Hyperbranched molecular structures with potential antiviral activity: Derivatives of 5,6-dihydroxyindole-2-carboxylic acid

Article abstract of DOI:10.3390/11120968

In the search of new HIV-1 integrase (IN) inhibitors, we synthesized a series of multimeric 5,6-dihydroxyindole-2-carboxylic acid (DHICA) derivatives. Preliminary results indicate that hyperbranched architectures could represent a peculiar molecular requi

Full text of DOI:10.3390/11120968

Molecules 2006, 11, 968-977
molecules
ISSN 1420-3049
http://www.mdpi.org
Communication
Hyperbranched Molecular Structures with Potential Antiviral
Activity: Derivatives of 5,6-Dihydroxyindole-2-Carboxylic Acid
Mario Sechi 1,*, Fabio Casu 1, Ilaria Campesi 1, Stefano Fiori 2 and Alberto Mariani 2
1 Dipartimento Farmaco Chimico Tossicologico, Università di Sassari, Via Muroni 23/A, 07100
Sassari, Italy; E-mail: mario.sechi@uniss.it
2 Dipartimento di Chimica, Università di Sassari and local INSTM Research Unit, Via Vienna 2,
07100 Sassari, Italy; E-mail: mariani@uniss.it
* Author to whom correspondence should be addressed: E-mail: mario.sechi@uniss.it ; Tel. +39 079
228 753; Fax. +39 079 228 720
Received: 25 October 2006; in revised form: 8 December 2006 / Accepted: 15 December 2006 /
Published: 18 December 2006
Abstract: In the search of new HIV-1 integrase (IN) inhibitors, we synthesized a series
of multimeric 5,6-dihydroxyindole-2-carboxylic acid (DHICA) derivatives. Preliminary
results indicate that hyperbranched architectures could represent a peculiar molecular
requisite for the development of new antiviral lead compounds.
Keywords: Hyperbranched polymers; AB2 monomers; DHICA; HIV-1; antiviral agents.
Introduction
In the search for new HIV-1 IN inhibitors, we synthesized and evaluated the biological activity of
5,6-dihydroxyindole-2-carboxylic acid (DHICA, II), an intermediate in the pathway of eumelanin
production, and a series of its derivatives (IIIa-i, Figure 1). These compounds were designed as
conformationally constrained analogues of the acrylate moiety of caffeic acid phenethyl ester (CAPE,
I, Figure 1); several of them showed anti-IN activity in enzyme-based assays at low micromolar
concentrations [1a,b].

Molecules 2006, 11
Figure 1. Design of DHICA from CAPE and DHICA derivatives.
969
O
O
HO
HO
HO
HO
O
O
N
H
I (CAPE)
HO
HO
OH
N
H
O
II (DHICA)
HO
HO
HO
HO
OH
OH
X
R
N
H
N
H
N
H
O
O
O
IIIa-d
IIIe-i
R = substituted benzyl/phenylethyl-amines
X = bis-alkylamines (spacers) of
variable length and flexibililty
In the course of the preparation of II by a novel synthetic route (see below), we unexpectedly
obtained a macromolecular compound as the only product. On the basis of its physico-chemical
properties such as solubility and differential scanning calorimetry (DSC) measurements, its structure
IVa has been postulated to perhaps correspond to that of a hyperbranched compound. In order to
evaluate whether the macromolecular structure of IVa could be endowed with biological activity, we
prepared other derivatives in both hyperbranched oligomeric (IVb) and polymeric (IVc) forms (Figure
2). Indeed, since II bears one COOH (A) and two OH (B) groups, which are capable of mutually
reacting, it can be regarded as an AB2 monomer, typically giving hyperbranched macromolecules
(Figure 3).
Figure 2. Title compounds.
H O
a,b: oligomers
c: polymer
OH
N
H
H O
O
IVa-c

