# Glycyrrhetinic acid and its derivatives as inhibitors of poly(ADP-ribose)polymerases 1 and 2, apurinic/apyrimidinic endonuclease 1 and DNA polymerase b

A. Zakharenko, O. Salomatina, M. Sukhanova, M. Kutuzov, E. Ilina, S.

Khodyreva, Valérie Schreiber, N. Salakhutdinov, O. Lavrik

► To cite this version:

A. Zakharenko, O. Salomatina, M. Sukhanova, M. Kutuzov, E. Ilina, et al., Glycyrrhetinic acid and its derivatives as inhibitors of poly(ADP-ribose)polymerases 1 and 2, apurinic/apyrimidinic endonuclease 1 and DNA polymerase b. Biopolymers and Cell, 2012, 28 (3), pp.223-228. 10.7124/bc.000052. hal-05035045

HAL Id: hal-05035045

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<figure><img src="image_1.png" /></figure>

Distributed under a Creative Commons Attribution 4.0 International License
UDC 577.151.042

Glycyrrhetinic acid and its derivatives as inhibitors
of poly(ADP-ribose)polymerases 1 and 2, apurinic/
apyrimidinic endonuclease 1 and DNA polymerase β

A. L. Zakharenko, O. V. Salomatina¹, M. V. Sukhanova, M. M. Kutuzov,

E. S. Ilina, S. N. Khodyreva, V. Schreiber², N. F. Salakhutdinov¹, O. I. Lavrik

Novosibirsk Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences
8, Akademika Lavrentieva Ave., Novosibirsk, Russian Federation, 630090

¹N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences|
9, Akademika Lavrentieva Ave., Novosibirsk, Russian Federation, 630090

²UMR7242, University of Strasbourg, CNRS, ESBS
Cedex Illkirch Cedex, France, 67412

lavrik@niboch.nsc.ru; anvar@nioch.nsc.ru

**Aim.** For strengthening the efficiency of monofunctional alkylating antineoplastic drugs it is important to lower the capacity of base excision repair (BER) system which corrects the majority of DNA damages caused by these reagents. The objective was to create inhibitors of the key BER enzymes (PARP1, PARP2, DNA polymerase β, and APE1) by the directed modification of glycyrrhetinic acid (GA). **Methods.** Amides of GA were produced from the GA acetate by formation of the corresponding acyl chloride, amidation with the appropriate amine and subsequent deacylation. Small library of 2-cyano substituted derivatives of GA methyl esters was obtained by the structural modification of GA framework and carboxylic acid group. The inhibitory capacity of the compounds was estimated by comparison of the enzyme activities in specific tests in the presence of compounds versus their absence. **Results.** None of tested compounds inhibits PARP1 significantly. Unmodified GA and its morpholinic derivative were shown to be weak inhibitors of PARP2. The derivatives of GA containing keto-group in 11 triterpene framework were shown to be moderate inhibitors of polβ. Compound 3, containing 12-oxo-9(11)-en moiety in the ring C, was shown to be a single inhibitor of APE1 among all compounds studied. **Conclusions.** The class of GA derivatives, selective pol β inhibitors, was found out. The selective inhibitor of APE1 and weak selective inhibitor of PARP2 were also revealed.

Keywords: DNA polymerase β, poly(ADP-ribose)polymerases 1 and 2, apurinic/apyrimidinic endonuclease 1, glycyrrhetinic acid, inhibitor.

**Introduction.** Alkylating reagents being the oldest class of anticancer drugs are still commonly used; they play an important role in the treatment of several types of cancer. Alkylated bases are predominantly removed by base excision repair (BER) [1]. Apurinic/apyrimidinic endonuclease 1 (APE1) and DNA polymerase β (pol β) involved in processing of apurinic/apyrimidinic sites and DNA synthesis, the common stages of BER independent on type of base damage,

can be considered as the most relevant targets. For targeting the whole BER process an alternative approach can be used. It is based on the inhibition of proteins, which regulate the overall efficiency of BER. Poly(ADP-ribose)polymerases 1 and 2, PARP1 and PARP2, respectively, are considered as regulators of BER [2]. Several PARP inhibitors in combination with an alkylating drug, temozolomide, are included in current clinical trials [3].

Thus, specific targeting BER enzymes, catalyzing the key stages, in combination with alkylating reagents is considered as a perspective approach in cancer therapy.
Glycyrrhetinic acid (GA) possesses a broad spectrum of pharmacological activities and serves as a base for highly active drug preparations [4, 5]. GA is an aglycone of glycyrrhizic acid obtained from the roots of licorice plants and represents the main product of its metabolism [4, 5]. In the two past decades, there has been growing interest in the study of licorice, one of the most ancient medicinal plants that were widely used in Chinese and Tibetan medicine.

