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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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dicyclohexylurea as an impurity in the first synthetic approach, this
base-catalyzed intramolecular cyclization is more suitable for preparing
purpurins with imide ring systems.
1. Propionic Acid Modification
The formation of 17-alkylamide analogues of purpurin imide from the
corresponding methyl ester affords a simple approach for the preparation
of photosensitizers with additional lipophilic characteristic for
optimizing the PDT efficacy of the parent molecule. Such modification of
the pyropheophorbide analogues has induced significant
170
Pandey and Zheng
Scheme 10. Conversion of purpurin-18 to purpurin imides by HMDS method.

R = CH2CH2N(CH3)2
Scheme 11. Alkyl ether analogue of purpurin imides.
HBr/AcOH_
R1OH
COoMe
22

R, R = various alkyl group (1-12 carbon units)
30. R = Hexyl, R1 = Heptyl
31. R = Heptyl, R1 = Hexyl
improvement in photosensitizing efficacy as reported by Dagan et al.119
For preparing such analogues, Zheng and Pandey141 used a Lewis-
acid/hexamethydisilazane-pro-moted approach and the 17-alkylamide-
purpurinimides 29 were obtained in good yields (Scheme 10).
2. Vinyl Group Modification
Another functional group available for chemical modification in purpurin-
18 is the vinyl functionality at positon 3 of the macrocycle. For the
preparation of 3-devinyl-3-alkyl ether analogues, various purpurin-18-N-
alkylimides 30 (R = hexyl, R1 = heptyl) were treated with HBr/AcOH; the
intermediate bromo derivatives were not isolated but were immediately
reacted with various primary alcohols to produce a congeneric series of
the corresponding alkyl ether derivatives with a long wavelength
absorption near 700 nm. Preliminary studies suggested that the antitumor
activity of purpurinimides increased along with the lipophilicity and
reached a maximum for those compounds possessing medium lipophilicity
(log P= 10.32 to 10.83).142 Interestingly, in this series, for compounds
with the same lipophilicity, it was observed that the presence and
position of the alkyl groups (O-alkyl vs N-alkyl) play an important role
in in vivo uptake, selectivity in tumor vs muscle, and in vivo PDT
efficacy. However, on the basis of the limited in vivo data, no precise
correlation can
be established. Among the various purpurinimides studied so far, the 3-
(l-heptyloxy)ethyl-purpurin-18-N-hexylimide
30 and 3-(l-hexyloxy)ethyl-purpurin-18-N-heptylimide
31 were found to be the best candidates for PDT142 (Scheme 11).
IV. Synthetic Chlorins
The potential lack of stability of chlorophyll a and the fact that there
are only a few functionalities available for modification led many
research groups to concentrate on various synthetic chlorin-like systems.
A. BENZOPORPHYRIN DERIVATIVES (BPD)
Benzoporphyrin derivatives were first synthesized by Callot et al.143 by
reacting protoporphyrin IX with strongly activated dienophiles. Thus,
reaction of dimethyl acetylene dicarboxlate (DMAD) with protoporphyrin IX
dimethyl ester 32 gave the corresponding [4 + 2] Diels-Alder addition
products named as benzoporphyrin derivatives (BPD).77 As shown in Scheme
12, due to the asymmetry associated with protoporphyrin IX dimethyl ester
32, the reaction with DMAD and subsequent reaction with DBU (base-
catalyzed rearrangement of the 1:1 adduct gave the conjugated system)
produced both ring-A and ring-B
43/Porphyrins as Photosensitizers in Photodynamic Therapy
171
Scheme 12. Synthesis of BPDMA from protoporphyrin IX dimethyl ester, 32
isomers 35 and 36, which were then separated into individual isomers by
chromatography. The propionic ester functionality of the ring-A adduct
was then hydrolyzed to give the corresponding monoacids 37 and 38.
Interestingly, the ring-A-reduced mono- acid 37 (BPDMA) was found to be
effective if the patients are treated only at 3 hours post injection of
the drug. Under similar treatment conditions, the ring-B -reduced
analogue did not show any promising activity.144'145 One of the main
problems associated with BPDMA is the separation of the individual
isomers in large quantities.
Pandey et al. developed another approach for preparing benzoporphyrin
derivatives 37 and 38 by using 8-acetyl-3-vinyl- 40 and 3-acetyl-8-
vinylprotoporphyrin-IX dimethyl esters 39, respectively, as
substrates.146 These compounds were then converted into various alkyl
ether derivatives by following the standard methodology (Scheme 13).147
Among the alkyl ether analogues synthesized so far, the 8-(l-
hexyloxyethyl)-derivative 41 was found to be more effective than was
BPDMA.132 Preparation of benzoporphyrin analogues from the isomeric pure,
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