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970
Figure 3. Schematic architecture of the hyperbranched macromolecules originating from
AB2 monomers.
HO
HO
OH
B
B
A
N
H
O
II
B
B
B
B
B
B
B
B
B
B
B
B
B
B
B
B
n
B
B
B
A
B
A
B
B
B
B
B
B
B
B
B
B
B
B
In the last decades, AB2 monomers have been widely used as starting materials for the synthesis of
dendritic structures [2,3]. This macromolecular family comprises dendrimers and hyperbranched
polymers. Both classes are characterized by having a tree-like architecture in which all linkages
converge towards a central core. However, whereas dendrimers are obtained by stepwise growth in
long sequences, hyperbranched polymers are obtained in one step. As far as dendrimers are concerned,
their applications in treatment of several human diseases are under critical investigation and looks
very promising; these macromolecules serve as targeted drug, carriers and delivery agents as well as
imaging agents in human systems [4-6]. In particular, polymers having a dendrimer-based structure
have emerged from several research programs focused on the development of inhibitors of HIV and
other enveloped viruses [7-19].
From a merely structural point of view, purification and deprotection steps for dendrimers are
aimed at synthesizing monodisperse, defect-free macromolecules. On the contrary, hyperbranched
polymers are characterized by a certain number of defects, which generally do not significantly affect
their peculiar features. Although the synthetic chemistry efforts in modern drug research have been
focused on the drive to discover orally bioavailable small-molecule drugs, the study of
macromolecular entities could reveal novel and significant scenarios. For example, it is well-known
that many of the biological targets are in fact macromolecules which rely heavily on
polyvalent/multivalent interactions in their binding and signalling cascades. In this context, with the
hope of identifying an original class of antiviral agents, all title compounds will be tested against HIV-
1 viral strain.
Results and Discussion
Our synthetic approach to compounds II and IVa-c is depicted in Schemes 1-4. Starting from the
aldehydes 1a and 1b and methyl azidoacetate (2), azidocinnamates 3a and 3b were prepared in high
yields via the Hemetsberger reaction [1a]. Intermediates 3a and 3b were converted in refluxing xylene
into the esters 4a and 4b, from which the acids 5a and 5b were obtained in 98% yields on alkaline
hydrolysis. Deprotection of the catechol moiety with BBr3 in dichloromethane at –40 °C gave the
expected DHICA II (Scheme 1). Compound IVa was obtained by demethylation of intermediate 4b to

Molecules 2006, 11
971
give methyl 5,6-dihydroxyindole-2-carboxylate (6), which was treated with 12% KOH at reflux for 1
h (Scheme 2).
Scheme 1.
O
H
R
R
R
COOCH3
COOCH3
H
i
ii
+
COOCH3
N3
N
H
N3
R'
R'
R'
1a,b
3a,b
4a,b
2
R
R'
iii
a
OCH2O
b OCH3 OCH3
R
iv
II
COOH
N
R'
H
5a,b
Reagents and conditions: i) CH3ONa, CH3OH, -15 °C for 4 h; ii) xylene, reflux for 15 min; iii)
12% KOH, reflux for 1 h; vi) BBr3, CH2Cl2, H2O, -40 °C for 4 h.
Scheme 2.
H3CO
H3CO
HO
HO
ii
i
OCH3
OCH3
IVa
N
H
N
H
O
O
ii
4b
6
II
Reagents and conditions: i) BBr3, CH2Cl2, CH3OH, -40 °C, 4 h; ii) 12% KOH, reflux, 1 h.
It is noteworthy that, due to transesterification reactions, compound II was not obtained, thus
confirming that oligomerization was favoured. The synthesis of IVb was carried out by reacting
equimolar amounts of 7 and II in anhydrous DMF for 60 h, in the presence of a catalytic amount of
triethanolamine (Scheme 3).
Scheme 3.
HO
HO
F
HO
O
F
F
F
OH
i
IVb
+
N
H
N
H
HO
O
O
F
7
II
H3CO
H3CO
F
F
H3CO
H3CO
O
F
F
ii
iii
OH
7
N
N
O
H
O
F
H
8
5b
Reagents and conditions: i) Triethanolamine, anhydrous DMF, 80 °C, 60 h; ii) Pentafluoro-
phenol, dioxane, r.t. for 4 h; iii) BBr3, CH2Cl2, H2O, -40 °C for 4 h.

