Synthesis and characterization of new galactosylated-based N2O-donors tridentate ligands

Article abstract of DOI:10.1080/00397911.2019.1599953

The synthesis and characterization of three novel N₂O-donor ligands containing the group 4-[1-β-d-2,3,4,6-tetra-O-acetyl-galactosyl)]benzaldehyde are presented. The insertion of this group was designed to increase the absorption of the prodrug in tumor cells, and is part of an ongoing work in our group with tridentate ligands to develop potential cobalt(III) prodrugs. The synthetic route described here allowed the isolation of pure ligands with yields ranged 81–89%. Finally, compounds were characterized by IR, NMR and HRMS (ESI⁺).

Full text of DOI:10.1080/00397911.2019.1599953

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Synthesis and characterization of new
galactosylated-based N2O-donors tridentate
ligands
Lidiane C. Castro, Yasmim R. Jaconiano, Tereza C. S. Evangelista, Sabrina B.
Ferreira & Marciela Scarpellini
To cite this article: Lidiane C. Castro, Yasmim R. Jaconiano, Tereza C. S. Evangelista, Sabrina B.
Ferreira & Marciela Scarpellini (2019): Synthesis and characterization of new galactosylated-based
N2O-donors tridentate ligands, Synthetic Communications, DOI: 10.1080/00397911.2019.1599953
To link to this article: https://doi.org/10.1080/00397911.2019.1599953
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SYNTHETIC COMMUNICATIONSV
https://doi.org/10.1080/00397911.2019.1599953
Synthesis and characterization of new galactosylated-based
N2O-donors tridentate ligands
Lidiane C. Castroa, Yasmim R. Jaconianoa, Tereza C. S. Evangelistab, Sabrina B.
Ferreirab, and Marciela Scarpellinia
a
ꢀ
^
ꢀ
^
Departamento de Quımica Inorganica, Instituto de Quımica, Universidade Federal do Rio de Janeiro,
b
ꢀ
ꢀ
Rio de Janeiro, Brazil; Departamento de Quımica Organica, Instituto de Quımica, Universidade Federal
do Rio de Janeiro, Rio de Janeiro, Brazil
ABSTRACT
ARTICLE HISTORY
Received 29 January 2019
The synthesis and characterization of three novel N2O-donor ligands
containing the group 4-[1-b-D-2,3,4,6-tetra-O-acetyl-galactosyl)]ben-
zaldehyde are presented. The insertion of this group was designed
to increase the absorption of the prodrug in tumor cells, and is part
of an ongoing work in our group with tridentate ligands to develop
potential cobalt(III) prodrugs. The synthetic route described here
allowed the isolation of pure ligands with yields ranged 81–89%.
Finally, compounds were characterized by IR, NMR and HRMS (ESIþ).
KEYWORDS
Cancer; cobalt; complexes;
galactose; ligands;
prodrug; synthesis
GRAPHICAL ABSTRACT
Introduction
Solid tumors present hypoxia and acid pH as features that became targets for the devel-
opment of selective drugs.[1–3] Those related to the cytotoxicity only after metabolic
activation are classified as Pro-Drugs Activated by Hypoxia (PDAH), and comprises
organic and inorganic compounds.[2b,4] Metal-containing candidates to metallodrugs
have the ability to vary the coordination number, geometry and redox states, besides
the possibility to carry organic-based drugs and modify or improve their pharmaco-
logical properties.[1b,4,5] In an effort to decrease the side effects and resistance caused by
ꢀ ꢀ
^
Departamento de Quımica Inorganica, Instituto de Quımica,
Universidade Federal do Rio de Janeiro, Av. Athos da Silveira Ramos, 149 - Cidade Universitaria, Rio de Janeiro – RJ,
21941-909, Brazil.
CONTACT Marciela Scarpellini
marciela@iq.ufrj.br
ꢀ
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
Supplemental data for this article is available online at on the publisher’s website.
ß 2019 Taylor & Francis Group, LLC

