Synthesis, Characterization, and Antiproliferation Activity Test of

Dibutyltin(IV)di-2-Hydroxybenzoate and

Dibutyltin(IV)di-3-Hydroxybenzoate Against Cervical Cancer Line

Hela

Sutopo Hadi

, Hendig Winarno

, Ermin Katrin Winarno

, Susanto

Mitha Nurmaya Angely

, Amelia Mareta

, Khairun Nisa Berawi

and Tati Suhartati

Department of Chemistry, University of Lampung Bandar Lampung 35145 Indonesia

Research Center for Radiation Process Technology, Research Organization for Nuclear Energy (BATAN) - National

Research and Innovation Agency (NRIA), Gedung 90, KST B.J. Habibie, Jl. Puspiptek, Muncul, Kec. Setu, Tangerang

Selatan, Banten 15314, Indonesia

Medical Faculty, University of Lampung Bandar Lampung 35145 Indonesia

Keywords: Antiproliferation Test, Dibutyltin (IV) hydroxybenzoate, HeLa cells, IC

Abstract: Due to the various side effects of conventional cancer treatment therapy, efforts to find anticancer agents with

minimum side effects are in great demand. One of them is the synthesis of organotin (IV) hydroxybenzoate

derivatives. Two organotin (IV) compounds, namely dibutyltin (IV) 2-hydroxybenzoate and dibutyltin (IV)

di-3-hydroxybenzoate, have been successfully synthesized. The products were obtained by reacting the

dibutyltin (IV) oxide with 2-hydroxybenzoic acid and 3-hydroxybenzoic acid. The compounds synthesized

were fully characterized by UV-Vis, FT-IR, and NMR spectroscopies and microelemental analyzer to see the

purity of the compounds. The antiproliferative activity of compounds have been tested against the HeLa

cancer cell line. The results of the antiproliferation test showed that the compound dibutyltin (IV) 2-

hydroxybenzoate had better antiproliferation activity than the compound dibutyltin (IV) 3-hydroxybenzoate

and showed high selectivity.

1 INTRODUCTION

The interest in the bioactivity of organotin (IV)

derivative compounds is not without reasons. Apart

from the chemical structure of organotin (IV)

compounds are interesting to study, they show good

potential in various biological tests (Annisa et al.,

2017; Hadi et al., 2018; Hadi et al., 2023a; Hadi et

al., 2023b; Roner et al., 2011; Samsuar et al., 2021;

Sirajuddin et al., 2021). The bioactivity of organotin

(IV) derivative compounds itself is determined by the

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chemical properties and number of organic groups

bound to the central atom of Sn (Pellerito and Nagy,

2002). Meanwhile, the bound anion only plays a role

as a secondary determinant of the bioactivity of

organotin (IV) compounds (Pellerito and Nagy, 2002;

Hadi et al., 2021a; Hadi et al., 2022.

Many bioactivity studies on organotin (IV)

compounds as alternative materials have been widely

carried out and are still interesting to continue

considering the large potential in these compounds.

Organotin(IV) compounds have been tested to have

228

Hadi, S., Winarno, H., Winarno, E. K., Susanto, , Angely, M. N., Mareta, A., Berawi, K. N. and Suhartati, T.

Synthesis, Characterization, and Antiproliferation Activity Test of Dibutyltin(IV)di-2-Hydroxybenzoate and Dibutyltin(IV)di-3- Hydroxybenzoate Against Cervical Cancer Line Hela.

DOI: 10.5220/0013668400003873

Paper published under CC license (CC BY-NC-ND 4.0)

In Proceedings of the 1st International Conference on Medical Science and Health (ICOMESH 2023), pages 228-233

ISBN: 978-989-758-740-5

bioactivity such as antimicrobial (Gilles et al., 2011;

Hadi et al., 2021b; Sirajuddin et al., 2021), antifungal

activity (Kovala-Demertzi et al., 2002; Hadi et al.,

2021a), antimalarial (Hadi et al., 2018; Hadi et al.,

2021b), antioxidant (Arraq and Hadi, 2023; Hussain

et al., 2023; Sari et al., 2020; Tyurin et al., 2015) as

well as antitumor and anticancer (Al-Rikabi et al.,

2023; Cepeda et al., 2007; Hadi et al., 2023a; Hadi et

al., 2023b). In previous research (Hadi et al., 2023),

the results of in vitro tests of dibutyltin (IV)

hydroxybenzoate derivatives against leukemia cancer

cells were reported, obtaining an IC

value of 24.4

µg/mL. If the IC

of this compound is ≤ 50 μg/mL,

then the organotin (IV) 3-hydroxybenzoate

compound has the potential to be an anticancer

compound (Mans et al., 2000). Therefore, it is hoped

that the compounds dibutyltin (IV) di-2-

hydroxybenzoate and dibutyltin (IV) di-3-

hydroxybenzoate, which are benzoic acid derivative

compounds, have anticancer activity and have IC

values that are lower than previous studies.