Molecules 2006, 11
972
The intermediate 7 was obtained by treating 5b with pentafluorophenol to afford the
pentaflurophenyl ester 8. The latter was then deprotected to give 7 in good yield. Since hydroxy and
pentafluorophenolic ester were the only reactive groups under such reaction conditions, a typical AB2
+ B2 polymerization occurred, thus giving rise to dendritic oligomeric structures of relatively low
molecular weight. This procedure was carried out with the aim of obtaining, by a different synthetic
procedure, an oligomer comparable to IVa. As a matter of fact, when compared to II, both IVa and
IVb showed a larger solubility in many polar solvents (water included). Besides, a further synthesis
was designed and carried out: polymer IVc was prepared by reacting monomer II following a well-
known polymerization route commonly used in the lab-scale direct preparation of high molecular
weight polyesters from carboxylic acids (Scheme 4) [2].
Scheme 4.
HO
i
OH
IVc
N
HO
O
H
II
Reagents and conditions: i) Anhydrous N-methyl pyrrolidone/pyridine (5:1, v/v); triphenyl-
phosphine, hexachloroethane, 25 °C, 4 h.
Compound IVc was characterized by a solubility even larger than that of II, IVa, and IVb, thus
suggesting the presence of more numerous OH groups and confirming a (highly-)branched structure
which behaves as a unimolecular micelle. In order to obtain information about the polymeric structure
of the title compounds, a full characterization of IVa-c is under way and will be reported elsewhere.
However, some preliminary results can be here briefly outlined. DSC experiments show broad melting
peaks for all samples, thus indicating the typical polydispersion state of a one-step-obtained synthetic
oligo- or polymeric compound.
According to the expected increase of polydispersity as the molecular weight increases, typical for
step-growth polymerization, melting peaks become larger in the following order: IVa < IVb << IVc;
this behavior being due to the increasing number of different molecular species that characterize any
of the above compounds. Furthermore, also melting temperatures give some indications; indeed, their
values increase in the following order: IVa < IVb < IVc (i.e. 75 < 80 < 85 °C, respectively) that is
what expected on the basis of the molecular weight of the three compounds, from the lowest to the
highest.
Biological Activity
Preliminary biological data on cytotoxicity and antiviral activity of the title compounds are
reported in Table 1. The compound concentrations required to reduce the viability of mock-infected
cells by 50% (CC50) and to achieve 50% protection of MT-4 cells from the HIV-1 induced
cytopathogenicity (EC50), were determined by the MTT method [20]. In cell-based assays, IVa-c
showed cytotoxicity and antiviral activity which were inversely related to their molecular weight. In
particular, with comparable EC50 values, the oligomers IVa and IVb (EC50s = 0.5 and 1.5 µg/mL for

