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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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Ť-propanol).99 It has been shown that the meso-tetraphenylporphyrins with
lower numbers of sulfonate groups are much more efficient in cell
inactivation than is H2(TPPS4) (see Scheme «).100-101 In order to
investigate the effect of the position of hydroxyl groups on biological
activity, Bonnett synthesized
Scheme 3. TPP-related photosensitizers
10 R = (p - S03H)n, n = 1 to 4
11 R = o-, m-, p-OH 12R = m-NHCOCH3 13 R = (p-OCH3)3and
Pandey and Zheng
a series of o-, m-, and p-isomers of tetra(hydroxyphenyl)-porphyrin
H2(THPP) 11 (Scheme 3).78 Among these isomeric porphyrins, the ortho-
isomer was found to be highly phototoxic. However, both H2(m-THPP) and
H2(p-THPP) showed promising activity and tissue selectivity in
photonecrosis. Interestly, H2(m-THPP) was found to be about 25 to 30
times more potent than HpD.102
Hagan et al. reported a group of picket-fence porphyrins (PFP) 12 as
potential phototherapeutic agents (Scheme 3).103 This class of porphyrins
was originally studied by Collman et al. as models for the study of
oxygen binding to heme.104 These compounds are stable and are relatively
easy to prepare in high yields. In vivo and in vitro experiments
demonstrated that H2(3,l-TPro) was an effective photosensitizer for
PDT.105 This compound was easy to formulate and had a long wavelength
absorption at 650 nm. It showed preferential localization in mitochondria
and sufficient photosensitization potency in vivo to cause reduction in
tumor ATP levels.
Czuchajowski and Lozynski showed that replacement of phenyl groups in
H2(TPP) with para-cyclophanyl substituents 14 causes bathochromic shifts
of all the absorption bands (X,max 417, 514, 549 and 645 nm).106 However,
these compounds were found to be inactive in vivo.91
Another clinical application which takes advantage of the tumor-
localizing properties of many tetrapyrrolic compounds is the early
diagnosis of tumors by infrared imaging (IRI), which is based on the
fluorescence emission exhibited by porphyrin chromophores.9'84,107 This
application is presently limited by three main factors: (1) the
selectivity (tumor vs normal tissue); (2) the phototoxicity; and (3) the
fluorescence quantum yield. Therefore, the development of safe and
reliable photodiagnostic procedures requires the availability of highly
fluorescent, selective tumor-localizing compounds which are devoid of any
appreciable phototoxicity. For this purpose, Reddi et al.10S reported
porphyrin-carotene conjugates 13 in which a carotene moiety is covalently
linked to one of the phenyl rings of H2(TPP). The carotene moiety
efficiently quenches the photosensitizing activity of the porphyrin while
a relatively large yield of fluorescence emission around 650 nm was
III. Chlorin-based Photosensitizers
Chlorins, as reported by Cubeddn et al, show photophysical properties
similar to those of the porphyrin systems,109 but have enhanced and red-
shifted Q bands (~ 670 nm) which make chlorin-containing systems better
candidates for PDT. Chlorophyll a 15, the green photosynthetic pigment,
is one prototype of the chlorin class of natural products. It or its
derivatives can be extracted from certain Spirulina species without any
contamination with chlorophyll b,110 thus avoiding a tedious
chromatographic separation. Extensive work has been done by several
investigators to modify chlorophyll a and to synthesize other chlorin-
like chromophores in order to examine their photosensitizing effi-
In addition to their potential application in PDT, chlorophyll
derivatives and chlorins in general might also
be used in cancer prevention rather than therapy. A water-soluble
chlorophyll derivative, also known as tri-sodium copper(II) chlorin e6,
has been used in the treatment of various human ailments with no evidence
of toxicity, skin sensitization or other serious side effects.111
Several approaches have been made in the chlorophyll a molecule 15, by
introducing a large number of metals,112 modification of the isocyclic
ring,113-115 modification of the vinyl group at position 3,116117 as well
as by replacing the phytyl group at the propionyl residue through either
trans-esterification or conversion of the ester functionality into the
corresponding amide derivatives118119 (see Scheme 4, also see Chapter 1
by Smith).
Chlorin e6 18 itself is very toxic but polyamide derivatives have been
reported to be potent photosensitizers by Bommer et al.120 and Nelson et
al.121 reported the in vitro characterization of two chlorin e6
derivatives, monoaspar-tyl-chlorin e6 18a (MACE) and diaspartyl-chlorin
e6 (DACE) 18b.121 Both compounds have strong absorbance maxima at 664 nm
and are effective in vitro and in vivo.122'123 Song et al. compared the
PDT efficacy of NPe6 (also known as MACE) and HpD in a human cholangio-
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