Synthesis, characterization, optical and electrochemical properties and antifungal and anticancer activities of ferrocenyl conjugated novel dendrimers

Article abstract of DOI:10.1039/c6nj01120a

A new class of triazoloferrocenyl conjugates (1, 2 and 3) was obtained by copper(i) catalyzed click chemistry, specifically the alkyne azide cycloaddition (CuAAC) of bis(β-hydroxyl)arylalkyneether with suitable ferrocenyl azides. The synthesized bis(β-hydroxyl)arylether linked ferrocenyl conjugates 1, 2 and 3 exhibit antifungal activity against fungal pathogens, viz. Candida albicans, Candida glabrata and Candida crusi, comparable to that of amphotericin B and also show excellent anticancer activity against MCF-7 cell lines.

Full text of DOI:10.1039/c6nj01120a

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PAPER
Jason B. Benedict et al.
The role of atropisomers on the photo-reactivity and fatigue of
diarylethene-based metal–organic frameworks
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Synthesis, characterization, optical, electrochemical properties and
antifungal, anticancer activities of ferrocenyl conjugated novel dendrimers
a
a,b
a
Velautham Saravanan, Ayyavoo Kannan and Perumal Rajakumar *
a
Department of Organic Chemistry, University of Madras, Chennai, 600 025, India.
b
Department of Chemistry, University of the Free State, Bloemfontein, South Africa
*
Eꢀmail: perumalrajakumar@gmail.com; Fax: +91 044 22300488;
Tel: +91 044 22202814; 9551379907
Abstract
New class triazoloferrocenyl conjugates 1, 2 and 3 were obtained by copper (I)
catalyzed click chemistry of alkyne azide cycloaddition (CuAAC) of bis(β–
hydroxyl)arylether with suitable ferrocenyl azides. The synthesized bis(β–hydroxyl)arylether
linked ferrocenyl conjugates 1, 2 and 3 exhibit antifungal activity against the fungal
pathogens viz Candida albicans, Candida glabrata and Candida crusi comparable to that of
amphotericin B and also shows excellent anticancer activity against the MCFꢀ7 cell lines.
Keywords: Ferrocenyl dendrimers, β–hydroxypropargylether, click chemistry, antifungal
and anticancer activity amphotericin B.
Introduction
1
Copper (I) catalyzed azide–alkyne cycloaddition (CuAAC) known as click chemistry
developed before few decades has been quickly applied for the synthesis of new dendritic
2
architectures. The triazolyl moiety is a perfect choice known for its interaction with many
anions, transition metals cations and neutral molecules and also has wide range of
applications in the field of pharmacological and biological chemistry. The introduction of
triazolyl group into the dendrimer system would rather enable the encapsulation of guest
molecules. Triazolyl moiety is a privileged class of five member heterocyclic systems, which
has attracted both medicinal and synthetic chemists due to its synthetic and biological
applications. The triazolyl group is highly stable under basic, acidic, reductive and oxidative
1

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conditions and also have high dipole moment, rigidity, stability and capability to form
hydrogen bonding with biological targets. Ferrocenyl motif has played a unique role in the
modern medicine because of its excellent features including nonꢀtoxicity and stability under
3
physiological conditions. The ferrocenyl unit, has now been recognized as a useful motif for
the development of new class and effective drugs viz. antiꢀandrogen nilutamide and
ferrocenyl analogs of commercial antiꢀestrogen tamoxifen which display higher cytotoxicity
4
against breast and prostate cancer cells respectively in comparison to the reference drugs.
Certainly, the ferrocene appended chloroquine (CQ) known as Ferroquine (FQ), has
enhanced the biological activity of the drug molecule by 22 times more than CQ against CQꢀ
5
R strain of P. Falciparum. Ferrocene derivatives are highly active in vitro and in vivo,
6
against several fungal and bacterial infections, including Human Immunodeficiency Virus
7
8
9
(
HIV), Malaria and Cancer. Ferrocenyl conjugates play an important role in electronꢀ
transfer reactions which are involved in many biological systems and also in synthetic
10
11
chemistry as multiꢀredox nanosystems, viz., as biosensors, vectors, biological redox
12
13
14
15
processes, catalysis, semiconductors, redox recognition, etc., and biological properties
16
17
18
like antitumour agent, antimalarial, antiꢀcancer effect in human lung cancer cells, Many
ferrocenyl compounds display interesting cytotoxic, antiꢀtumor, antimalarial, antifungal and
1
9
DNA cleaving activities.
In particular, ferrocenyl compounds have been synthesized for a wide range of
2
0
applications in the medicinal and pharmaceutical disciplines. The drug resistance in the
microbial pathogens has drastically increased and surpassed the development and delivery of
new effective antimicrobial drugs. As a result there is a threat to the global health and the
currently available therapeutics will no longer be effective in treating infections due to
increasing drug resistance in microbial pathogens. To fight against such increase in drug
resistance, discovery of new antimicrobial agents is essential.
2