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L. C. CASTRO ET AL.
Scheme 1. Representative scheme of the tridentate ligands investigated by Scarpellini et al.[2c,10]
the most widely used metallodrug (cisplatin), others are under investigation including
bioreductive agents based on Pt4þ, Ru3þ, Cu2þ and Co3þ [1b,4,6,7]
.
In the last decade, we and our coworkers have employed the approach of tripodal
ligands to prepare potential Co3þ prodrug carriers, with two labile positions prone to
coordinate well known antitumoral molecules.[2e,8] The choice for Co3þ lies on its high
ligand field stabilizing energy, that assure the kinetic stability required to reach the
reducing environment of hypoxia and release the drug after reduction to Co2þ, which is
more labile.[9] Furthermore, we have also explored tridentate N2O-donor ligands
(Scheme 1) to obtain Co3þ complexes as new PDAH.[2c,10] We have shown that the in
situ reduced Co2þ complexes with Hbepa-H and Hbha-H inhibit S. cerevisiae cell
growth, with IC50 (0.5 lM) lower than cisplatin (0.6 lM). It indicates their great poten-
tial as PDAH, considering that their oxidized (Co3þ) forms did not show expressive
activity in cell death and cellular inhibition when compared to the reduced ones
(Co2þ).[10] Later, we further investigated the Co3þ complexes with Hbepi-H, Hbepi-
NO2, Hbepa-H and Hbepa-NO2, as inhibitors of cell growth of the B16F10 murine mel-
anoma cell line.[2c] We were able to tune the redox potential of the complexes according
the -R groups (–NO2 or –H), but no correlation could be addressed with the viability of
B16F10 cell line.[2c]
In order to improve the potential of this class of complexes as PDAH, here we exploit
the strategy of linking the galactose group to the tridentate ligands backbone. This is
based on the highly altered structure of carbohydrate chains in cancer cells, and in their
requirement for high amounts of sugars.[11,12] So, carbohydrates are believed to play a
key role in many biological processes and are of interest for medicinal chemistry,[11,13]
under the hypothesis that the sugar increases the solubility in water and favors perme-
ability through cell membranes.[14,15]
Results and discussion
Here, the synthesis and characterization of three non-galactosylated N2O-donors ligands
are presented and are derived from the precursors: 1,[10a] 2[16] and 3.[10b]
Ligands 1, 2 and 3 were synthesized according to the general synthetic route shown
in Scheme 2. Firstly, the respective imines were obtained by the condensation reactions
of 2-(2-aminoethyl)-pyridine and the respective aldehyde. After 3.5 h under stirring, the
reduction was carried out in situ with NaBH4. The reaction mixture was kept under
stirring overnight, and the solvent was evaporated to dryness. Water was added and the

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SYNTHETIC COMMUNICATIONSV
3
Scheme 2. General scheme of the synthetic route for preparing tridentate ligands 1, 2 and 3.
Scheme 3. Synthetic route for the preparation of compounds 8 and 7.
product extracted three times with dichloromethane. The organic phases were com-
bined, filtered and dried with anhydrous Na2SO4. After filtration, the solvent was com-
pletely removed under vacuum and the crude compounds 1 (yield: 81%), 2 (yield: 89%)
and 3 (88%) were obtained as light-yellow oils.
For the synthesis of the galactosylated ligands it was first necessary to synthesize its
respective aldehyde (7). The synthetic route was initiated with the preparation of com-
pound 8 (Scheme 3) that was prepared by the hydrobromination reaction of the penta-
O-acetylgalactopyranose (9), in anhydrous dichloromethane.[17] The reaction mixture
was kept on ice bath and stirred for 30 minutes. It was monitored by silica-based thin-
layer chromatography (TLC), using ethyl acetate and hexane (2:3) as mobile phase.
After 3.5 h, dichloromethane was added and washed twice (50 mL) with saturated
NaHCO3 solution and once (50 mL) with distilled water. Organic phases were com-
bined, dried with anhydrous Na2SO4, filtered and the solvent was removed under
reduced pressure. Compound 8 was isolated as a white solid and with 95% yield.
Compound 7, was prepared by the nucleophilic substitution reaction with the p-hydrox-
ybenzaldehyde (Scheme 3), according to the literature with 78% yield.[15]
Finally, the novel ligands 11, 12 and 13 were synthesized by the condensation reac-
tions of 1, 2 or 3, respectively, and aldehyde 7, according to Scheme 4. Methanolic solu-
tions of 1, 2 or 3 were added to a reactor containing 7 (in methanol), 3 drops of acetic
acid and Pd/C 10% catalyst. The hydrogenation system was coupled to a H2 line, purges
were performed, and an initial pressure of 138 kPa was applied. The reaction mixture
was maintained under stirring for 24h, when the reaction mixture was analyzed by TLC
(hexane/diethyl ether, 2:8). The catalyst was filtered off through a Celite layer, the solv-
ent was removed under low pressure to give the novel ligands 11, 12 and 13, in the
form of very viscous brown oils with 98, 91 and 96% yields, respectively.
The comparative analysis between infrared spectra of compounds 1, 2 and 3 (precur-
sors) and the spectra of compounds 11, 12 and 13 shows the main vibrations related to