Molecules 2006, 11
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IVa and IVb, respectively) seem significantly capable to prevent the HIV-1 multiplication in acutely
infected MT-4 cells with respect to the polymer IVc (EC50 = >30 µg/mL). Meanwhile, cytotoxicity
values support this observation (CC50s = 5, 15, and >100 µg/mL for IVa, IVb and IVc, respectively).
Interestingly, with respect to the monomer II and its derivatives IIIa-i, which were toxic and did not
yield therapeutic efficacy [1a], the multimeric compounds have been proved to be effective in the
HIV-1 multiplication, thus showing cytoprotection activity in cell-based assays. Although IVa and
IVb proved significantly less potent than the reference compound Efavirenz (EC50 = 0.5 and 1.5
µg/mL v. 0.0031 µg/mL), a non-nucleoside reverse transcriptase inhibitor (NNRTI) commonly used in
therapeutic protocols [21], they showed a similar biological profile when compared to Merck L-
731,988 [22] (an important HIV-1 integrase inhibitor lead compound).
Table 1. Cytotoxicities and Antiviral Activities of ΙVa-c.
Cpd
aCC50
bEC50
cTI
II
IVa
0.9
5
>0.9
0.5
-
10
IVb
15
1.5
10
IVc
>100
15.6
11
>100
0.43
0.0031
-
dL-731,988
eEFV
36
>1000
b
aCC50: Cytotoxic concentration 50%; EC50: Effective Concentration 50%; cTI:
d
e
Therapeutic index = CC50/EC50; L-731,988: Merck’s lead compound; EFV:
Efavirenz. Due to their oligo/polymeric nature, data referring to biological
activities of multimeric derivatives (and those of the reference compounds for
comparison) are expressed in µg/mL.
Conclusions
These preliminary results for IVa,b are consistent with the conclusion that a hyperbranched
oligomeric backbone with relatively low molecular weight and relatively high degree of branching
could represent an interesting structural archetype for HIV-1 inhibition as well as for other potential
antiviral activities. Moreover, the possibility that hyperbranched derivatives might target the
adsorption/fusion steps of HIV multiplication cycle in cells could be considered. Detailed cytotoxicity
and antiviral activity as well as inhibition activities toward cellular targets of these compounds are
under investigation and will be discussed in due course.
Experimental
General
The synthesis of monomer II and intermediates 3a,b, 4a,b, 5a,b, 7 and 8 used for the preparation
of the title compounds was previously reported [1a]. These compounds have been prepared by using