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The occurrence of breast cancer in Asian women has been increasing in the last few
decades. The breast tumors are resistant to the conventional treatment which shows side
effects. Radiation therapy and surgical treatments are not sufficient and not satisfactory for
most of the developing countries. According to World Health Organization (WHO) the
chemotherapy is employed for more than 90% of women affected with breast cancer. Owing
to the need of new drugs for the chemotherapeutic treatment of breast cancer and to find the
compounds with effective antifungal activity, we report herein the synthesis of ferrocenyl
conjugates 1ꢀ3 with β –hydroxyarylether focal point using the copper (I) catalyzed click
21
chemistry. The promising antifungal and anticancer activities of dendrimers 1, 2 and 3
provide useful information and serve as a new potential area of research.
42
N
N
N
N
N
N
N
N
N
N
N
N
O
O
O
O
N
N
N
N
N
N
N
N
O
O
N
N
N
O
O
O
O
N
OH
OH
O
O
N
N
N
N
N
N
O
O
O
O
N
N
3
(G2)
N
N
N
N
N
N
N
N
N
N
Figure 1: Structure of the ferrocenyl conjugates 1, 2 and 3.
3

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Results and discussion
Reaction of 3,5ꢀbis(propargyloxy)benzyl chloride 5 with 2.1 equiv. of ferrocenylazide
4
6
6
under Cu(I)ꢀcatalyzed click reaction conditions gave the first generation dendritic chloride
3
in 92% yield, which on further treatment with NaN in a mixture of acetoneꢀwater (4:1) at
o
0 C gave the dendritic azide7 in 96% yield. The second generation dendritic azide 9 was
obtained by a similar sequence by repeating of the above reaction sequence namely Cu(I)ꢀ
catalyzed click reaction followed by reaction with sodium azide. Reaction of 1.0 equiv. of
3,5ꢀbis (propargyloxy) benzyl chloride 5 with 2.1 equiv. of the azidodendron 7 under click
chemistry conditions gave the dendritic chloride 8 in 83% yield, which was further converted
3
into the dendritic azide 9 in 85% yield using NaN in a mixture of acetoneꢀwater (4:1) at 60
o
C (Scheme 1).
Scheme 1 Reagents and conditions: (i) CuSO
4 2
(5 mol%), sodium ascorbate (10 mol%), H Oꢀ
THF (1:1), rt, 12 h, 6 (92%), 8 (83%) (ii) 1.5 equiv. NaN , CH COCH ꢀH O (1:1), 60 ºC, 1ꢀ3
3
3
3
2
h, 7 (96%), 9 (85%).
1
The H NMR spectrum of the dendritic azide 7 displayed three different singlets at δ
4.16, 4.21 and 4.27 for the ferrocenyl protons, two different singlets at δ5.06 and 5.28 for the
4

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13
Oꢀmethylene and Nꢀmethylene protons, a singlet at δ 7.51 for the triazolyl proton. The C
NMR spectrum of the dendritic azide 7 displayed the ferrocenyl carbons at δ 68.6, 68.8, 68.9
and 69.1, and two different triazolyl carbons at 143.3 and 144.1 respectively. The appearance
of molecular ion peak at m/z 723 also confirmed the structure of the dendritic azide 7. Further
the constitution of dendritic azide 7 was confirmed from elemental analysis.
1
The HꢀNMR spectrum of the ferrocenyl dendritic azide 9 displayed two different
singlets at δ5.12 and 5.29 for the Oꢀmethylene and Nꢀmethylene protons, a singlet at δ 7.51
13
for the triazole proton in addition to the signals for aromatic and ferrocenyl protons. The C
NMR spectrum of the dendritic azide 9 displayed the triazole carbon at δ 143.6. The
appearance of molecular ion peak at m/z 723 also confirmed the structure of the dendritic
azide 9. Elemental analysis also supported the constitution of the dendritic azide 9.
The synthesis of the key intermediate, asymmetric bisoxirane 11 begins from the
readily available resorcinol. Reaction of 2.1 equiv. of epichlorohydrin with 1.0 equiv of
resorcinol in the presence of NaH in DMF at room temperature gave the bisoxirane 11 in
86% yield. The bisoxirane 11 was subjected to ring opening with 2.1 equiv. of propargyl
alcohol in dry DMF to afford the βꢀhydroxypropargyloxy ether 12 in 74% yield (Scheme 2).
O
O
HO
OH
i
O
O
10
11
ii
OH
OH
O
O
O
O
12
Scheme 2 Reagents and conditions: (i) 2.1 equiv. Epichlorohydrin, NaH, DMF, 0–25
2 h, 11 (86%). (ii) 2.1 equiv. Propargyl alcohol, Dry DMF, RT, 3h, 12 (74%)
2
ͦ C, N ,
1
5