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L. C. CASTRO ET AL.
Scheme 4. General scheme of the synthesis route for compounds 11, 12 and 13.
the precursors, and the disappearance of the stretching band (V) of secondary amine
NH (region 3295–3236 cmꢀ1). In addition, bands corresponding to the main vibrations
of the glycosidic precursors 7 and 8 are observed. The NMR spectra of compounds 11,
12 and 13 shows peaks related to groups of precursor compounds with slight displace-
ments, with the clear exception of the peak referring to the aldehyde functional group
(approximately 9.9 ppm). Thus, we suggest that the condensation reaction between the
aldehyde and the amine followed by reduction by catalytic hydrogenation has been
effective and the compounds of interest have been obtained. Mass spectrometry data
corroborate the obtaining of compounds 11, 12 and 13.
Conclusion
The desired galactoylated-based N2O-donors tridentate ligands (11, 12 and 13) were sat-
isfactorily synthesized by the condensation reaction of the precursors tridentate amines
(1, 2 and 3) and the galactoylated aldehyde (7), followed by catalytic reduction (H2, Pd/
C 10%, 138 kPa). All were isolated as very viscous brown oils in good yields: 98% (11),
91% (12) and 96% (13). Infrared spectroscopy, high resolution mass spectrometry and
nuclear magnetic resonance spectroscopy of hydrogen and carbon, confirmed the
obtainment of the desired compounds in high purity and by an efficient synthetic route.
It is worth to mention that, none of analogous galactosylated ligands with withdrawing
substituents (–R ¼ –NO2, –Br and –Cl) in the para position of the phenolate group,
could be isolated by this synthetic route, despite several attempts. We are now investi-
gating others approaches to prepare them. As mentioned, the data presented here are
part of an ongoing work to develop Co3þ complexes as novel PDAH, which are still
under investigation.
Experimental
Except for the reaction of Scheme 4, all others were performed under room atmosphere.
Dichloromethane was refluxed with phosphorus pentoxide for 3h, distilled and stored
in a round bottom flask containing molecular sieve (4Å), under argon atmosphere and

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SYNTHETIC COMMUNICATIONSV
5
protected from light. Acetonitrile was treated and stored similarly to dichloromethane,
but refluxing for 1 h. Methanol was refluxed with magnesium strips and iodine crystals,
for 2–3 h, distilled and stored in a similar way to the others. All chemical reagents and
other solvents were obtained from commercial suppliers and used as received. Reactions
were monitored with analytical Silica G TLC plates from Sorbent Technologies Inc., in
aluminum sheets and samples were visualized under UV light (254 nm). Purifications by
flash chromatography were performed on silica gel (Silica Gel Flash, 200–400 mesh).
Infrared spectra were recorded as thin films in KBr windows, with a NICOLE
1
6700 FT-IR spectrophotometer. H and 13C NMR spectra were recorded in a Bruker
AVHD 9.40 T (400.13 MHz 1H e 100.61 MHz 13C) system, in CDCl3 solutions.
Tetramethylsilane was used as the internal reference standard (0.0 ppm) and chemical
shifts (d) are given in parts per million. High-resolution mass spectra (HRMS) were
recorded with a Thermo Scientific Q Exactive Plus Orbitrap LC-MS/MS System instru-
ment using electrospray ionization (ESI) in positive mode.
Procedures
The numbered structures are found in the supplementary material.
2,3,4,6-Tetra-O-acetyl-D-galactopyranosyl bromide (8)
The synthesis of 2,3,4,6-tetra-O-acetyl-D-galactopyranosyl bromide (8) was performed by
the slow addition of a HBr solution stabilized in acetic acid (33% w/w–5.5 mL,
0.1 mmol), over a solution of penta-O-acetylgalactopyranose (3.25 g, 8.33 mmol), in
anhydrous dichloromethane (14 mL). The reaction mixture was kept in ice bath and
stirred for 30 min. The reaction was monitored by TLC using ethyl acetate/hexane (2:3)
as eluent. After 3.5 h, 15 mL of dichloromethane was added, washed twice with 30 mL of
saturated NaHCO3 solution and once with distilled water. The organic layer was dried
with anhydrous Na2SO4, filtered and the solvent removed under reduced pressure.
Compound 8 was obtained as a hygroscopic white solid, which turns into a colorless
1
oil. Yield 96% (3.26 g, 7.95 mmol). It was characterized by H-NMR, and agrees with
the literature.[18]
1H NMR (CDCl3, 300 MHz) d 1.98 (s, 3H, CH3), 2.03 (s, 3H, CH3), 2.08 (s, 3H,
CH3), 2.12 (s, 3H, CH3), 4.05–4.19 (m, 2H, H-7a and H-6), 4.46 (t, 1H, J ¼ 6.4 Hz, H-
7b), 5.02 (dd, 1H, J ¼ 10.6 and 3.9 Hz, H-2), 5.37 (dd, 1H, J ¼ 10.6 and 3.3 Hz, H-3),
5.48–5.49 (m, 1H, H-1), 6.67 (d, 1H, J ¼ 4.0 Hz, H-4).
4-[1-b-D-(2,3,4,6-Tetra-O-acetylgalactosyl)]benzaldehyde (7)
Compound 7 was synthesized according to the literature[15] by the reaction of 8 (1.83 g,
4.5 mmol), with p-hydroxybenzaldehyde (0.64 g–5.3 mmol). The synthesis was performed
in 50 mL of anhydrous acetonitrile in the presence of Ag2O (5.07 g–21.9 mmol), in an
ice bath and under magnetic stirring for 4 h. Reaction progress was monitored with
TLC using a mixture of hexane/diethyl ether (2:8). The volatiles were removed under
reduced pressure and a brown oil was obtained. It was dissolved in 30 mL of ethyl

