Novel dendrimeric lipopeptides with antifungal activity

Article abstract of DOI:10.1016/j.bmcl.2011.12.051

A series of new cationic lipopeptides containing branched, amphiphilic polar head derived from (Lys)Lys(Lys) dendron and C₈ or C ₁₂ chain at C-end were designed, synthesized and characterized. Antimicrobial in vitro activity expresse

Full text of DOI:10.1016/j.bmcl.2011.12.051

Bioorganic & Medicinal Chemistry Letters 22 (2012) 1388–1393
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Novel dendrimeric lipopeptides with antifungal activity
a
b
c
c
d
´
Jolanta Janiszewska , Marta Sowinska , Aleksandra Rajnisz , Jolanta Solecka , Izabela Ła˛cka ,
d
b,
⇑
´
Sławomir Milewski , Zofia Urbanczyk-Lipkowska
a Institute of Industrial Research, L. Rydygiera 8, 01-793 Warsaw, Poland
b Institute of Organic Chemistry PAS, Kasprzaka 44/52, 01-224 Warsaw, Poland
c National Institute of Public Health—National Institute of Hygiene, Chocimska 24, 00-791 Warsaw, Poland
d Department of Pharmaceutical Technology and Biochemistry, Gdansk University of Technology, 80-233 Gdansk, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of new cationic lipopeptides containing branched, amphiphilic polar head derived from
(Lys)Lys(Lys) dendron and C8 or C12 chain at C-end were designed, synthesized and characterized. Anti-
microbial in vitro activity expressed as minimal inhibitory concentration (MIC) was evaluated against
Gram-positive and Gram-negative bacteria and yeasts from the Candida genus. A significant enhance-
ment of antimicrobial potency along with increased selectivity against Candida reference strains was
detected for derivatives with the C12 residue. Several compounds were characterized by a low hemotox-
icity. The antifungal activity of branched lipopeptides is multimodal and concentration dependent. Sev-
eral compounds, studied in detail, induced potassium leakage from fungal cells, caused morphological
alterations of fungal cells and inhibited activity of candidal b(1,3)-glucan synthase.
Received 21 October 2011
Revised 9 December 2011
Accepted 10 December 2011
Available online 17 December 2011
Keywords:
Dendrimers
Lipopeptides
Candida genus
Potassium channel
b(1,3)-Glucan synthase
Ó 2011 Elsevier Ltd. All rights reserved.
The wide spread of microbial infections, re-emergence of previ-
ously extinct diseases, hospital acquired infections and, most of all,
a multi-drug resistance against conventional antibiotics is currently
a big concern of public health system.1 Shortage of novel antibiotics
to combat microbial infections led to initiation of numerous studies
focused on a search for new natural and synthetic lead compounds.
One of the recent streams of research in this area is targeting micro-
bial membranes by natural and synthetic antimicrobial peptides and
lipoppeptides.2,3 Unlike in the case of conventional antibiotics, such
molecules act non-specifically and bacteria are less likely to develop
resistance against them.4 Recently, the semi-synthetic analogs of
lipopeptides received a considerable attention.5 Several such com-
pounds, either separately or in combination with other antimicrobi-
als, are currently at various stages of preclinical trials.6 Few, such as
polymyxin B and E, daptomycin,7 caspofungin8 and micafungin9
have been already successfully evaluated in the clinics. Typically,
these lipopeptides are constructed from cyclic peptide scaffolds
and a short exocyclic N-terminal peptide tails, terminated with fatty
acid residue of C14–C18 length. The structure-activity studies showed
that their high potency and selectivity are modulated by the amph-
iphilicity and charge of the peptide part and by structure of an acyl
chain.10 Despite recent advances in the design of synthetic analogs
of lipopeptides,11 the antimicrobial therapy, particularly against
Gram-negative and fungal infections is still very inefficient.