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1
The H NMR spectrum of the bisoxirane 11 displayed two doublets of doublet at δ
.20, 3.90 for OCH protons, the oxirane protons appeared as doublets of doublet at δ 2.90,
.73 in addition to the signals for the other aliphatic and aromatic protons. The C NMR
4
2
2
13
spectrum of the bisoxirane 11 displayed the oxirane carbons at δ 44.6, 50.1 and the OCH
2
carbon at δ 68.8 in addition to the signals for the other aromatic carbons. The appearance of
molecular ion peak at m/z 222 in mass spectrum and also elemental analysis confirmed the
1
structure of the bisoxirane 11. The H NMR spectrum of the βꢀhydroxypropargyloxy ether 12
displayed triplet at δ 2.47 for acetylenic protons, the OCH protons appeared as a doublet at δ
2
1
3
4
.02 in addition to the signals for the other aliphatic and aromatic protons. The C NMR
spectrum of βꢀhydroxypropargyloxy ether 12 displayed the acetylenic carbons at δ 75.0 and
9.3, the propargyl ꢀCH carbon appeared at δ 58.7 in addition to the signals for the other
7
2
aliphatic and aromatic carbons. The appearance of molecular ion peak at m/z 334 in mass
spectrum and also the elemental analysis confirmed the structure of the βꢀ
hydroxypropargyloxy ether 12.
Reaction of the 1.0 equiv. of the βꢀhydroxypropargyloxy ether 12 with 2.1 equiv. of
the dentric azide 4, 7 and 9 under click chemistry conditions in presence of copper sulphate
(
5 mole%) and sodium ascorbate (10 mol %) in a mixture of THF ꢀ H O (1:1) at room
2
temperature afforded the ferrocenyl conjugates 1, 2 and 3 in 92%, 89%, 82% yields,
respectively (Scheme 3).
Scheme 3. Ragents and conditions: (i) CuSO (5 mol %), sodium ascorbate (10 mol %),
4
H O/THF (1:1), rt, 12 h, 1 (92%), 2 (89%) and 3 (82%).
2
6

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Optical and property of ferrocenyldendrimers 1, 2 and 3
The UVꢀVis absorption spectrum of the ferrocenyl conjugates 1, 2 and 3 was obtained
ꢀ5
in DCM (1 X 10 M) and the absorption maxima is observed at 433, 435 and 434 nm, for the
dendrimer 1, 2 and 3 respectively (Figure 2A). In the absorption spectra, the absorption
intensity of the UVꢀvisible band increases from ferrocenyl conjugate 1 to 3 at the same
concentration though λmax remains almost constant, which is due to the presence of more
22
number of ferrocenyl units, usually called valence effect in dendrimer chemistry. Figure 2B
shows the linear increase in the absorption intensity of the ferrocenyl dendrimers with
increase in the number of ferrocenyl units.
ꢀ5
Figure 2: (A) UVꢀvis absorption spectra of ferrocenyl conjugate 1, 2 and 3 in DCM (1X10
M) at room temperature: (B) Linear relation of absorption with number of ferrocenyl units.
Electrochemical studies
The redox properties of the ferrocenyl dendrimers 1, 2 and 3 was studied using cyclic
voltammetry (CV) technique. The cyclic voltammogram for dendrimer 1 to 3 was obtained in
2 2
the potential range of 0.0 V to 1.0 V at room temperature in CH Cl containing 0.1 M TBAP
as the supporting electrolyte at the scan rate 50 mV/s (Figure 3). The reversible oxidation
potential for the ferrocenyl dendrimer 1ꢀ3 is obtained at 419, 497 and 599 mV and the
7

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reversible reduction peak is observed at 597, 613 and 649 mV respectively. The increase in
the dendrimer generation from 1 to 3 increases the redox peak potential from less positive to
more positive peak pontential due to the presence of more number of triazolyl units and
ferrocenyl groups in 3 than in dendremers 1 and 2, though the current intensity remains
constant.
1
5.0ꢁ
0.0ꢁ
1
2
3
1
5.0ꢁ
0.0
ꢀ5.0ꢁ
ꢀ10.0ꢁ
ꢀ15.0ꢁ
0.0
0.2
0.4
0.6
0.8
1.0
Potential (V)
Figure 3. Cyclic votammogram of ferrocenyldendrimers 1, 2 and 3 in DCM at room
ꢀ1
temperature. (scan rate at 50 mV s ) and 0.1 m tetrabutylammonium perchlorate as a
supporting electrolyte in dry DCM.
Table 1. Optical and electrochemical parameters of ferrocenyl dendrimers 1, 2 and 3 in DCM
ꢀ5
(
1 X 10 M). Ferrocenyl dendrimers 1, 2 and 3 are almost identical and exhibit an intense
absorption band at 433ꢀ435 nm (Figure 2).
Dendrimers
λ
abs max Optical Molar absorptivity
E
pa
E
pc
(nm)
density
coefficient ( ɛ)
L mol cm )
ꢀ1
ꢀ1
1
2
3
433
435
434
0.24
0.38
0.62
24000
0.42
0.50
0.60
0.60
0.61
0.65
38000
62000
8

