order
to optimize the photodynamic effect, it seems promising to combine, on
the one hand, the accumulation of the sensitizer in the very important
inner mitochondrial membrane system and, on the other hand, the
generation of singlet oxygen by specially designed porphyrin sensitizers.
XII. Cationic Porphyrins, Chlorins and Phthalocyanines
Pandey et a/.336-337 described a simple and efficient procedure for
transformation of readily available porphyrins containing cationic
functionalities, aimed at targeting the
mitochondria membranes. The structures of a series of cationic porphyrins
and chlorins 445-449 that have recently been reported by various
investigators are shown in Scheme 91 338-342 ^ bis(N,N-
dimethylaminomethyl) deuteropor-phyrin IX dimethyl ester 441, obtained by
reacting deuteroporphyrin IX dimethyl ester with Eschenmoser's, was
converted into the corresponding platinum(II) complex 449 by Brunner and
Obermeier.343 This compound demonstrated additive cytotoxic and
photodynamic activity.
The most intriguing cationic benzochlorin-type photosensitizers are
the copper iminium salt of octaethylbenzo-chlorins 451 (Scheme 92).344
The photosensitizer 451 has a delocalized positive charge and absorbs
around 720-750 nm. It exhibits a large red shift (~30nm) when polarity of
the solvents is changed from polar to nonpolar solvents. Despite the
presence of a paramagnetic metal (Cu) in the center of the core (which
limits the lifetime of the triplet energy state and thus the ability to
produce singlet oxygen), such compounds were found to be effective
photosensitizers for PDT. Studies also showed that one of the mechanisms
of tumoricidal action of copper benzochlorin PDT is a decrease in tumor
blood flow, a finding often seen with other photosensitizers. Selman et
al. recently reported a structure-activity relationship study on copper
benzochlorins and revealed that the coexistence of the copper inside the
aromatic ring and the iminium group at the meso position were both
required for the photodynamic effect.345 The mechanism for cell killing
these compounds requires molecular oxygen and seems to be caused by a
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