6
L. C. CASTRO ET AL.
acetate, filtered through a thin Celite layer, which was washed three times with ethyl
acetate (50 mL). The solvent was removed under reduced pressure and a dark brown oil
was isolated. Silica gel column chromatography was employed for purification, using
hexane/ethyl ether (2:8) as eluent. The pure product was isolated after solvent removal
as colorless crystals in the form of needles. The yield of the reaction was 78%
(1.57 g–3.48 mmol).
1H NMR (CDCl3, 400.13 MHz) d 2.03 (s, 3H, CH3), 2.05 (s, 3H, CH3), 2.09 (sl, 3H,
CH3), 2.20 (s, 3H, CH3), 2.21 (s, 3H, CH3), 3.12 (t, 2H, J ¼ 5.9 Hz, H-8), 3.22 (t, 2H,
J ¼ 5.9 Hz, H-7), 3.39 (d, 2H, J ¼ 1.0 Hz, H-10 or H-19), 4.05 (s, 2H, H-10 or H-19),
4.08–4.26 (m, 3H, H-31 and H-32), 5.03–5.08 (m, 1H, H-29), 5.13 (dd, 1H, J ¼ 10.4 and
3.4 Hz, H-28), 5.47–5.53 (m, 2H, H-30 and H-27), 6.83 (d, 1H, J ¼ 8.2 Hz, H-15), 6.86
(s, 1H, H-12), 6.94 (d, 1H, J ¼ 8.2 Hz, H-14), 7.01 (dd, 2H, J ¼ 8.3 and 3.2 Hz, H-21 and
H-25), 7.10–7.14 (m, 2H, H-2 and H-6), 7.19 (d, 1H, J ¼ 8.3 Hz, H-22 or H-24), 7.40 (d,
1H, J ¼ 8.3 Hz, H-22 or H-24), 7.56–7.60 (m, 1H, H-1 or H-5), 8.47 (d, 1H, J ¼ 4.7 Hz,
H-5 or H-1).
2-(Pyridin-2-yl) ethylaminoethyl phenol (1)
The pre-ligand 1 was synthesized according to the literature (Scheme 2).[10,16] In a
round bottom flask, 2-(2-aminoethyl)-pyridine (1.25 mL–10 mmol) was added to 50 mL
of methanol, under magnetic stirring and ice bath. After 15 min, a methanolic solution
of salicylaldehyde (1.05 mL - 10 mmol) was slowly dropwised, and the mixture was
stirred for 3.5 h, when NaBH4 was added in small amounts (0.57 g–15 mmol). The reac-
tion was kept under stirring overnight. The solvent was removed to dryness under
reduced pressure, 30 mL of water were added to the crude product and extracted three
times with 50 mL of dichloromethane. The organic phases were combined, dried with
anhydrous Na2SO4 and filtered. The solvent was completely evaporated resulting in a
brown oil. Yield 81% (1.85 g–8.1 mmol). It was characterized and confirmed as the
desired amine.
IR (film): 3295, 3064–2850, 1592 1438, 1363, 1260, 848, 756, and 627 cmꢀ1
.
1H NMR (CDCl3, 400.13 MHz) d 3.01–3.04 (m, 2H, H-8), 3.10 (t, 2H, J ¼ 6.4 Hz, H-
7), 4.01 (s, 2H, H-10), 6.76 (t, 1H, J ¼ 7.3 Hz, H-13), 6.82 (d, 1H, J ¼ 8.0 Hz, H-12), 6.98
(d, 1H, J ¼ 7.3 Hz, H-14), 7.14 (t, 3H, J ¼ 6.8 Hz, H-2 and H-6 and H-15), 7.61 (t, 1H,
J ¼ 7.6 Hz, H-1), 8.51-8.52 (m, 1H, H-5). 13C NMR (CDCl3, 100.61 MHz) d 37.21 (C-7),
47.80 (C-10), 52.51 (C-8), 116.53 (C-15), 119.10 (C-13), 121.76 (C-6), 122.58 (C-11),
123.60 (C-2), 128.60 (C-14), 128.87 (C-12), 136.82 (C-1), 149.50 (C-5), 158.42 (C-16),
159.62 (C-3). HRMS (ESIþ, CH3OH): m/z [M þ Hþ] calcd for C14H17N2O: 229.1296;
found: 229.1332.
2-(Pyridin-2-yl) ethylaminoethyl-4-methoxyphenol (2)
The pre-ligand 2 was synthesized as described above for 1, but using the following
amounts of the reactants: 2-(2-aminoethyl)pyridine (0.63 mL–5.25 mmol), 2-hydroxy-5-
methoxybenzaldehyde (0.63 mL–5.1 mmol) and NaBH4 (0.38 g–10 mmol). The product