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Antifungal activity of ferrocenyl dendrimers 1, 2 and 3
Minimum Inhibitory Concentration (MIC):
The MIC for the antifungal activity of the dendrimers is determined by resazurin dye
23
reduction assay method. The change of the colour of the dye from blue or purple to pink is
considered as the indication of MIC values. The conversion of resazurin to pink colored
resorufin is due to the presence of enzyme oxidoꢀreductase in unicellular fungus. The
reduction of resazurin indicates presence of viable cells. But when the fungal cells dies, then
it could not convert the resazurin to resorufin and thus the colour of the dye remains blue.
The ferrocenyl dendrimers 1, 2 and 3 when added to the assay wells kills the fungal cells after
appropriate incubation, viz., the fungal suspension was added in well plate then incubated in
37° C at 18ꢀ24 h then the dye was added to the proper well and then incubated in 37° C at 2ꢀ3
h and the colour change from blue to colour was observed pink. This was observed by the
blue colour in the respective wells. The pink colour formation in the wells even after treating
with ferrocene dendrimers or commercial drug indicates the presence of viable cells. Thus the
least dilution in which the colour remains blue was taken as the MIC value of the particular
compound. The ferrocenyl dendrimers 1, 2 and 3 showed antifungal activity against the
fungal viz Candida albicans, Candida glabrata and Candida crusi. The MIC values lie
between from 3.12 to 50 ꢁg/mL for all the synthesized compounds. The ferrocenyl dendrimer
1
was found to show be better activity than 2 and 3 in antifungal assay against Candida
albicans, Candida glabrata and the results are shown in Table 2. Figure 4 shows the
antifungal activity of the dendrimer 1, 2 and 3 with amphotericin B as the standard.
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Antifungal photo:
Figure 4: The antifungal activity of the ferrocenyl dendrimer 1, 2 and 3.
2
4
For unicellular and multicellular organism, iron happens to be an essential element.
It is interesting to note that some of the fungal pathogens use iron from host molecule for
25
their metabolism, growth and invasion during infection. Microorganism such as Candida
albicans, Candida glabarata and Candida crusi can even utilise haemoglobin as an iron
26
resource. In our current study, surprisingly addition of ferrocenyl dendrimer help the fungal
pathogens to utilise the iron present in the host molecule for their generation. Dendrimer 1
has lower iron content and hence its can effectively inhibit the growth of the three fungal
pathogens viz Candida albicans, Candida glabarata and Candida crusi. However as we
move on to the first and second generation dendrimer 2 and 3, the iron content increases and
hence the inhibition of the growth of the fungal organism decreases rapidly. In fact the
second generation ferrocenyl dendrimer 3 do not inhibit the growth of the fungal organism
and hence the MIC value are much larger than the standard viz AmphotericinꢀB. In
1
0

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conclusion the presence of ferrocenyl dendrimer do not inhibit that much the growth of
fungal organism viz Candida albicans, Candida glabarata and Candida crusi mainly due to
the presence of iron in it. Further from the study it is clear that though the presence of
triazolyl group could try to increase the inhibition of the growth of fungal pathogens the iron
present in the dendrimers helps the growth of the tested fungal pathogens and hence the MIC
values are much larger than the standard.
Table 2: Minimum Inhibitory Concentration of the ferrocenyl dendrimer 1, 2 and 3 by
resazurin reduction assay against fungal pathogens
MIC ꢁg/mL
Fungal pathogens
Compounds/generation
Candida
albicans
Candida
glabrata
3.12
Candida crusi
6.25
12.5
50
1
2
3
(
(
(
G0
G1
G2
)
)
)
12.5
6.25
12.5
0.78
50
50
Standard ꢀ AmphotericinꢀB
1.56
3.12
Anticancer activity of ferrocenyl dendrimers 1, 2 and 3
The ferrocene dendrimers were then tested for anticancer activity by MTT assay
against the MCFꢀ7 cell lines and all the three ferrocene dendrimers exhibited good anticancer
activity against the MCFꢀ7 cell lines. The viability of MCFꢀ7 cells decreases gradually as the
concentration of the compounds increases. A dose response graph was plotted and the IC50
value was calculated. The IC value of the compounds are calculated by the three parameter
50
27
logistic fixed bottom (3PLFB) model and IC50 values of the compounds 1, 2 and 3 are found
to be 20.55 µg/mL, 10.91 µg/mL, 3.12 µg/mL and for SD viz, doxorubicin the IC50 values is
2.61 µg/mL. The error was less by 3PLFB model and hence fixing bottom at 100% is
1
1

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employed as the activity base was unable to fit a fixed top model and the IC value increases
50
by more than twoꢀfold. Among the three ferrocenyl dendrimers tested, the ferrocenyl
dendrimer 3 was found to be more effective against the MCFꢀ7 cells with effective IC50 value
(Table 3 and Figure 5). Further molecular docking studies of these ferrocenyl dendrimers are
underway to find their mode of actions against the MCFꢀ7 cells.
Table 3: Anticancer activity of ferrocenyl dendrimers
S.N
o
Concentration (µg/mL)
Den 1 Den 2 Den 3 SD
Absorbance (OD in nm)
Cell viability (%)
Den 1 Den 2 Den 3 SD
Den1
Go)
Den2
(G1)
Den 3 SD
(G2)
(
1
2
3
4
5
6
7
100
50
100
50
100
50
50
0.09
0.12
0.28
0.31
0.37
0.43
0.07
0.12
0.24
0.28
0.32
0.40
0.58
0.04
0.10
0.19
0.25
0.29
0.33
0.58
0.02 15.51
0.06 20.69
0.10 48.27
0.16 53.44
0.27 63.79
0.36 74.13
0.58 100
12.06
20.69
41.37
48.27
55.17
68.96
100
6.89
3.44
25
17.24
32.75
34.48
43.10
50.00
100
10.34
17.24
27.58
46.55
62.06
100
25
25
25
12.50
6.25
3.12
1.56
12.50
6.25
3.12
12.50
6.25
3.12
12.50
6.25
3.12
Contro Contro Contro contro 0.58
l
l
l
l
Den 1= dendrimer 1, Den 2 = dendrimer 2, Den 3 = dendrimer 3, SDꢀ standard drugꢀ doxorubicin
Figure 5: Anticancer activity of ferrocenyl dendrimers 1 (G0), 2 (G1) and 3 (G2) against
MCFꢀ7 cells
1
2