In an attempt to construct the new amphiphilic molecules with
antimicrobial properties, we have recently developed simple, low
molecular weight dendrimeric peptides constructed from amino
acids with basic (Lys, Orn) and lipophilic (Phe, Tyr, Ala, etc.) side-
chains located at various places of the dendrimer ‘tree’ (adapting
the so-called ‘non-sequential pharmacophore’ strategy).12 These
simple cationic compounds expressed broad antimicrobial potency
against Gram(+), Gram(À) bacteria and fungi from C. albicans
genus.13
It has been reported previously that the lipophilic modification
at the C-terminus of Lactoferricin H,14 as well as the presence of
6-octanoyl/heptanoyl or diaminobutyl residues in the cationic cyc-
lic antimicrobial peptide polymyxin B,15 led to the significantly en-
hanced antimicrobial potency. In the present study, a series of
novel cationic synthetic lipopeptides with a polar, branched heads
and aliphatic side chains of C8 or C12 length located at C-terminus
were synthesized and characterized. The significance of such
substitution in context of biological activity was tested in vitro
against a range of Gram(+), Gram(À) bacteria, three human patho-
genic yeast of the Candida genus and human erythrocytes. Scan-
ning electron microscopy and fluorescent staining of the cell
envelope along with inhibitory activity towards b(1,3)-glucan syn-
thase and potassium release tests were performed for representa-
tive compounds from the series to shed some light on their mode
of action.
All dendrimers were synthesized utilizing the Boc chemistry in
solution, as outlined in Scheme 1. The crude lipopeptides were
purified by gel filtration on Sephadex LH-20.
⇑
Corresponding author. Tel.: +48 22 343 2207; fax: +48 22 632 6681.
E-mail addresses: ocryst@icho.edu.pl, zofia.lipkowska@icho.edu.pl (Z. Urban´ c-
zyk-Lipkowska).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.12.051

J. Janiszewska et al. / Bioorg. Med. Chem. Lett. 22 (2012) 1388–1393
1389
a
b
Boc-Phe-NH(CH2)nCH3
Boc-PheOH
HCl*Phe-NH(CH2)nCH3
1: n=7; 2: n=11
3: n=7; 4: n=11
d
c
Boc-Lys(Boc)-Phe-NH(CH2)nCH3
7: n=7: 8: n=11
5: n=7; 6: n=11
HCl*Lys(HCl)-Phe-NH(CH2)nCH3
g
13: n=7; 14: n=11
21: n=7; 22: n=11
k
17: n=7; 18: n=11
e
9: n=7; 10: n=11
i
Boc-Lys(Boc)
Boc-Lys(Boc)-Lys-Phe-NH(CH2)nCH3
Z-Lys(Boc)
Z-Lys(Boc)-Lys-Phe-NH(CH2)nCH3
l
h
23: n=7; 24: n=11
15: n=7; 16: n=11
Z-Lys(HCl)
(HCl)*Lys(HCl)
Z-Lys(HCl)-Lys-Phe-NH(CH2)nCH3
(HCl)*Lys(HCl)-Lys-Phe-NH(CH2)nCH3
Boc-Lys(2-Cl-Z)
Boc-Lys(2-Cl-Z)-Lys-Phe-NH(CH2)nCH3
(2-Cl-Z)-Lys(Boc)
(2-Cl-Z)-Lys(Boc)-Lys-Phe-NH(CH2)nCH3
f
11: n=7; 12: n=11
j
19: n=7; 20: n=11
HCl*Lys(2-Cl-Z)
(2-Cl-Z)-Lys(HCl)
HCl*Lys(2-Cl-Z)-Lys-Phe-NH(CH2)nCH3
(2-Cl-Z)-Lys(HCl)-Lys-Phe-NH(CH2)nCH3
Scheme 1. Synthesis of dendrimers 11–12, 15–16, 19–20 and 23–24. Reagents and conditions: (a) NH2(CH2)nCH3, DCC/HOBt, DMF, 4 h at À5 to 0 °C and overnight at rt, yield:
94% for 1, 90% for 2; (b) HCl/AcOEt, overnight at rt; yield: 97% for 3, 92% for 4; (c) Boc-Lys(Boc)OH, DCC/HOBt, DMF, 4 h at À5 to 0 °C and overnight at rt; yield: 80% for 5, 75%
for 6; (d) HCl/AcOEt, overnight at rt; yield: 93% for 7, 90% for 8; (e) Boc-Lys(2-Cl-Z)OH, DCC/HOBt, DMF, 4 h at À5 to 0 °C and overnight at rt; yield: 66% for 9, 70% for 10; (f)
HCl/AcOH, overnight at rt; yield: 65% for 11, 64% for 12; (g) Z-Lys(Boc)OH, DCC/HOBt, DMF, 4 h at À5 to 0 °C and overnight at rt; yield: 67% for 13, 62% for 14; (h) HCl/AcOH,
overnight at rt; yield: 66% for 15, 64% for 16; (i) (2-Cl-Z)-Lys(Boc)OH, DCC/HOBt, DMF, 4 h at À5 to 0 °C and overnight at rt; yield: 69% for 17, 65% for 18; (j) HCl/AcOEt,
overnight at rt; yield: 65% for 19, 64% for 20; (k) Boc-Lys(Boc)OH, DCC/HOBt, DMF, 4 h at À5 to 0 °C and overnight at rt; yield: 72% for 21, 70% for 22, (l) HCl/AcOEt, overnight
at rt; yield: 70% for 23, 68% for 24.
