Bioorganic & Medicinal Chemistry Letters
Novel polycarboxylate porphyrins: Synthesis, characterization,
photophysical properties and preliminary antimicrobial study
against Gram-positive bacteria
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Ahmad Jiblaoui, Stéphanie Leroy-Lhez, Tan-Sothea Ouk, Karine Grenier, Vincent Sol
Université de Limoges, Laboratoire de Chimie des Substances Naturelles, EA 1069, 123 Avenue Albert Thomas, 87060 Limoges, France
a r t i c l e i n f o
a b s t r a c t
Article history:
We describe the synthesis, characterization and photophysical properties of two new polycarboxylic
photosensitizers. Owing to their structural design, these two compounds show water solubilities larger
than natural carboxylic photosensitizers (e.g., protoporphyrin IX, hematoporphyrin, etc.) and also good
singlet oxygen quantum yields. These compounds were tested as photo-antimicrobial agents against
Staphylococcus aureus and Bacillus cereus strains. Results reveal that their photocytotoxicities are strongly
dependent on their amphiphilic character and more precisely the number and position of the carboxylic
acid and mesityl substituents.
Received 30 October 2014
Revised 10 November 2014
Accepted 11 November 2014
Available online xxxx
Keywords:
Photosensitizers
Photodynamic antimicrobial chemotherapy
Oxygen singlet quantum yield
Carboxylic porphyrins
Antibacterial agents
Ó 2014 Elsevier Ltd. All rights reserved.
Antimicrobial resistance is a global issue of concern, highlighted
by failure of antibiotic treatment of previously treatable infections,
additional morbidity and skyrocketing health care costs.1 Multire-
sistant strains represent major causes of nosocomial infections,
well exemplified by methicillin-resistant Staphylococcus aureus
(MRSA).2 Hence, the urgent need of new and more powerful thera-
peutic strategies. Photodynamic antimicrobial chemotherapy
(PACT) is a promising approach to overcome such stubborn infec-
tions.3 PACT relies on the photochemical activation of a photosensi-
tive drug that, in presence of dioxygen, gives rise to reactive oxygen
species (ROS) which rapidly react with a variety of biomolecules
then leading to cell damaging and eventual death.4 So, increasing
effort has been recently devoted to the design and synthesis of
highly structured artificial porphyrin rings in order to increase their
efficiency against bacteria. Owing to their hydrophobicity, tetra-
pyrrolic macrocycles are prone to form aggregates in aqueous
media with a concomitant decrease in the production of ROS.5
Covalent grafting of hydrophilic motifs has been used to increase
the amphiphilic character of these photosensitizers,6 and, hence,
their ability to bind and diffuse across bacterial walls and mem-
branes; these motifs can be summarized according to their chemi-
cal structure: cation (pyridinium, quaternary ammonium),7 anion
(sulfonate, carboxylate or phosphonate),8 peptides,9 carbohy-
drates,10 polyethylene glycol,11 polyamine12 and their derivatives.
Biological results have shown that Gram+ as well as GramÀ bacte-
ria prove more sensitive to PACT when photosensitive macrocycle
bear positive charges.4,13 Nevertheless, natural porphyrins and
their derivatives such as PhotofrinÒ, hematoporphyrin, protopor-
phyrin IX (Fig. 1), deuteroporphyrin and chlorin e6 which possess
anionic charges (carboxylate moieties) have attractive photophysi-
cal properties that allow their use in photodynamic therapy of
tumors (PDT)14 and photodynamic antimicrobial chemotherapy
(PACT).15
However, carboxylic acid motif has been less studied than the
other water solubilization moieties. Indeed, despite the good
results obtained even on highly resistant micro-organisms, only
few studies have reported the photophysical and antimicrobial
activities of porphyrins bearing carboxylic acid moieties.16,17 As
shown by recent studies, Gram-positive bacteria such as MRSA
have developed resistance to various antibiotics including
b-lactams (oxacillin and ampicillin), vancomycin.18 Thus, in this
work, we have focused on the evaluation of antimicrobial activity
of anionic photosensitizers against Gram+ bacteria because their
cytoplasmic membrane is surrounded by a relative porous layer
of peptidoglycan and lipoteichoic acid which allow easier penetra-
tion of neutral or anionic photosensitizers. In this paper and in con-
nection with our work on the synthesis of new amphiphilic
tetrapyrrolic photosensitizers,10,12 we describe the synthesis, char-
acterization and photophysical properties of two new porphyrins
bearing six or eight carboxylic functions attached to the macrocy-
cle (Scheme 1). Number and position of theses functional groups
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Corresponding author.
0960-894X/Ó 2014 Elsevier Ltd. All rights reserved.