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Conclusion
In conclusion, ferrocenyl conjugated dendrimers 1, 2 and 3 with triazole as the
bridging unit has been obtained through click chemistry in excellent yield. The zeroth
generation ferrocenyl dendrimer 1 showed better activity against fungal pathogens candida
albicans, candida glabrata and candida crusi when compared to the first and second
generation dendrimer 2 and 3, whereas second generation dendrimer 3 showed excellent
anticancer activity against the MCFꢀ7 cells, when compared with the zeroth and first
generation dendrimer 1 and 2. Further studies on such these biological active ferrocenyl
dendrimers are essential to explore their complete biological potentials.
Experimental
Material and methods
All reagents were commercially available and used as such unless otherwise stated.
Analytical TLC was performed on commercial Merk plates coated with Silica Gel GF254.
Analytical samples were obtained from silica gel chromatography, using silica gel of 100ꢀ200
mesh and elution with the solvent system as mentioned under each experiment section. The
melting points were determined by using a Metler Toledo melting point apparatus by open
1
13
capillary tube method and were uncorrected. H and C NMR spectra were recorded on a 300
13
MHz BRUKER AVANCE (75 MHz for C NMR,) spectrometer. UVꢀVis absorption spectra
were measured with a Perkin–Elmer Lambda 35 UVꢀvis spectrometer, Cyclic voltammetry
measurements were performed in a conventional three electrode system on a CHI model
1100A series electrochemical analyzer (CH Instrument, Austin, TX). The measurements were
based on a three electrode system, with a glassy carbon (GC) electrode (of geometric area
2
0
.07 cm ) being used as the working electrode, a Pt wire in the form of a spiral (with a high
1
3

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2
geometrical surface area B20 cm ) being used as the auxiliary electrode and Ag/AgCl as the
ꢀ1
reference electrode with a scan rate of 50 mV s . The supporting electrolyte of 0.1 M TBAP.
General procedure for the Cu (I) catalyzed click reaction (procedure A)
A mixture of acetylenic derivative (1.0 mmol, 1equiv.) and azido derivative (5.1
mmol, 5.1equiv.) was dissolved in THFꢀH O (1:1; 8 mL) and added sodium ascorbate (0.4
2
mmol, 0.4 equiv.) followed by the addition of CuSO
mixture was stirred overnight at room temperature. The solvent was evaporated and the crude
product was dissolved with EtOAc (2 X 100 mL), washed with NH Cl solution (50 mL) and
brine solution (50 mL), dried over Na SO and concentrated to give a residue, which was
4
(0.2 mmol, 0.2 equiv.). The reaction
4
2
4
purified by column chromatography (SiO ), using the eluent as mentioned under each
2
compound.
General procedure for convertion of dendritic chloride to azide (procedure B)
Dendritic chloride (1.0 mmol, 1.0 equiv.) was dissolved in a mixture of acetoneꢀwater
(
4:1; 8 mL) and added NaN (1.5 mmol, 1.5 equiv./ 2.5 mmol, 2.5 equiv.), and the mixture
3
0
was heated to 60 C for 3 h. The reaction mixture was cooled to room temperature, acetone
was evaporated, diluted with water (100 mL), and extracted with EtOAc (2 X 100 mL). The
2 4
organic layer was washed with saturated NaCl (100 mL), dried over Na SO and evaporated
to give the corresponding azido compounds.
Azidomethylferrocene 4:
2
8
Azidomethylferrocene 4 was prepared as reported in the literature from hydroxyl
methyl ferrocene (2g, 9.3 mmol) and NaN (1.2g, 18.5 mmol).
3
3,5ꢀbis(propargyloxy)benzyl chloride 5:
29
3
,5ꢀBis(propargyloxy)benzyl chloride 5 was prepared as reported in the literature
1
4