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SYNTHETIC COMMUNICATIONSV
7
was also isolated as a brown oil. Yield 89% (1.16 g–4.5 mmol). It was characterized and
the data corroborate to the proposed structure.[16]
IR (film): 3236, 3062–2832, 1596-1439, 1371, 1257/1040, 813, 759, and 634 cmꢀ1
.
1H NMR (CDCl3, 400.13 MHz) d 3.02 (t, 2H, J ¼ 5.7 Hz, H-8), 3.09–3.12 (m, 2H, H-
7), 3.71 (d, 3H, J ¼ 4.8 Hz, OCH3), 3.97 (d, 2H, J ¼ 4.8 Hz, H-10), 6.58–6.77 (m, 1H, H-
12), 6.68–6.77 (m, 2H, H-14 and H-15), 7.12–7.15 (m, 2H, H-2 and H-6), 7.58–7.92 (m,
1H, H-1), 8.49–8.51 (m, 1H, H-5). 13C NMR (CDCl3, 100.61 MHz) d 36.87 (C-7), 47.71
(C-10), 52.22 (C-8), 55.92 (OCH3) 113.93 (C-15), 114.64 (C-6), 116.96 (C-2), 121.78 (C-
14), 122.96 (C-13), 123.58 (C-12), 136.84 (C-1), 149.40 (C-1), 149.50 (C-5), 151.99 (C-
11), 152.54 (C-16), 159.45 (C-3). HRMS (ESIþ, CH3OH): m/z [M þ Hþ] calcd for
C15H19N2O2:259.1402 found: 259.1436.
Acknowledgments
ꢀ
ꢀ
Authors would like to thank the Laboratorio de Apoio ao Desenvolvimento Tecnologico
ꢀ
(LADTEC) and Laboratorio de Espectrometria de Massas (LABEM) for the HRMS analyses.
Funding
ꢀ
ꢀ
We gratefully acknowledge the Conselho Nacional de Desenvolvimento Cientıfico e Tecnologico
(CNPq) for the fellowships of L. C. C. (process number 141341/2013-0) and Y. R. J. (process
~
ꢀ
number 141341/2013-0), the Coordenac¸ao de Aperfeic¸oamento de Pessoal de Nıvel Superior –
Brasil (CAPES) for financial support and for the fellowship of T. C. S. E. (financial code 001)
~
ꢁ
and Fundac¸ao Carlos Chagas Filho de Amparo a Pesquisa do Estado do Rio de Janeiro (FAPERJ)
(process numbers E-26/111.177/2011 and E-26/110.157/2014).
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