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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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carcinoma model.124 NPe6 appeared to induce greater tumor regression than
HpD, with decreased tumor regrowth and duration of cutaneous
photosensitization.
Chlorin p6 derivatives, such as the lysyl derivative 16, which can be
prepared from purpurin-18 17 by opening the anhydride ring with L-lysine
in aqueous pyridine, has also attracted attention due to its potential as
a photosensitizing agent.125-126 In clonogenic assays, lysyl chlorin p6
16 was found to be more phototoxic than Photofrin. Rosenbach-Belkin et
al.127 prepared water-soluble serine conjugates of chlorophyll and
bacteriochlorophyll by transesterfication and found that they are highly
effective PDT agents in vitro.
It has been demonstrated that by use of conjugate and complex
formation of various photosensitizers with macro-molecular carriers, the
specificity of photosensitizers for tumors can be enhanced.128 Soukos et
al. synthesized a series of polylysine chlorin e6 conjugates containing
neutral, cationic or anionic charge129 and suggested that such conjugates
might have different tissue-localizing properties which play an important
role in understanding the mechanism of photosensitization.
Among all the chlorophyll a derivatives prepared so far, the alkyl
ether analogues of methyl pheophobide a and pyropheophorbide a have
attracted the most attention.55-130 In these series of compounds it was
observed that the biological activity increased by increasing the length
of the the alkyl ether carbon chain, being maximal in compounds with n-
hexyl and n-heptyl chains. Pyropheophorbides with secondary ether chains
were found to be less active. Interestingly, under similar treatment
conditions, photosensitizers containing cis- and /rans-3-hexenyl side
chains were ineffective. Thus, both stereochemical and steric factors as
well as lipophilicity caused differences in sensitizing activity. In
general, pyropheophorbide a analo-
43/Porphyrins as Photosensitizers in Photodynamic Therapy
165
Scheme 4. Modification of chlorophyll a.
/
18 R = R1 = COOH (chlorin e6)
18a R1 = C02H (NPe6)l r =-NHCHCH2C02H 18b R1 = R (DACE) J
cq2H
C02H
19
Hexyl ether derivative of pyropheophorbide a (HPPH)
gues were found to be more active than the related compounds in the
chlorin e6 series, in which the isocyclic ring is cleaved. Among this
series, 3-devinyl-3-(1-hexyl -oxy)ethyl-pyropheophorbide a H2(HPPH) 19
was found to be most active. HPPH posesses a strong absorption at 660 nm
(e~ 45,000) with a good singlet oxygen quantum yield ( = 0.48). It is
highly selective with reduced phototoxicity compared with Photofrin. HPPH
is effective at a very low dose and is easy to formulate in injectable
solvents. While this drug has many desirable properties,93 its long
wavelength absorption is still not optimal to take advantage of maximum
tissue penetration by light. Furthermore, this drug consists of two
stereoisomers that are difficult to separate and which might differ in
their pharmacokinetic (clearance and uptake) behavior. Interestingly,
Pandey et al.55 later synthesized a series of alkyl ether analogues
(including the hexyl ether derivative) of 9-deoxypyropheophorbide a (in
which the C=0 group at position 132 is reduced to CH2) and found it also
to have significant tumorcidal activity in vivo.
It is well accepted that the biological response of drugs administered
to living organisms are at least partly governed by the physicochemical
properties of the molecule. In quantitative structure/activity
relationship (QSAR) studies which relate the physicochemical properties
of a molecule to biological activity, many parameters describing lipophi-
licity, steric effects and electronic effects should be considered. In
designing an effective drug, studies are generally based on the
modification of the structure of an
active molecule (parent compound) and on monitoring the effects of these
changes on biological activity.
Earlier work has shown that variation of substituents in a variety of
systems makes a remarkable difference in biological activity. For
example, in a congeneric series of pyropheophorbide photosensitizers, it
was observed that in vivo photodynamic efficacy could be increased by
increasing the length of the carbon chain, which is at its maximum in
compounds with n-hexyl and n-heptyl chains at position 3 (ring A).55 56
The structural elements evaluated in this in vivo quantitative QSAR study
include the length and shape (alkyl, alkenyl, cyclic and secondary
analogues) of the ether side chain. The tumor growth delay, tumor cell
lethality and vascular perfusion with this series of photosensitizers
revealed highly comparable QSAR patterns that reflected a function of the
alkyl ether chain length and drug lipophilicity, which is defined as the
log of the octanol: water partition coefficient (log P). When compensated
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