The fraction containing pure peptide was lyophilized and its
purity was confirmed by ESI MS and NMR spectroscopy. Table 1
and Figure 1 show synthesized compounds and general motifs A
and B of the synthesized lipopeptides. Compounds from group A
have more branched structure of the amphiphilic head (pairs
15–16 and 19–20). Isomeric compounds from group B have long
lipophilic arms, terminated with 2-chlorocarbobenzoxy groups
and involve pair 11–12. In each pair the first compound has octyl
(C8) and the second compound has dodecyl (C12) carbon chain
located at the C-end. Because the more charged compounds are
usually more potent against Gram-positive strains, compounds
23 and 24 bearing the (+)4 charge were also synthesized. The
in vitro antimicrobial activity measured as the minimal inhibitory
concentration (MIC) was evaluated for Gram-positive and Gram-
negative bacterial strains and yeasts of the Candida genus, using
the serial microdilution methods described previously.16 The
biological activities of the synthesized analogs along with two
reference compounds terminated with PheNH2 residue [compound
25–non-lipidated analog of 15 (structure A) and compound
26–non-lipidated analog of 11 (structure B)] are summarized in
Table 2. Our previous studies showed that isomers with structure
B were significantly more potent against broad range of microor-
ganisms and more hemotoxic.17 In the present case, the introduc-
tion of aliphatic chain at C-end resulted in an enhancement of
antimicrobial potency of compounds of A series by a factor of
4–15. For compounds with structure B a 4.5-fold enhancement in
inhibitory potency against Candida genus was observed for
compounds with C12 chain (e.g., compds 12 vs 26) and 2-fold
increase in potency against Escherichia coli for compounds with
C8 chain (e.g., 25 vs 11).
Interestingly, all compounds containing the C12 chain, irrespec-
tive of stereochemistry of the branched fragment, became selective
and potent against yeast-like microorganisms of the Candida
genus. As expected, (+4)-charged compound 24 is potent against

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J. Janiszewska et al. / Bioorg. Med. Chem. Lett. 22 (2012) 1388–1393
Table 1
(15 and 20), 100 lM (12 and 19) and 300 lM (11 and 23). In
particular, compounds 11 (active against E. coli), 12 and 20 (selec-
Structure of compounds synthesized via Scheme 1
R4
tive and potent against Candida strains) demonstrated 1%, 11% and
13% hemotoxicity at the 100 lM concentration, respectively. For
R3
Lys
R2
compounds 12, 16, 20 and 24, that express high activity against
Candida genus hemolysis was also measured for red blood cells
resuspended in L-glutamine deficient RPMI-1640 (Sigma) medium
R1 Lys-Lys-Phe-NH-(CH2)n-CH3
(used before for inoculation of Candida strains during MIC mea-
surements). As can be seen in Figure 3, replacement of PBS buffer
with RPMI medium significantly reduces hemolysis of the com-
pounds 24 and 16, whereas enhances hemolysis of compound 12.
The possible explanation might be, that very nutritious RPMI med-
ium (optimal for efficient growth of Candida cells) offers different
experimental conditions than PBS. It contains variety of amino
acids, saccharides, inorganic salts, etc., that although present in
small quantities, very likely can interact non-covalently not only
with positively charged lipopeptides [particularly with (+)-4
charged 24] but also with molecules located on external surface
of erythrocytes or with the released heme.
Compd
R1
R2
R3
R4
n
Rfa
11
12
15
16
19
20
23
24
NH2
NH2
Z
2-Cl-Z
2-Cl-Z
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
Z
2-Cl-Z
2-Cl-Z
NH2
NH2
NH2
NH2
NH2
NH2
7
11
7
11
7
11
7
0.61
0.61
0.49
0.49
0.50
0.50
0.10
0.10
Z
Z
2-Cl-Z
2-Cl-Z
NH2
NH2
2-Cl-Z
2-Cl-Z
NH2
NH2
11
a
TLC Silica gel 60 F254: n-BuOH/AcOH/H2O (3:1:1).
methicillin-susceptible and methicillin-resistant reference strains
of Staphylococcus aureus (Gram-positive). Compound 11 (C8 chain)
is more selective and potent against susceptible and resistant E. coli
(Gram-negative).
