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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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Scheme 63. (a) An identified porphyrin dimer with C-C linkage; (b) other
suggested bridges; (c) mechanisms of C-C bridge formation.
PM =
CH2CH2C02H 296
oligomeric components of commercial Photofrin contain up to nine
porphyrin units.267 Due to the complex nature of Photofrin and difficulty
in separating the individual components, various research groups' efforts
had concentrated on the synthesis of possible components of the active
tumor-localizing fraction.268
The first porphyrin dimer 297 with an ether linkage was synthesized by
Pandey et al.269 by reacting 2-(l-hydro-xyethyl)-deuteroporphyrin
dimethyl ester 298 with HBr/ acetic acid (Scheme 64). This dimer was
found to be an effective in vivo photosensitizer. This methodology was
later used for the preparation of a series of isomerically pure dimers
300-303 and trimers 304-305 with ether linkages as some of the possible
components of Photofrin.270-271 Among these ether-linked porphyrin
dimers, the divinyl dimer 302 either as an individual isomer or as an
isomeric mixture was found to be more effective than Photofrin, and also
showed reduced skin phototoxicity. Higher oligomers (e.g., trimers)
showed similar efficacy as well as skin phototoxicity similar to that
reported for Photofrin.
Pandey et al212 also synthesized porphyrin dimers 308-311 and trimers
312a, 312b with ester linkages by reacting the appropriate acid chlorides
306 with mono- and di-(l-hydroxyethyl) porphyrins 307. In the mouse tumor
model, most of the ester-linked dimers were significantly less effective
than Photofrin (Scheme 65).
Porphyrin dimers with carbon-carbon linkages have known about for
quite some time.273 However, the utility of
these types of dimers was first investigated for their application as
effective photosensitizers for PDT by Kessel et al.214 Pandey and
coworkers270-275 reported an efficient method for the preparation of
porphyrin dimers 313-320 that are similar to those putative carbon-
carbon-linked components present in Photofrin (Scheme 66). These dimers
were obtained by treatment of 3- and 8-(l-hydroxyethyl)-porphyrins with
triflic acid under mild conditions. Among these dimers, the divinyl dimer
320 was found to be most effective photosensitizer.276
Although a considerable amount of work has been published on porphyrin
dimers with ether, ester and carbon-carbon linkages, there are only a few
reports dealing with the preparation of chlorin dimers and their utility
as long-wavelength photosensitizers. A few of them 321-324 are shown in
Scheme 67.277-279
As discussed previously, certain porphyrins found to be poor
photosensitizers as monomers showed, when converted into carbon-carbon-
linked bisporphyrins, significant increase in photosensitizing
efficacy.259 Keeping these results in mind, Smith and coworkers280
prepared dimers 327-328 by reacting 8-(l-hydroxyethyl)- 325 and 3-(l-
hydroxyethyl)-benzoporphyrin derivative 326 with triflic acid (Scheme
Pandey and Zheng
Scheme 64. Prophyrin dimers and trimers with ether linkages.
299a R = C0CH3 299b R = CH=CH2
300 R = COCH3
301 R = CH(0H)CH3
302 R = CH=CH2
PMs = CH2CH2C02CH3
305 R = CH=CH2
Surprisingly, these BPD dimers did not show any significant antitumor
activity, although the monomeric counterpart- the ring A reduced
benzoporphyrin derivative monoacid (BPDMA) - is an effective
photosensitizer. In their quest to understand more about the effect of
the nature of such linkages in PDT efficacy, this acid-catalyzed
dimerization approach was extended to those monomers which had shown some
PDT efficacy. Unfortunately, for dimerizing such monomers [e.g.,
H2(HPPH)] that contain acid labile functionality, the triflic acid method
cannot be used. Thus, the Roswell Park group tried several milder methods
for preparing the HPPH dimer, and the best yield was obtained by reacting
v/c-dihydroxy-bacteriochlorin 330 in refluxing
o-dichlorobenzene. The desired dimer 332 was formed but also, the
corresponding 8-vinyl-chlorin 333a and 8-ketobacteriochlorin 333b (as a
minor component) were isolated. This approach was then followed for the
synthesis of other chlorin dimers 336 and 340 from the corresponding
vi'c-dihydroxybacteriochlorins 335 and 337 (Scheme 69).281 The mechanism
of the formation of the 8-vinyl-chlorins, 8-ketobacteriochlorins as well
as the dimers with carbon-carbon linkages is depicted in Scheme 70.
Interestingly, in the above reaction, when chlorins containing alkyl-
ether functionalities (e.g., 330) were used as substrates, besides the
formation of the expected products, an unexpected 3,8-divinylchlorin 333b
was isolated.282 Formation of divinyl-
43/Porphyrins as Photosensitizers in Photodynamic Therapy
Scheme 65. Porphyrin dimers and trimers with ester linkages. (Only one of
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