Among various organotin (IV) complexes,

organotin (IV) carboxylates have strong bioactivity

anticancer agent (Al-Rikabi et al., 2023; Cepeda et

al., 2007; Hadi and Rilyanti, 2010; Hadi et al., 2012;

Hadi et al., 2023a; Hadi et al., 2023b). This is also

driven by the increase in cancer sufferers throughout

the world, where according to the latest data from the

Global Cancer Observatory (2021), in 2020 in

Indonesia there were more than 396 thousand cases

of cancer recorded with 234 thousand patients dying,

which is 9.2 % of them are deaths due to cervical

cancer. This makes researchers in this field try to find

potential anticancer agents with minimum side effects

for sufferers.

In this research, we reported the synthesis and

characterization of dibutyltin (IV) di-2-

hydroxybenzoate and dibutyltin (IV)-di-3-

hydroxybenzoate to then test their antiproliferative

activity against the cervical cancer cell line, HeLa.

2 MATERIALS AND METHOD

2.1 Materials

All reagents used were of Analytical Reagent grade.

Dibutyltin(IV) oxide (1), 2-hydroxybenzoic acid, 3-

hydroxybenzoic acid, Dulbecco’s Modified Eagle’s

Medium (DMEM), NaHCO

fetal bovine serum

(FBS) were obtained from Sigm-Aldrich (MA,

USA). Methanol and dimethylsulfoxide (DMSO)

were obtained from Merck Millipore (MA, USA). All

of these reageants were used as received and without

any further purification. Cervical cancer line Helas

was obtained from Elabscience®, USA.

2.2 Synthesis of Dibutyltin (IV)

hydroxybenzoate

The synthesis procedure for the compounds 2 and 3

was adopted from the procedure carried out (Hadi &

Rilyanti, 2010; Hadi et al., 2012), which was an

adaptation of the procedure used by Szorcsik et al.

(2002).

In the synthesis of dibutyltin(IV) di-2-

hydroxybenzoate (2) the starting materials used as

follows: 1.3579 grams of dibutyltin(IV) oxide (1) was

reacted with 0.9036 grams of 2-hydroxybenzoic acid

in 10 mL of methanol p.a. as a solvent The reaction

mixture was refluxed for 4 hours in a hotplate stirrer

at a temperature of 60-61℃. After the reaction was

complete, the methanol was evaporated and dried in

a vacuum desiccator until dry crystals with constant

weight are obtained. The compound was then

characterized using an UV-Vis, FT-IR,

H-NMR and

C-NMR spectroscopic analyses, the composition of

the element (hydrogen and carbon) was determined

using a microelemental analyzer, and then tested its

antiproliferative activity against cervical cancer cell

line HeLa. The same procedure was used in the

preparation of compound 3.

The compounds synthesized obtained were as

follows:

Compound 2: white solid; UV λ

max

. (MeOH) nm

(log ε): 242 and 304.8; IR ν

max

. (KBr) cm

-1

: 2928.98-

2870.07 (C-H (-CH

) in Bu), 1558.7 (C=O), 1419.6

(CO

asym), 1251.74 (Sn-O-C), 1077.62 (Sn–C in

Bu), 753.35 (Sn–O);

H NMR (in DMSO-d

, 600

MHz) δ (ppm): Hα: 1.6 (t), Hβ:1.4 (m); Hγ: 1.29 (t);

Hδ: 0.93 (t), H in benzoate = 7.35–7.85 (m);

C NMR

(in DMSO-d

, 150 MHz): δ (ppm): Cα: 26.8, Cβ:

25.5, Cγ: 21.4, Cδ: 13.5, C1: 164.3; C2: 131.5, C3:

132.2, C4: 138.4, C5: 125.1, C6: 128.6, C7: 129.7;

microelemental analysis: found (calculated): C 52.29

(52.07), H 5.48 (5.52).

Compound 3: white-light yellowish solid; UV

max

. (MeOH) nm (log ε): 243 and 299; IR ν

max

. (KBr)

-1

: 2958.78-2872.92 (C-H (-CH

) in Bu), 1558.7

(C=O), 1419.6 (CO

asym), 1258.73 (Sn-O-C),

1079.10 (Sn–C in Bu), 763.34 (Sn–O);

H NMR (in

DMSO-d

, 600 MHz) δ (ppm): Hα: 1.6 (t), Hβ:1.4

(m); Hγ: 1.29 (t); Hδ: 0.93 (t), H in benzoate = 7.35–

7.85 (m);

C NMR (in DMSO-d

, 150 MHz): δ

(ppm): Cα: 26.8, Cβ: 25.5, Cγ: 21.4, Cδ: 13.5, C1:

164.3; C2: 131.5, C3: 132.2, C4: 138.4, C5: 125.1,

C6: 128.6, C7: 129.7; microelemental analysis: found

(calculated): C 52.29 (52.07), H 5.48 (5.52).