The renewed interest in licorice reflects the general trend observed in medicinal practice, where remedies of natural origin are finding increasing application despite considerable success in the use of many synthetic drugs. The drug preparations based on modified natural compounds frequently exceed the parent substances in activity. For instance, several GA derivatives display considerable antitumor activity [6–8].

**Materials and methods.** *Materials.* Rainbow molecular mass markers («Amersham», USA) and the main components of buffers, β-NAD⁺ («Sigma», USA; or Russian, ultrapure grade). 18βH-Glycyrrhetinic acid acetate obtained from a licorice extract was used as a starting material (purity ~94 %) [9].

*Synthesis of GA derivatives.* Methyl-2-cyano-3,11-dioxo-18βH-olean-12(13)-en-30-oate (1) was synthesized according to described method [10]. Methyl-2-cyano-3,11-dioxoolean-1(2),12(13),18(19)-trien-30-oate (2) and methyl-2-cyano-3,12,19-trioxoolean-1(2),11(9),13(19)-trien-30-oate (4) was synthesized according to [11]. Methyl-2-cyano-3,12-dioxoolean-1(2),11(9)-dien-30-oate (3) was synthesized according to [6].

*Synthesis of 18βH-GA-30-oic acid amides (5–7).* Amides of GA **5–7** were produced from the GA acetate by formation of the corresponding acyl chloride (oxalyl chloride), amidation with the appropriate amine and subsequent deacylation (KOH, MeOH-tetrahydrofuran). N-(pyrrolidin-1-yl)-3β-hydroxy-11-oxo-18βH-olean-12(13)-en-30-oic acid amide (5) was synthesized according to general method with yield 42 %. N-(piperidin-1-yl)-3β-hydroxy-11-oxo-18βH-olean-12(13)-en-30-oic

acid amide (6) was synthesized according to general method with yield 30 %. N-(morpholino-4-yl)-3β-hydroxy-11-oxo-18βH-olean-12(13)-en-30-oic acid amide (7) was synthesized according to general method with yield 20 %.

**Physicochemical description** (Mp, ¹H and ¹³C data) of amides **5–7** are in agreement with literature data [12].

*Enzymes and their activity tests.* Human PARP1, rat pol β and human APE1 were expressed in *Escherichia coli* cells and isolated as described in [13–15], respectively. Murine PARP2 was expressed in insect cells and purified according to [16]. Pol β, PARP1, and PARP2 activity assays were carried out as described [14, 17, 18], respectively. APE1 activity assay was carried out essentially as described in [15].

*Estimation of the inhibitory characteristics of compounds.* The inhibitory capacity of the compounds was estimated by comparison of the enzyme activities in specific tests in the presence of compounds at variable concentrations versus their absence. The concentration of potential inhibitors was varied in the range from 100 nM to 1 mM. Depending on properties of tested compounds (solubility in DMSO) and enzyme, we used two types of inhibitory characteristics: residual activity at fixed concentration of compounds or $IC_{50}$ values (inhibitor concentration reducing the enzyme activity by half).

**Results and discussion.** Influence of GA derivatives on poly(ADP-ribose) (PAR) synthesis catalyzed by PARP1 and PARP2. PARP1 and PARP2 are molecular sensors of DNA breaks. Their activity is efficiently stimulated by DNA lesions [19]. Involvement of both PARPs in regulation of response to genotoxic stress caused by ionizing radiation and alkylating reagents was proved in cells and animal models [19]. Catalytic domains of PARP1 and PARP2 display high level of homology and therefore can efficiently recognize the same compounds-inhibitors [20]. While, there are structural differences (small insertion in PARP2), which are considered as a basis for creation of selective PARP2 inhibitors [21].

Influence of GA derivatives at different concentration of compounds on PARPs activity was determined at linear part of the dependence of the rate of PAR synthesis versus NAD⁺ concentration. Data for all compounds are summarized in Table and Fig 1. Typical curve for PAR synthesis catalyzed by PARP2 in the presence of GA is shown in Fig. 2.
<table><caption>Inhibitory characteristics of compounds in specific reactions catalyzed by PARP1, PARP2, DNA polymerase β and APE1 (see Figure)</caption><thead><tr><th>Designation</th><th>PARP1 residual activity, %* at 1 mM inhibitor</th><th>PARP2 residual activity, %* at 1 mM inhibitor</th><th>Influence on DNA polymerase β activity* IC<sub>50</sub>, mM</th><th>APE1 residual activity, %* at 0.1 mM inhibitor</th></tr></thead><tbody><tr><td><strong>GA</strong></td><td>38</td><td>0.3 mM**</td><td>&gt; 0.1</td><td>100</td></tr><tr><td><strong>1</strong></td><td>59</td><td>67</td><td>0.07</td><td>80</td></tr><tr><td><strong>2</strong></td><td>45</td><td>65</td><td>0.06</td><td>86</td></tr><tr><td><strong>3</strong></td><td>78</td><td>38</td><td>&gt; 0.1</td><td>0.03 mM**</td></tr><tr><td><strong>4</strong></td><td>84</td><td>42</td><td>&gt; 0.1</td><td>77</td></tr><tr><td><strong>5</strong></td><td>56</td><td>53</td><td>0.07</td><td>122</td></tr><tr><td><strong>6</strong></td><td>56</td><td>37</td><td>0.06</td><td>92</td></tr><tr><td><strong>7</strong></td><td>46</td><td>0.7 mM**</td><td>&gt; 0.1 mM</td><td>98</td></tr></tbody></table>

