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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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for differences in tumor photosensitizer concentration, the n-hexyl-
derivative (HPPH) (optimal lipophilicity) was found to be five times more
potent than the related n-dodecyl-derivative (more lipophilic), and three
times more potent than the n-pentyl analogues (less lipophilic). These
studies clearly indicate that lipophilicity plays an important role in
photodynamic efficacy of the photosensitizers.
In their further attempts to determine the effect of hexyl ether side
chains in other types of photosensitizers, Pandey et al.130 introduced
just such a substituent at position 8 (ring B) of the most effective
isomer of benzoporphyrin derivative
/
166
Pandey and Zheng
(ring A reduced BPD), and found it to be more effective than the parent
BPD analogue.
Dagan and coworkers have reported the synthesis and in vitro
photodynamic efficacy of a series of pheophorbide a derivatives in which
the C(173)-carboxylic group was linked via alkyl amide side chains with
variable carbon lengths.119 In in vitro experiments, optimal
photosensitizer uptake and photosensitizing activity were observed with
compounds containing the substituents with 4-6 carbon units. The N-(4-
hydroxybutyl)amide derivative with optimal activity was found to be much
more effective than Photofrin. These results indicate that similar to the
alkyl ether derivative of pyropheophorbide a, the amide analogues with
variable carbon units also exhibit a significant increase in
photosensitizing efficacy. However, no in vivo data with this series of
compounds are as yet reported.
IMPORTANCE OF LIPOPHILICITY
Lipophilicity has proven to be a very important molecular descriptor and
is often well correlated with the bioactivity of chemical entities. It is
quantified by lipophilicity indices, such as the logarithm of a partition
coefficient, log P, which reflects the equilibrium partitioning of a
molecule between an apolar and a polar phase, such as an n-octanol/water
system. Partition coefficients can be measured experimentally by several
techniques, ranging from the simple "shake flask" technique to quite
popular chromatographic methods such as reversed-phase HPLC. For
designing new compounds in a particular series, efforts have been made to
develop an efficient method for determining lipophilicity by introducing
various substituents or by modifying the basic
skeleton. Hence, numerous theoretical methods have been developed to
predict lipophilicity by calculating the log P value. The most frequently
applied methods are based on the fragmental approach,131-133 making use
of the additive-constitutive nature of log P. The basic idea of these
methods relies on the definition of n constant (substituent constant), n
= log PX - log PY, where PX is the partition coefficient of a derivative,
and PY is the partition coefficient of the parent molecule. Although
values vary for a given functional group depending on its electronic
environment, this variation is generally small.133 For example, the
substituent constant () for CH3 is 0.5, which is mostly true for both
aromatic and aliphatic systems and thus the inclusion of this group will
increase the log P by 0.5. In the pyropheophorbide a series, it has been
shown that there was a linear relationship between the log HPLC retention
times vs the carbon chain lengths. Similarly, calculated octanol-water
partition coefficients (log P at pH 7.4, predicted by a program module of
the PALLAS system) were linear with chain length, ranging from 3.1 for Cl
to 8.6 for C12.56 The measured log P data were also in agreement with the
calculated values. Thus, the PALLAS program is useful in predicting the
log P values in a homologous series.
Having developed a QSAR for one series of photosensitizers, Pandey and
coworkers134 extended this approach to photosensitizers different from
the pyropheophorbide ethers in photophysical, physicochemical and steric
factors to examine the generality of the relationships found. The main
objective was to establish a generic requirement(s) for effective
photosensitizers. In their approach, methylpheophorbide a was used as a
substrate due to its availability in gram quantity from Spirulina
Scheme 5. Formation of purpurin-18 N-alkylimides.
17
C02Me
20a - 20i
a. R = Methyl
b. R = Ethyl
c. R = Propyl
d. R = Butyl
e. R = Hexyl
f. R = Heptyl
g. R = Octyl
h. R = Decyl
i. R = Dodecyl
43 / Porphyrins as Photosensitizers in Photodynamic Therapy
167
alga.135 It was then converted into purpurin-18 methyl ester
17 and was used as a precursor due to: (1) its strong absorption near ~
700 nm which provides an advantage over pyropheophorbide ethers and other
chlorin systems and; (2) its inherent in vitro photosensitizing ability
as reported by Hoober et al.136 As shown in Scheme 5, the functional
groups available for chemical modifications of purpurin-18 include the
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