Molecules 2006, 11
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the same experimental procedure. Anhydrous solvents and all reagents were purchased from Aldrich,
Merck or Carlo Erba. All reactions involving air- or moisture-sensitive compounds were performed
under nitrogen atmosphere using oven-dried glassware and syringes to transfer solutions. Melting
points (m.p.) were determined using an Electrothermal melting point or a Köfler apparatus and are
uncorrected. Infrared (IR) spectra were recorded as thin films or nujol mulls on NaCl plates with a
Perkin-Elmer 781 IR spectrophotometer and are expressed in ν (cm-1). Nuclear magnetic resonance
13
(1H-NMR and C-NMR) spectra were determined in 1:3 CDCl3/DMSO-d6 or DMSO-d6 and were
recorded on a 200 MHz Varian XL-200 instrument. Chemical shifts (δ scale) are reported in parts per
million (ppm) downfield from tetramethylsilane (TMS) used as an internal standard. Splitting patterns
are designated as follows: s, singlet; d, doublet; t, triplet; q, quadruplet; m, multiplet; brs, broad
singlet; dd, double doublet. The assignment of changeable protons (OH and NH) was confirmed by
the addition of D2O. Analytical thin-layer chromatography (TLC) was done on Merck silica gel F-254
plates. For flash chromatography Merck Silica gel 60 was used with a particle size 0.040-0.063 mm
(230-400 mesh ASTM). Elemental analyses were performed on a Perkin-Elmer 2400 spectrometer,
and were within ±0.4% of the theoretical values. Differential Scanning Calorimetry (DSC)
measurements were performed using a DSC Q100 V9.0 (TA Instrument, New Castle, USA) as
detailed below.
Preparation of methyl 5,6-dihydroxy-1H-indole-2-carboxylate (6). To a solution of 5,6-dimethoxy-
1H-indole-2-carboxylic acid methyl ester 4b (1.0 mmol) in dichloromethane (130 mL), a 1M BBr3 sol.
in dichloromethane (4 mmol) was added at -40 °C and under nitrogen atmosphere. The mixture was
stirred at the same temperature for 4 h, then, the reaction was quenched in methanol and the solvents
were removed under reduced pressure. The residue was washed three times with methanol. After
purification by silica gel flash column chromatography, the product was recrystallized from isopropyl
alcohol. Yield = 80 %; m.p. = 248 - 249 °C (lit. [23] 255 – 260 °C); IR (nujol) ν cm-1 = 3480 (OH);
3320 (NH); 1690 (C=O); 1H-NMR (CDCl3/DMSO-d6) δ 10.98 (s, 1H, NH), 8.76 (s, 1H, OH), 8.35 (s,
1H, OH), 6.93 (s, 1H, Ar-H), 6.88 (s, 2H, Ar-H), 3.83 (s, 3H, CH3); 1H-NMR (DMSO-d6) δ 11.28 (s,
1H, NH), 9.15 (s, 1H, OH), 8.65 (s, 1H, OH), 6.89 (s, 2H, Ar-H), 6.79 (s, 1H, Ar-H), 3.81 (s, 3H,
13
CH3); C-NMR (DMSO-d6): δ 161.7, 146.5, 142.2, 132.9, 124.5, 119.8, 107.5, 104.9, 96.9, 51.3;
Anal. Calcd. for C10H9NO4: C, 57.97; H, 4.38; N, 6.76. Found: C, 58.11; H, 4.22; N, 6.89.
Preparation of IVa. In a 25 mL round bottom vessel, 6 (0.200 g, 0.960 mmol) was dissolved in 12%
KOH (9 mL, 19.20 mmol) and the mixture was allowed to stir for 30 min at reflux. The dark solution
formed was then poured onto ice and acidified with 6N HCl. Thereafter, the mixture was poured into
diethyl ether and the precipitated oligomer IVa was filtered to provide a dark powder that was washed
with water and diethyl ether and dried in a vacuum oven for 24 h at 40 °C. DSC: Tm = ~75 °C.
Preparation of IVb. Compound II (0.054 g, 0.27 mmol) and 7 (0.096 g, 0.27 mmol) in anhydrous
DMF (7.5 mL) containing anhydrous triethylamine (0.1 mL) were placed in a 10 mL round bottom
vessel at room temperature. The vessel was sealed and heated in an oil bath set at 80 °C. The mixture
was allowed to react under stirring for 60 h. The mixture was then poured into diethyl ether and the

Molecules 2006, 11
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precipitated oligomer IVb was filtered to give a dark powder that was washed with diethyl ether and
dried in a vacuum oven for 24 h at 40 °C. DSC: Tm = ~80 °C.
Preparation of IVc. In a 5 mL round bottom vessel compound II (0.050 g, 0.26 mmol) was dissolved
in an N-methylpyrrolidone/pyridine mixture (1.5 mL, 5:1, v/v) and triphenylphosphine (0.080 g, 0.49
mmol) and hexachloroethane (0.093 g, 0.57 mmol) were added. The vessel was sealed and the mixture
was allowed to stir for 4 h at room temperature, then diethyl ether (15 mL) was added and the
precipitated polymer IVc was recovered and washed several times by centrifugation in the presence of
methanol to give a brown powder. DSC: Tm = ~85 °C.
Differential Scanning Calorimetry (DSC) measurements
The DSC instrument was calibrated with indium (calibration standard, purity 99.999%) for melting
point and heat of fusion. A heating rate of 10 °C/min was employed in the range 20–250 °C. Analyses
were performed under an Ar purge (50 mL/min). Standard aluminium sample pans were used. About
8-9 mg sample was taken for analysis. An empty pan was used as reference.
Acknowledgements
The authors thank Dr Maria Orecchioni for assistance with NMR spectroscopy, and Dr Gianfranco
Angotzi for the preparation of some intermediates. Financial support to M.S. from the “Ministero
dell'Istruzione, dell'Università e della Ricerca” (MIUR), Rome, Italy, is gratefully acknowledged.
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