leotide excision repair [27]. Thus pol β inhibitors can provide a therapeutic effect, especially in combination with DNA targeted drugs.

All synthesized GA derivatives were tested as potential pol β inhibitors. A typical curve of the residual pol β activity at variable concentration of 5 is shown in Fig. 3. Data on influence of GA derivatives on pol β activity are summarized in Table.

The ester of GA bearing keto group at the 11 position (ring C), 1 and 2, unlike compounds 3 and 4 with keto group at the 12 position, significantly affect pol β activity. In addition, the inhibitory effect is displayed by pyrrolidine amide 5 and hyperidine amide 6 unlike the morpholine amide 7. It should be noticed that the last compound has a mild inhibitory effect on PARP2 activity. In line with our observation, several triterpe-

<figure><img src="image_2.png" /><figcaption>Fig. 1. Structural formulas of new derivatives (see Table)</figcaption></figure>

As whole, GA and its derivatives are inefficient inhibitors of PAR synthesis catalyzed by both PARPs. GA and 7 (morpholine amide of GA) displayed somewhat better inhibition of PARP2 activity.

*Influence of GA derivatives on DNA polymerase β activity.* Pol β is the main DNA polymerase of base excision repair proceeding via short- and long patch pathways [22–24]. The level of pol β expression and activity is enhanced in some cancer cells [25, 26] that leads to its competition with more accurate replicating DNA polymerases and, as a consequent, to involvement of pol β in extrinsic DNA repair processes, for instance nuc-

noid derivatives were also shown to inhibit pol β activity with IC<sub>50</sub> being in micromolar range ([28, 29] and references therein).

By and large, all known inhibitors of pol β irrespectively of compound class have IC<sub>50</sub> values in micromolar range [28, 29].

*Influence of GA derivatives on APE1 activity.* Human APE1 is a multifunctional enzyme. APE1 is involved in BER, which eliminates base lesions and spontaneous AP sites being the main AP site hydrolyzing enzyme of higher eukaryotes [30, 31]. APE1 expression is altered in numerous cancers [31, 32]. High level of

<footnote>*Mean of at least two determinations; **IC<sub>50</sub>.</footnote>
<figure><img src="image_3.png" /><figcaption>Fig. 2. Dependence of PARP2 residual activity on concentration of gly-
cyrrhetinic acid. Concentration of PARP2 was 200 nM, NAD⁺ – 400 µM</figcaption></figure>

<figure><img src="image_4.png" /><figcaption>Fig. 4. Dependence of APE1 residual activity on concentration of com-
pound 5. Concentration of AP DNA was 100 nM, APE1 – 0.3 nM</figcaption></figure>

APE1 protects cells from the action of different genoto-
xic agents; on the contrary, suppression of APE1 leads
to apoptosis and renders cells to become more sensitive
to genotoxic agent exposure ([33] and references the-
rein). Thus APE1 is considered as potential therapeutic
target. Selective APE1 inhibitors can be useful both as
monotherapy drugs and sensitizers in combined thera-
py. APE1 inhibitors have demonstrated potentiation of
cytotoxicity of alkylating agents in preclinical models
[31, 34–36].

Representative curve of 3 influence on APE1 activity
is shown in Fig. 4. Compound 3 is the only compound,
which causes practically full inhibition of APE1 acti-
vity at 100 µM concentration. None of other tested com-
pounds influences significantly the AP site hydrolysis
(Table).

<figure><img src="image_5.png" /><figcaption>Fig. 3. Dependence of pol β residual activity on concentration of com-
pound 3. Concentration of pol β was 400 nM</figcaption></figure>

IC₅₀ values of APE1 specific inhibitors discovered
to date lie in the submicromolar–low micromolar ran-
ge [36, 37].

**Conclusions.** The class of GA derivatives, selecti-
ve pol β inhibitors, was found out. The selective inhibi-
tor of APE1 and weak selective inhibitor of PARP2 we-
re also revealed.

**Acknowledgments.** This work was supported by the Program of Russian Academy of Sciences N 6 «Molecular and Cellular Biology» and SC N 16.512.11. 2241.