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from 3,5ꢀbis(propargyloxy)benzyl alchohol (1.2g, 5.6 mmol) and thionyl chloride (0.8 mL,
1.1 mmol).
1
Ferrocenyldendritic chloride 6:
The dendritic chloride 6 (0.45 g) was obtained as pale yellow solid from 3,5ꢀbis
(propargyloxy) benzyl chloride 5 (0.16 g, 0.68 mmol) and azidomethylferrocene 4 (0.35 g,
1
1
4
5
.4 mmol) under click chemistry conditions following the procedure A. Yield: 92 % MP:
o
1
24ꢀ126 C H NMR: 300 MHz, CDCl ): δH 4.18 (s, 10H), 4.22 (s, 6H), 4.28 (s, 4H), 5.12 (s,
3
1
3
3 C
H), 5.29 (s, 4H), 6.53 (s, 1H), 6.56 (s, 2H), 7.51 (s, 2H). C NMR: (75 MHz, CDCl ): δ
0.2, 62.2, (68.7, 68.9. 69.1,Cp) 80.6, 101.8, 107.5, 122.2, 137.8, 143.6, 159.7. MS (ES): m/z
+
=
716 [M ]. Elemental Anal. Calcd for C35
H
33Fe
2
N
O
6 2
Cl: C, 58.64, H, 4.64, N, 11.72%.
Found: C, 58.54, H, 4.61, N, 11.68%.
Ferrocenyldendritic azide 7:
Following the general procedure B, the dendritic azide 7 (0.95 g) was obtained as
light yellow solid from the dendritic chloride 6 (1 g, 1.4 mmol) and NaN (0.18 g, 2.8 mmol).
4.16 (s, 10H), 4.22 (s, 6H),
3
o
1
Yield: 96% MP: 134ꢀ136 C H NMR: (300 MHz, CDCl
3
):
δ
H
13
4
.28 (s, 4H), 5.12 (s, 4H), 5.29 (s, 4H), 6.53 (s, 1H), 6.56 (s, 2H), 7.51 (s, 2H). C NMR: (75
MHz, CDCl
3
):
δ
C
50.2, 62.2, (68.7, 68.9. 69.1,Cp) 80.6, 101.8, 107.5, 122.2, 137.8, 143.6,
+
1
59.7. MS (ES): m/z = 724 [M ]. Elemental Anal. Calcd for C35
H33Fe
2
N
9
O
2
: C, 58.11, H,
4.60, N, 17.43%. Found: C, 58.00, H, 4.47, N, 17.36%.
Second generation ferrocenyldendritic chloride 8:
The ferrocenyl dendritic chloride 8 (0.77 g) was obtained as yellow solid from 3,5ꢀbis
propargyloxy) benzyl chloride 5 (0.13 g, 0.55 mmol) and the dendritic azide 7 (0.86 g, 1.16
(
mmol) under click chemistry conditions following the procedure A. Yield: 83% MP: 130ꢀ132
o
1
3 H
C H NMR: (300 MHz, CDCl ): δ 4.10 (s, 2H), 4.16, 4.21, 4.27 (s, 36H; Cp), 5.06 (s, 8H),
1
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5.14 (s, 4H), 5.28 (s, 8H), 5.39 (s, 4H), 6.46 (s, 4H), 6.53 (s, 3H), 6.56 (s, 2H), 7.51 (s, 4H),
13
7
.59 (s, 2H). C NMR: (75 MHz, CDCl ): δC 50.1, 54.1, 54.6, 62.0, (68.6, 68.8, 68.9, 69.1,
3
Cp), 80.7, 101.7, 102.0, 107.5, 122.4, 123.1, 133.5, 136.8, 137.8, 143.3, 144.1, 159.6, 159.8.
+
MS (ES): m/z = 1680 [M ]. Elemental Anal. Calcd for C H Fe N O Cl: C, 59.29, H, 4.62,
83
77
4
18
6
N, 14.99%. Found: C, 59.23, H, 4.58, N, 14.91%.
Second generation ferrocenyldendritic azide 9:
The dendritic azide 9 (0.43 g) was obtained as pale yellow solid from the dendritic
chloride 8 (0.5 g, 0.3 mmol) and NaN (0.04 g, 0.6 mmol) following the procedure B. Yield:
5% MP: 134ꢀ136 C H NMR: (300 MHz, CDCl ): 4.12 (s, 2H), 4.16, 4.21, 4.27 (s, 36H;
Cp), 5.06 (s, 8H), 5.14 (s, 4H), 5.28 (s, 8H), 5.39 (s, 4H), 6.46 (s, 4H), 6.53 (s, 3H), 6.56 (s,
3
o
1
8
3
δ
H
13
2
H), 7.51 (s, 4H), 7.59 (s, 2H). C NMR: (75 MHz, CDCl3): δC 50.1, 54.1, 54.6, 62.0,
(68.6, 68.8, 68.9, 69.1, Cp), 80.7, 101.7, 102.0, 107.5, 122.4, 123.1, 133.5, 136.8, 137.8,
+
1
43.3, 144.1, 159.6, 159.8. MS (ES): m/z = 1687 [M ]. Elemental Anal. Calcd for
83 4 21 6
C H77Fe N O : C, 50.06, H, 4.60, N, 17.43%. Found: C, 49.99, H, 4.44, N, 17.37%.
Bis(epoxy methyl) resorcinol 11
Bis(epoxy methyl) resorcinol 11 (0.95 g) was obtained as gummy solid by the
reaction of resorcinol (1 g, 1.4 mmol) with epichlorohydrin(0.18 g, 2.8 mmol) in presence of
1
NaH followed by elution from the column with CHCl Hexane (3:2). Yield : 85% H NMR
3
ꢀ
:
3 H
(300 MHz, CDCl ): δ 2.72ꢀ 2.74 (dd , J =5.2 ,4.1 Hz , 2H) 2.89 ꢀ 3.31 (dd, J = ,5.3 ,4.2 Hz
,
2H) 3.31ꢀ3.36 (m, 2H ) 3.87ꢀ 3.92 (dd, J = 9.3, 4.2Hz , 2H ) 4.18ꢀ 4.23 (dd, J = 9.3, 4.2Hz ,
1
3
2
1
2
H) 6.51ꢀ7.19 (m , 4H); C NMR : (75 MHz, CDCl
3
):
C
δ 44.6, 50.1, 68.8, 101.8, 107.3,
+
30.0, 159.7.m/z= 222 [M ]. Elemental Anal. Calcd for C H O : C, 64.85, H, 6.35, O,