Synthesis, Characterization, and Antiproliferation Activity Test of Dibutyltin(IV)di-2-Hydroxybenzoate and Dibutyltin(IV)di-3-

Hydroxybenzoate Against Cervical Cancer Line Hela

229

2.3 Antiproliferation Activity Test

The procedure for testing antiproliferative activity as

an anticancer in this study is part of a series of cancer

cell bioassays adopted from procedures carried out by

Winarno et al., (2009) and Hadi & Rilyanti (2010).

The media was prepared as follows: 10.4 grams

of Dulbecco’s Modified Eagle’s Medium (DMEM)

that is containing L-glutamine was dissolved in 1 L

of aquabiadest and then was added with 2.3 grams of

NaHCO

that was dissolved in 1 L of aqubidest in an

Erlenmeyer flask, then the solution mixture was

stirred until homogeneous, and the pH of the solution

was then measured with a pH indicator until a normal

pH was obtained (pH 7-7.5). For cell culture

purposes, 15 mL of 10% fetal bovine serum (FBS)

was added to 85 mL of the prepared media. All works

were carried out in laminar air flow under sterile

conditions.

The activity test was carried out on each sample

dissolved in DMSO. 5 concentration variations were

used, i.e. 0; 0.5; 1; 4; 8 µg/mL which was then

compared with Vero cells with 5 concentration

variations at 0; 16; 32; 64, 128 µg/mL. Media

containing HeLa cell suspension (2 x 10

cells/mL)

was placed into a multi-well plate tissue's culture with

24 wells, 1 mL in each well. As a control, 10 µL of

DMSO was used to which 990 µL of HeLa cell

suspension was added and a sample of the compound

tested was added in each concentration. Then, 30 µL

of penicillin as an antibiotic was added. The

experiment was carried out in triplicate, then the cell

suspension filled with the test substance was closed

tightly and wrapped in HVS. Then, incubated for 72

hours at 37°C in a 5% CO

incubator.

Cell counting was carried out using an improved

Neubauer hemocytometer. To differentiate between

live cells and dead cells, before counting, 20 µL of

1% tryphan blue solution was added and

homogenized. A mixture of samples that had been

stained with tryphan blue in the amount of 100 µL of

solution was flowed into the Neubauer Improved

Haemocytometer. The cell suspension was inserted

into the chamber where the suspension must be

sufficiently dilute so that cells or other particles do

not overlap in the counting chamber and must be

evenly distributed. After that, the number of living

cells was counted under a microscope with 4000x

magnification. Live cells appear as clear spheres with

a blue spot of cell nucleus in the center of the sphere,

while dead cells appear as dark blue-black spots with

an irregular shape. The percentage of inhibition of the

test substance on the growth of HeLa cancer cells was

calculated as follows:

% inhibition = 1 – 𝐴/𝐵 x 100% (1)

A: the number of living cells in the medium

containing the test substance

B: number of living cells in media that does not

contain the test substance (control).

The inhibition percentage data was plotted into a

probit table to obtain a probit value. Then a graph was

made between log concentration (x) and probit (y) to

obtain the linear regression equation y = a + bx. By

entering the value y = 5 (probit of 50%), the x value

(log concentration) was obtained, the IC

value by

converting the log concentration value to anti-log

form. IC

is the concentration of the test substance

that can inhibit cell division by 50% after an

incubation period of 72 hours. The activity of a

sample is said to be active as an anti-cancer if the IC

value is ≤ 50 µg/mL (Mans et al., 2000).

3 RESULTS AND DISCUSSION

3.1 Synthesis and Characterization of

Dibutyltin (IV) hydroxybenzoate

Compounds 2 and 3 were obtained as white solids

with the yields of 84.45% and 80.88% respectively.

Characterization using UV, FT-IR,

H NMR, and

NMR, provide good spectra, and the values of micro

elemental analysis data are in agreement with those

of the theoretical values, confirming successful

synthesis of the compounds. The reaction scheme for

the preparation of 2 and 3 is shown in Figure 1.