Except of the 19–20 pair, the hemotoxicity of compounds with
the same structure of polar head is higher for those bearing the
dodecyl chain (Fig. 2). However, even in this group of derivatives,
the hemotoxicity grows exponentially above MIC value for only
two compounds of group B, namely 16 and 24. For the remaining
The selective anticandidal activity of 12, 16, and 20 suggested a
specific mode of action of these compounds on Candida cells. In
fact, in the comparative studies, on the effect of 11 (very low
hemotoxicity and low anticandidal activity), and 12 (low hemotox-
icity and good anticandidal activity) on C. albicans morphology, it
was found that the yeast cells treated with these compounds under
conditions reported previously18 underwent some structural alter-
ations. No changes were observed in cultures containing 11 at
<60 lM or 12 at <7 lM while some alterations were noted for cells
six compounds, 10% of hemolysis was observed at about 50
lM
treated with higher concentrations of these compounds. The most
Cl
O
NH3+
O
O
NH
NH
O
O
NH
NH
O
NH3+
NH
NH
O
O
NH
NH
O
NH
O
NH
NH3+
O
O
NH
O
Cl
O
Cl
NH3+
NH
O
Cl
O
A (comp. 19)
B (comp. 11)
Figure 1. General structure of lipopeptides: A–more branched (compd 19) and B–less branched (compd 11).
Table 2
Antimicrobial activity of compounds synthesized via Scheme 1
MIC (M)
Compound
11
12
15
16
19
20
23
24
25
26
Micro-organism
C8
C12
C8
C12
C8
C12
C8
C12
NH2
NH2
S. aureus ATCC 25923
S. aureus ATCC 43300
E. coli ATCC 25922
E. coli ATCC BAA-198
Pseudomonas aeruginosa ATCC 27853
Bordetella bronchiseptica ATCC 4617
Klebsiella pneumoniae subsp. pneumoniae ATCC 13882
Acinetobacter baumanii ATCC 19606
Candida albicans ATCC 90028
Candida krusei ATCC 6258
30
8
8
8
120
7
119
60
60
15
15
28
28
56
64
114
14
114
114
7
32
16
30
8
32
8
128
128
32
16
16
15
8
30
8
64
7
121
121
8
16
16
32
32
32
8
128
>256
32
16
16
32
16
32
32
64
8
>256
>256
8
128
128
>256
>256
>256
32
>256
>256
256
128
64
8
4
>144
>144
>144
>144
>144
144
>144
>144
>128
>144
>144
33
17
33
16
67
8
34
67
33
33
33
32
64
64
8
>256
>256
16
7
7
8
8
8
8
4
4
Candida parapsilosis ATCC 22019
16
The MIC (minimal inhibitory concentration) values were determined by the serial dilution microplate method.
MICs of the reference compounds: Penicillin G against S.
aureus ATCC 25923–6.6 M; polymyxin B against E. coli ATCC 25922 and P. auruginosa ATCC 27853–0.55 M; fluconazole and aculeacin A against C. albicans–13 and 0.5 M,
respectively.

J. Janiszewska et al. / Bioorg. Med. Chem. Lett. 22 (2012) 1388–1393
1391
100
90
80
70
60
50
40
30
20
10
0
Changes in surface morphology of C. albicans cells on exposure
to lipopeptide 12 and 16 were studied by scanning electron
microscopy (Fig. 5). Both compounds, already at 0.5ÂMIC (2 h), in-
duced severe alterations to the cell envelope and some leakage of
the intracellular contents was observed (Fig. 5B and D, for 12 and
16, respectively). Small number of Candida cells completely lost
their integrity on exposure to 12 at 1.5ÂMIC concentration
11
12
15
16
19
20
23
24
(Fig. 5D). However, at 64
lM (8ÂMIC), lipopeptide 16 caused a
massive destruction of the cell surface (Fig. 5E). Such changes are
characteristic for the action of fungicidal inhibitors of the cell wall
b(1,3)-glucan biosynthesis.19
The morphological changes observed upon the action of lipo-
peptides under study thus suggested their interference in biosyn-
thesis of the yeast cell envelope, especially that of its major
component, namely b(1,3)-glucan. A possible effect of novel lipo-
peptides on b(1,3)-glucan synthase, that is, the enzyme responsible
for the biosynthesis of b(1,3)-glucan in yeast cells, was therefore
studied, using the microtiter method.20
0.001 0.005 0.01
0.05
c [mmol/l]
0.1
0.2
0.4
Figure 2. Hemolysis induced by lipopeptides on red blood cells suspended in PBS
buffer; N–with the C8 chain, d–with the C12 chain located at C-terminus.