12
14
4
8.80%. Found: C, 53.80, H, 6.25, O, 28.15%.
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β –hydroxypropargyl ether 12.
β–Hydroxypropargyl ether 12 (0.70 g) was obtained by the reaction of from bis(epoxy
methyl) resorcinol 11 (1 g, 1.4 mmol) with propargyl alcohol (0.18 g, 2.8 mmol) dry DMF
1
(
20 ml) followed by elution from the column with CHCl : MeOH (25:1) Yield: 72% H NMR
3
:
3 H
(300 MHz, CDCl ): δ 2.46ꢀ2.60 (s ,2H), 2.61 (d, J = 2.6 ,2H), 3.65ꢀ3.77 (m , 2H ), 3.76 (d
,
J= 2.8, 2H ), 4.04ꢀ4.17 (d , J = 3.4 ,4H ) 4.17ꢀ4.23 (s, 4H ), 6.52 (q , 2H), 6.55 (d , J = 6.2 ,
1
3
2
3 C
H ), 7.17 (d, J = 7.1 , 1H ) 7.27 (s , 1H, ) C NMR : (75 MHz, CDCl ): δ 58.7, 69.0, 69.1,
+
7
0.8, 75.0, 79.28, 101.8, 107.33, 130.01, 159.76.m/z= 334[M ]. Elemental Anal. Calcd for
C H O : C, 64.66, H, 6.63, O, 28.71%. Found: C, 64.60, H, 6.57, O, 29.98%.
18
22
6
Ferrocenyldendrimar 1:
Following the general procedure A, the ferrocenyl dendrimer 1 (0.95 g) was obtained
as light yellow solid from the ferrocenyl azide 4 (1 g, 2.1 mmol) and β –hydroxypropargyl
ether 12 (1.7g, 1.0 mmol) and after eluting from the column with CHCl : MeOH (25:1).
3.20 (s, 2H), 3.66 (d, J =
.1 4H), 3.95 (d, J = 2.1, 4H), 4.14 (s, 2H), 4.17ꢀ 4.25 (m, 18H), 4.63 (s, 4H), 5.24 (s, 4H),
3
o
1
3 H
Yield : 96% M. P. : 134ꢀ136 C H NMR : 300 MHz, CDCl ): δ
2
6
6
8
1
3
3 C ,
.46 (t ,3H) 7.13(t , 1H) 7.42 (S, 2H). C NMR :(75 MHz, CDCl ): δ 30.1 50.1, 64.7, 68.9,
9.0, 69.1, 71.4, 80.6, 101.7, 107.2, 121.9, 129.9, 144.6, 159.8.MS (MALDIꢀTOP): m/z =
+
39.25 [M+Na ]. Elemental Anal. Calcd for C40
H
44Fe
2
N
6
O
6
: C, 58.84, H, 5.43, N, 10.29%.
Found: C, 58.80, H, 5.47, N, 10.24%.
Ferrocenyldendrmar 2:
Following the general procedure A, the ferrocenyl dendrimer 2 (0.95 g) was obtained
as light yellow solid from the ferrocenyl dendritic azide 7 (1.7g, 1.0 mmol) and
β–hydroxypropargyl ether 12 (1 g, 1.4 mmol) and after eluting from the column with CHCl3:
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1
MeOH (25:2) Yield: 86% H NMR : (300 MHz, CDCl
3
):
H
δ 3.68 (s, 4H), 3.90 (d, J = 2.1
4H), 4.01 (d, J = 2.1 2H), 4.11ꢀ 4.65(m, 36H), 4.93 (s, 43H) , 5.04 (s, 8H), 5.34 (s, 8H), 5.45
13
(
s ,4H) 6.44 ꢀ6.53 (m ,9H ) 7.48(t , 1H) 7.56ꢀ7.72 (s, 6H) C NMR : (75 MHz, CDCl
3
):
δ
C
5
1
0.2, 58.7, 62.1, 64.8, 68.6, 68.8, 68.9, 69.0, 69.1, 70.8, 75.0, 76.6, 77.0, 77.4, 80.7, 101.6,
01.8, 102.1, 107.4, 122.5, 122.9, 130.0, 133.5, 136.9, 143.3, 145.2, 159.9.MS (MALDIꢀ
+
TOP): m/z = 1803.39 [M+Na ]. Elemental Anal. Calcd for C88
H
88Fe
4
N
18
O10: C, 59.3, H,
4.98, N, 14.16%. Found: C, 59.1, H, 4.85, N, 14.26%.
Ferrocenyl dendrimer 3:
The ferrocenyl dendrimer 3 (0.99 g) was obtained as light brown solid by the reaction
of β –hydroxypropargyl ether 12 (0.05 g, 0.14 mmol) with ferrocenyl dendritic azide 9 (1.16
3
g, 0.69 mmol) under click chemistry condition and after eluting from the column with CHCl ꢀ
o
1
MeOH (25:2) Yield: 81% M.P 165ꢀ167 C H (300 MHz, CDCl
3 H
): δ 3.57(s, 4H), 3.66 (d, J
=
2.1 4H), 3.84ꢀ 4.07(m, 72H), 4.18 (s, 16H), 4.52 (s,2H), 4.91(s, 24H), 5.17ꢀ 5.25 (s, 16H),
1
3
6
.33 (m , 12H ) 6.43 (s, 9H), 6.98 (s, 1H), 7.45ꢀ7.49 (s, 14H) C NMR : (75 MHz, CDCl
3
):
δC 49.1, 52.9, 57.2, 60.9, 67.7, 67.9, 68.0, 68.1, 68.7, 72.4, 74.1, 74.4, 75.6, 76.1, 76.5, 79.8,
100.8, 101.0, 106.2, 106.4, 106.6, 121.49, 122.5, 129.8, 142.2, 144.2, 148.8, 158.7, 163.6,
+
1
67.5, 175.7. (MALDIꢀTOP): m/z = 3733.67 [M+Na ]. Elemental Anal. Calcd for
C H Fe N O : C, 59.56; H, 4.78; N, 15.85; Found: C, 59.38, H, 4.71, N, 15.52%.
184 176
8
42 18
Minimum Inhibitory Concentration
The minimum inhibitory concentrations of the compounds against the human
2
3
pathogens were analyzed by resazurin reduction assay described by Sarkar et al. .
Method to Prepare Resazurin dye solution