Figure 1: The Scheme of the preparation of the compounds

studied

The UV spectroscopy analysis of compounds 2

and 3 produced characteristic absorption values with

max

of the compounds prepared, associated with

transitions of π→π* and n→π*. At the same time, the

starting material 1 gives only one characteristic peak

ICOMESH 2023 - INTERNATIONAL CONFERENCE ON MEDICAL SCIENCE AND HEALTH

230

at 203 nm resulted from a π→π* transition due to

delocalization of butyl electrons. In Figure 1a, the

reaction of 1 with 2-hydroxybenzoic acid to produce

compound 2, a bathochromic shift, occurs due to the

influence of the chromophore group from the

carbonyl group and addition of the benzene ring. In

compound 2, there is also a n→π* transition at 304

nm due to alone pair electrons at the hydroxide group.

Similar shift changes were also observed in the

formation of compounds 3 (Hadi and Rilyanti, 2010;

Hadi et al. 2012; Hadi et al., 2022; 2023a; Hadi et al.,

2023b).

The

H and

C NMR spectra of compounds 2 and

3 were carefully evaluated. The data for compound 2

were compared with those previously available for

similar compounds (Hadi and Rilyanti, 2010; Hadi et

al. 2012; Hadi et al., 2022; 2023a; Hadi et al., 2023b).

H NMR, the chemical shifts of the butyl protons

bound to the Sn atom appeared as expected in the

range of 0.836 – 1.673 ppm, while the chemical shifts

of the benzoate protons were in the range of 7.544 –

7.808 ppm.

Figure 2. The numbering system of carbon atoms in

compound 2

The

C NMR of the butyl bonded to the Sn atom

showed absorption at 130.012 – 166.125 ppm and for

benzoate carbon at 166.125. The expected chemical

shift of carbonyl carbon appears at 166-167 ppm

(Hadi and Rilyanti, 2010; Hadi et al. 2012; Hadi et

al., 2022; 2023a; Hadi et al., 2023b). A similar

pattern was observed for compound 3. The example

of numbering the carbon atom for compound 2 is

shown in Figure 2 and the

H and

C NMR spectra

of the compound are presented in Figure 3a and 3b.

3.2 Antiproliferative Activity

The results of the antiproliferative activity test of

compounds 2 and 3 against cervical cancer line HeLa

are shown in Table 1. Based on these data, it was

found that both compounds 2 and 3 have very low

values. The relatively small IC

value (IC

< 20

µg/mL) shows that the activity of the compounds

Figure 3: (a) The

H NMR and (b)

C NMR spectra of

compound 2

synthesized is categorized to be active as an

anticancer based on the National Cancer Institute

(NCI) Guideline so that further clinical testing can be

carried out for its use as a safe anticancer agent.

Futhermore based on the IC

value for Vero cells, the

selectivity index (SI) can be calculated by dividing

the IC

of Vero cells by the IC50 of HeLa cells. The

SI numbers of compounds 2 and 3 for Hela cells were

3.94 and 5.82, respectively. A sample is said to have

high selectivity if it has a SI > 3 (López-Lázaro,

2015), therefore, compounds 2 and 3 have high

selectivity.

Table 1: Results of antiproliferative activity test of

compounds against HeLa cancer cells

Compound IC

Value

against HeLa

(µg/mL)

Value

against Vero

(µg/mL)

2 6.11 24.09

3 16.68 97.10

The reported results are almost similar to the

results obtained by several other researchers such as

Gielen (2003) and Pellerito et al. (2006). More

promising fact is that based on the IC

values data in

the literatures (Gielen, 2003; Pellerito et al., 2006),

the results obtained in the research that has been

carried out show that the compound that has been

synthesized actually shows higher anticancer activity

than the

currently available cisplatin, cis-

Synthesis, Characterization, and Antiproliferation Activity Test of Dibutyltin(IV)di-2-Hydroxybenzoate and Dibutyltin(IV)di-3-

Hydroxybenzoate Against Cervical Cancer Line Hela

231

[Pt(NH

)

]. It is widely used to treat various types

of cancer. The results obtained are certainly very

promising that organotin (IV) carboxylate derivative

compounds are potential candidates for metal-based

anticancer drugs in the future.

4 CONCLUSIONS

The results showed that the two dibutyltin (IV)

hydroxybenzoates synthesized have quite high

anticancer activity when viewed from their

antiproliferative activity. The antiproliferative

activity of the tested compound indicated that the IC

value of compound 2 is higher than compound 3 with

an IC

value of 6.11 µg/mL against cervical cancer

cell HeLa, although the SI of compound 3 against

Vero cell line is higher than 2. Therefore, these two

compounds are promising to be candidate as

anticancer metal based-drug.

ACKNOWLEDGEMENTS

Thanks must go to Higher Education Technology and

Innovationa (HETI) Universitas Lampung, Republic

of Indonesia for providing the funding through

Domestic Innovation Research and Collaboration

2023 with contract number of

10629/UN26/HK.01.00/2023, 17 October 2023. We

also thank Dr. Huy Hoang of Institute of Molecular

Biosciences (IMB) University of Queensland for

NMR experimentation.

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