Data showed in Figure 6 clearly indicate that both 11 and 12
inhibited this enzyme present in the membrane fraction of
C. albicans cells, in the concentration-dependent manner and
compound 12 appeared a stronger enzyme inhibitor than its 11
analogue. Inhibition of 50% of b(1,3)-glucan synthase activity
(IC50) was observed at 51
187 M (200
g mlÀ1) inhibited the enzyme by 43% only and the
IC50 value for this compound was not actually determined. The
IC50 values for compounds 16 and 20 were in the 50–70 M range,
lM (57
6 l
g mlÀ1) for 12, while 11 at
l
l
l
that is, very similar to that found for compound 12. The known
glucan synthase inhibitor, trans-cinnamaldehyde21 taken as a
reference, inhibited the enzyme with IC50 = 1.15 mM, while for
the known antifungal lipopeptide aculeacin A,22 the respective
Figure 3. Hemolysis induced by selected lipopeptides on red blood cells suspended
in RPMI medium; d–compounds with the C12 chain located at C-terminus.
value was 12 lM. The IC50 values of compounds 11 and 12 against
C. albicans b(1,3)-glucan synthase were higher than their MICs
against the whole cells of this micro-organism. This phenomenon
is characteristic for lipophilic or amphipatic inhibitors of b(1,3)-
glucan synthase and was noted previously for aculeacin A, echino-
candins and caffeic acid derivatives.22,23 Such compounds are
supposed to accumulate in the cell membrane, to achieve there a
local concentration much higher than that in the growth medium.
Data shown inFigures 2 and 3 indicated some hemolytic action of
both compounds on human erythrocytes, although this effect was
the weakest for 11, relatively weak for 12 and 20 and stronger for
16, among the compounds tested. In order to find out whether 11
and 12 exhibit any membrane-disrupting effect in fungal cells, the
striking changes in cell morphology, observed in cultures treated
with both compounds at concentrations corresponding to 2ÂMIC
for 6 h, shown in Fig. 4, included apparent ‘chaining’ of the cells,
most likely resulting from the formation of pseudohyphal forms
or cell agglutination. These effects seemed to be a bit more pro-
found in the case of cells treated with 12. Most likely, cell aggluti-
nation may indicate some changes in the structure of the cell
surface, including its major component, b(1,3)-glucan. Both com-
pounds induced minimal changes in distribution of Calcofluor
White-stained chitin, localized mainly in the septum and bud scars
regions.
Figure 4. Visualisation of the effect of 11 and 12 on morphology of C. albicans ATCC 10231 yeast cells. Microphotographs were taken after 6 h incubation. (A–C) Cells stained
for chitin with Calcofluor White. (A) Control–untreated cells, (B) Cells treated with 11 at 120 M, (C) Cells treated with 12 at 14 M; (D–E) Cells stained for glucan with
Aniline Blue. (C) Control–untreated cells, (D) Cells treated with 11 at 120 M, (E) Cells treated with 12 at 14 M.
l
l
l
l

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J. Janiszewska et al. / Bioorg. Med. Chem. Lett. 22 (2012) 1388–1393
Figure 5. Scanning electron microscope image of the C. albicans cells. (A)–intact cells; (B–C)–cells after exposure to lipopeptide 12 at 4
(1.5ÂMIC); (D–E)–cells after exposure to lipopeptide 16 at 4 M (0.5ÂMIC) and at 64 M (8ÂMIC), respectively.
lM (0.5ÂMIC) and at 10 lM
l
l
efflux of potassium ions from the cells subjected to the compound
action was continuously monitored using the potassium-selective
electrode.18 Results are shown inFigure 7. Both compounds induced
potassium leakage in a very similar way. The effect was concentra-
tion-dependent and concentrations causing release of 50% of intra-
cellular potassium (EK50) in comparison to positive control were
13 lM (15 l lM (18 l
g mlÀ1) and 17 g mlÀ1) for 12 and 11, respec-
tively. Interestingly enough, the EK50 value of 12 is slightly higher
than its MIC, while 11 induced substantial release of intracellular
potassium at concentrations well below its MIC. This corresponds
to some extent with higher hemotoxicity of 12 (see Figs. 2 and 3).