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The Resazurindye solution was made by dissolving a 270 mg tablet in 40 mL of sterile
distilled water. The instrument vortex mixer was used to ensure that the resazurinsolution was
wellꢀdissolved and form homogenous solution.
Preparation of the activity plates
9
6 wells plates were prepared under aseptic conditions. 200ꢁL of the compound
(1mg/mL) in 5% (v/v) dimethyl sulfoxide was pipetted into the first row of the sterile 96
3
0
wells plate. To all other remaining wells 100ꢁL of Sabouraud dextrose broth was added.
The serial dilutions were performed with sterile pipette tips such that each well had 100ꢁL of
the test material in serially descending concentrations. To all these wells 10ꢁL of resazurin
6
dye solution was added. 10ꢁL of fungal suspension (5 × 10 cells/mL) was added to each
5
well to achieve a concentration of 5 × 10 cells/mL. The commercial antibiotic streptomycin
and amphotericinꢀB were used as positive controls in the assay plate. The plates were then
placed in an incubator at 37 °C for 18–24 h. The colour change was then observed visually.
The colour changes from purple to pink or colourless were recorded as reduction of dye by
the viable bacteria. The lowest concentration at which no colour change occurred was taken
as the MIC value.
MTT Assay:
The stock solution of MTT dye (3ꢀ[4, 5ꢀdimethylthiazolꢀ2ꢀyl]ꢀ2, 5ꢀdiphenyl
tetrazolium bromide) 5 mg per ml, was made in sterilized phosphate buffered saline. The
lysis solution was prepared by mixing 0.6 ml of acetic acid and 99.4 ml of dimethyl
sulphoxide. The MCFꢀ7 cells were incubated with the appropriate concentrations of sample
for 24 and 48 h. After incubation the consumed medium was carefully removed from all the
wells of the assay plate and was replaced with freshly prepared Dulbecco's Modified
Eagle Medium (DMEM). The MTT dye (100µl per ml of stock solution) was added to each
well and the culture plates were incubated for 3 h in CO incubation chamber. The
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supernatant was aspirated carefully, taking care not to remove formazan crystals formed with
in the cells. The lysis solution in amounts equal to that of the DMEM added before
incubation was added and the cells were lysated over 5 minutes and mixed thoroughly. 200 µl
of the lysate from each of the 24 well culture plate was transferred to the preꢀmarked 96 well
plate and then the optical density (OD) of the lysate was measured at 570 nm. The percentage
of OD value (OD value of Test/OD value of control x 100%) was calculated. A larger OD
value represented higher cell viability and thus adhesion.
Acknowledgements
The authors thank DSTꢀFIST for providing NMR facility to our department. VS and
AK thanks CSIR and UGC, New Delhi for fellowship.
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3
2
8
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Synthesis, characterization, optical, electrochemical properties and
antifungal, anticancer activities of ferrocenyl conjugated novel dendrimers
a
a,b
a
Velautham Saravanan, Ayyavoo Kannan and Perumal Rajakumar *
a
Department of Organic Chemistry, University of Madras, Chennai, 600 025, India.
b
Department of Chemistry, University of the Free State, Bloemfontein, South Africa
*
E-mail: perumalrajakumar@gmail.com; Fax: +91 044 22300488;
Tel: +91 044 22202814; 9551379907
Graphical abstract
New class triazolo ferrocenyl conjugates were prepared by copper (I) catalyzed Click
chemistry, which shows good antifungal activity against the fungal pathogens viz Candida
albicans, Candida glabrata and Candida crusi and also shows excellent anticancer activity
against the MCF-7 cells.
N
N
N
N
N
N
N
N
N
N
N
N
O
O
O
O
N
N
N
N
N
N
N
O
N
N
O
N
N
O
O
O
O
N
OH
OH
O
O
N
N
N
N
N
N
O
O
O
O
N
N
N
N
N
N
N
N
N
N
N
N