А. Л. Захаренко, О. В. Саломатина, М. В. Суханова,
М. М. Кутузов, С. С. Льїна, С. Н. Ходирева, В. Шрейбер,
Н. Ф. Салахутдинов, О. І. Лаврик

Гліциретова кислота і її похідні як інгібітори полі(АДФ-рибозо) полімераз 1 і 2, апуринової/апіримідинової ендонуклеази 1 та ДНК-полімерази β

Резюме

**Мета.** Щоб посилити ефективність впливу монофункціональних
алкілуючих протипухлинних препаратів важливим є зниження ак-
тивності системи ексцізійної репарації основ (ЕРО), яка виправ-
ляє значну частину пошкоджень ДНК, що виникають за дії цих
препаратів. Мета цієї роботи полягала у створенні інгібіторів
ключових ферментів ЕРО (ПАРПІ, ПАРП2, пол β, АРЕ1) за раху-
нок направленої модифікації гліциретової кислоти (ГК). **Методи.**
Аміди ГК одержували з ацетату ГК через утворення відповідно-
го ацилхориду, амідування відповідним аміном з наступним де-
ацилованням. Невелику бібліотеку 2-ціанозаміщених метилових
ефірів ГК отримано структурною модифікацією остова ГК і
карбоксильної групи. Інгібуючу активність сполук оцінювали у від-
повідних специфічних тестах за присутності або відсутності
сполук. **Результати.** Жодна з протестованих сполук не інгібує
ПАРПІ значною мірою. Немодифікована ГК і її морфоліновий
амід виявилися м'якими інгібіторами ПАРП2. Похідні ГК, які мі-
стять кето-групу в 11-му положенні тритерпенового остова,
пра้วили помірні інгібуючі властивості стосовно пол β. Сполука
3, яка вміцус 12-оксо-9(11)-єновий залишок у кільці С, — сдина се-
ред усіх вивчених сполук інгібус АРЕІ. **Висновки**. Знайдено клас
сполук, селективно інгібуючих ДНК-полімеразу β. Також виявле-
но селективний інгібітор АРЕІ та м'який інгібітор ПАРП2.

Ключові слова: ДНК полімераза β, полі(АДФ-рибозо)полімерази 1 і 2, апуринова/апіримідинова ендонуклеаза 1, гіліциретова кислота, інгібітор.

А. Л. Захаренко, О. В. Саломатина, М. В. Суханова,
М. М. Кутузов, Е. С. Ильина, С. Н. Ходырева, В. Шрейбер,
Н. Ф. Салахутдинов, О. И. Лаврик

Глицирретовая кислота и ее производные как ингибиторы
поли(АДФ-рибозо)полимераз 1 и 2, апуриновой/апиримидиновой
эндонуклеазы 1 и ДНК-полимеразы β

Резюме

Цель. Для усиления эффективности влияния монофункциональ-
ных alkилирующих противоохолевых препаратов важно сни-
зить активность системы эксцизионной репарации оснований
(ЭРО), исправляющей значительную часть повреждений ДНК,
возникающих при действии этих препаратов. Целью данной ра-
боты являлось создание ингибиторов ключевых ферментов ЭРО
(ПАРП1, ПАРП2, пол β, АРЕІ) за счет направленной модифика-
ции глицирретовой кислоты (ГК). **Методы**. Амиды ГК получены
из ацетата ГК через образование соответствующего ацилхлори-
да, амидирования соответствующим амином с последующим де-
ацилированием. Небольшая библиотека 2-цианозамещенных ме-
тиловых эфиров ГК получена структурной модификацией осто-
ва ГК и карбоксилиной группы. Ингибиторную активность соеди-
нений оценивали в соответствующих специфических тестах в
присутствии или в отсутствие соединений. **Результаты**. Ни
одно из протестированных соединений не ингибитует ПАРП1 в
значительной степени. Немодифицированная ГК и ее морфолио-
вый амид оказались мягкими ингибиторами ПАРП2. Производ-
ные ГК, содержащие кето-группу в 11-м положении тритерпе-
ного остова, проявили умеренные ингибирующие свойства в от-
ношении пол β. Соединение 3, содержащее 12-оксо-9(11)-еновый
остаток в кольце С, — единственное среди всех изученных соеди-
нений ингибитует АРЕІ. **Выздывы**. Обнаружен класс соединений,
селективно ингибирующих ДНК-полимеразу β. Также выявлены
селективный ингибитор АРЕІ и мягкий ингибитор ПАРП2.

Ключевые слова: ДНК полимераза β, поли(АДФ-рибозо)поли-
меразы 1 и 2, апуриновая/апиримидиновая эндонуклеаза 1, гицир-
ретовая кислота, ингибитор.

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