In the parallel determination, an antifungal polyene macrolide anti-
biotic Nystatin, well known for its channel-forming mode of anti-
fungal action,24 exhibited EK50 = 2.3 g mlÀ1 (2.4
l lM).
The data presented in this study concern a group of novel
cationic lipopeptides with amphiphilic, dendrimeric head and C-
terminal fatty acid chain. Introduction of a lipid tail at C-end
Figure 6. In vitro inhibition of b(1,3)-glucan synthase activity by 11 and 12. The
assay was performed using the microtiter-based fluorescence method.20 Values are
the means of three independent experiments. Bars represent SD.
(particularly C12
) yielded several compounds with enhanced

J. Janiszewska et al. / Bioorg. Med. Chem. Lett. 22 (2012) 1388–1393
1393
synthesized and purified by standard chromatographic methods.
Their branched structure may prevent enzymatic biodegradation,
similarly to the reported earlier branched MAP systems.26
Acknowledgment
Financial support from the Ministry of Science and Higher Edu-
cation, Grant N204 239436 is acknowledged.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2011.12.051.
Figure 7. Release of intracellular potassium from C. albicans ATCC 10231 induced
by 11 and 12. Potassium efflux was monitored with an ion-selective potassium
electrode. The K+ release induced is represented as the percentage relative to the
maximal K+ released upon boiling of the cell suspension (100%). Each value is the
mean of three independent determinations. Bars represent SD.
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antimicrobial potency, low hemotoxicity and selectivity shifted
towards yeasts of the Candida genus. These compounds induced
potassium leakage from fungal cells, caused morphological altera-
tions of fungal cells and inhibited activity of candidal b(1,3)-glucan
synthase. Since induction of potassium release leakage is
considered a consequence of alterations made upon the action of
an antifungal agent on the cell membrane and on the other hand,
b(1,3)-glucan synthase is the membrane-located enzyme, the
compounds under study are likely to target the fungal cell mem-
brane and at least one of the enzymatic proteins located there. It
seems that both effects may contribute to the fungistatic activity
of 11 and 12, but inhibition of b(1,3)-glucan synthase is more likely
to be a reason for differentiated antifungal potency of these com-
pounds, in spite of the fact that a direct correlation between en-
zyme inhibitory potency and antifungal activity was not found.
There is little doubt that inhibition of b(1,3)-glucan synthase is
responsible for the lysis of C. albicans cells observed by SEM for
16 at 64 lM, that is, at the concentration higher than the IC50 value
against the enzyme The inhibitory effect on fungal b(1,3)-glucan
synthase, shown in this report for 12, 16 and 20, has never been
reported before for any structurally related compounds. Obviously
the enzyme inhibitory potency of compounds 12, 16 and 20 is low-
er than that of aculeacin A and much lower than that reported for
the lipopeptide antifungal clinical drug caspofungin,23 but low
hemotoxicity, a feature noted also for caspofungin25 makes espe-
cially compounds 12 and 20 interesting leads for further modifica-
tions aimed at the improvement of its antifungal potency,
including optimization of the peptidic core and adjustment of the
fatty acid chain length. Compound 12 and its analogues studied
by us, have several advantages as the prospective antifungals in
terms of pharmaceutical analysis and characterization. They are
monodisperse, low molecular weight molecules that can be easily
24. Zotchev, S. B. Curr. Med. Chem. 2003, 10, 211.
25. Bartizal, K.; Gill, C. J.; Abruzzo, G. K.; Flattery, A. M.; Kong, L.; Scott, P. M.; Smith,
J. G.; Leighton, C. E.; Bouffard, A.; Dropinski, J.; Balkovec, F. J. Antimicrob. Agents
Chemother. 1997, 41, 2326.
26. Bracci, L.; Falciani, C.; Lelli, B.; Lozzi, L.; Runci, Y.; Pini, A.; De Montis, M. G.;
Tagliamonte, A.; Neri, P. J. Biol. Chem. 2003, 278, 46590.