Design, synthesis and antitumor activity of triterpenoid pyrazine derivatives from 23-hydroxybetulinic acid

Hengyuan Zhang; Yiwei Wang; Peiqing Zhu; Jie Liu; Shengtao Xu; Hequan Yao; Jieyun Jiang; Wencai Ye; Xiaoming Wu; Jinyi Xu

doi:10.1016/j.ejmech.2015.04.057

Design, synthesis and antitumor activity of triterpenoid pyrazine derivatives from 23-hydroxybetulinic acid

Hengyuan Zhang
, Yiwei Wang
, Peiqing Zhu
, Jie Liu
, Shengtao Xu
, Hequan Yao
, Jieyun Jiang
, Wencai Ye
, Xiaoming Wu
, Jinyi Xu

Microbiology, Immunology, and Molecular Genetics

Research output: Contribution to journal › Article › peer-review

32 Scopus citations

Abstract

Pyrazine-fused 23-hydroxybetulinic acid was synthesized by introducing a pyrazine ring between C-2 and C-3 position and further modifications were carried out by substitution of C-28 carboxyl group by ester and amide linkage to enhance the antitumor activity. The biological screening results showed that all of the derivatives exhibited more significant antiproliferative activity than the parent compound. In particular compound 12a exhibited the most potent activity with IC₅₀ values of 3.53 μM, 4.42 μM and 5.13 μM against cell lines SF-763, B16 and Hela, respectively. In the preliminary mechanism study, 12a caused cell arrest in G1 phase and significantly induced apoptosis of B16 cells in a dose-dependent manner. Furthermore, the in vivo antitumor activity of 12a was validated (tumor inhibitory ratio of 55.6% and 62.7%, respectively) in mice with H22 liver cancer and B16 melanoma.

Original language	English
Article number	7872
Pages (from-to)	235-244
Number of pages	10
Journal	European Journal of Medicinal Chemistry
Volume	97
DOIs	https://doi.org/10.1016/j.ejmech.2015.04.057
State	Published - Jun 5 2015

Bibliographical note

Publisher Copyright:
© 2015 Elsevier Masson SAS.

Funding

The project was funded by the National Natural Science Foundation of China (No. 81273377 ), Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources (Guangxi Normal University), Ministry of Education of China (No. CMEMR2013-B05 ), the Project for Research and Innovation of Graduates in Universities of Jiangsu Province (CXLX13_306) and the Project Program of State Key Laboratory of Natural Medicines, China Pharmaceutical University (No. SKLNMZZCX201404 ).

Funders	Funder number
Project for Research and Innovation of Graduates in Universities of Jiangsu Province	CXLX13_306
National Natural Science Foundation of China (NSFC)	81273377
Ministry of Education of the People's Republic of China	CMEMR2013-B05
Guangxi Normal University
State Key Laboratory of Natural Medicines, China Pharmaceutical University	SKLNMZZCX201404
State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

23-Hydroxybetulinic acid
Antitumor activity
Apoptosis
Pyrazine
Triterpenoid

ASJC Scopus subject areas

Pharmacology
Drug Discovery
Organic Chemistry

Access to Document

10.1016/j.ejmech.2015.04.057

Cite this

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title = "Design, synthesis and antitumor activity of triterpenoid pyrazine derivatives from 23-hydroxybetulinic acid",

abstract = "Pyrazine-fused 23-hydroxybetulinic acid was synthesized by introducing a pyrazine ring between C-2 and C-3 position and further modifications were carried out by substitution of C-28 carboxyl group by ester and amide linkage to enhance the antitumor activity. The biological screening results showed that all of the derivatives exhibited more significant antiproliferative activity than the parent compound. In particular compound 12a exhibited the most potent activity with IC50 values of 3.53 μM, 4.42 μM and 5.13 μM against cell lines SF-763, B16 and Hela, respectively. In the preliminary mechanism study, 12a caused cell arrest in G1 phase and significantly induced apoptosis of B16 cells in a dose-dependent manner. Furthermore, the in vivo antitumor activity of 12a was validated (tumor inhibitory ratio of 55.6\% and 62.7\%, respectively) in mice with H22 liver cancer and B16 melanoma.",

keywords = "23-Hydroxybetulinic acid, Antitumor activity, Apoptosis, Pyrazine, Triterpenoid",

author = "Hengyuan Zhang and Yiwei Wang and Peiqing Zhu and Jie Liu and Shengtao Xu and Hequan Yao and Jieyun Jiang and Wencai Ye and Xiaoming Wu and Jinyi Xu",

note = "Publisher Copyright: {\textcopyright} 2015 Elsevier Masson SAS.",

year = "2015",

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day = "5",

doi = "10.1016/j.ejmech.2015.04.057",

language = "English",

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AU - Zhang, Hengyuan

AU - Wang, Yiwei

AU - Zhu, Peiqing

AU - Liu, Jie

AU - Xu, Shengtao

AU - Yao, Hequan

AU - Jiang, Jieyun

AU - Ye, Wencai

AU - Wu, Xiaoming

AU - Xu, Jinyi

PY - 2015/6/5

Y1 - 2015/6/5

N2 - Pyrazine-fused 23-hydroxybetulinic acid was synthesized by introducing a pyrazine ring between C-2 and C-3 position and further modifications were carried out by substitution of C-28 carboxyl group by ester and amide linkage to enhance the antitumor activity. The biological screening results showed that all of the derivatives exhibited more significant antiproliferative activity than the parent compound. In particular compound 12a exhibited the most potent activity with IC50 values of 3.53 μM, 4.42 μM and 5.13 μM against cell lines SF-763, B16 and Hela, respectively. In the preliminary mechanism study, 12a caused cell arrest in G1 phase and significantly induced apoptosis of B16 cells in a dose-dependent manner. Furthermore, the in vivo antitumor activity of 12a was validated (tumor inhibitory ratio of 55.6% and 62.7%, respectively) in mice with H22 liver cancer and B16 melanoma.

AB - Pyrazine-fused 23-hydroxybetulinic acid was synthesized by introducing a pyrazine ring between C-2 and C-3 position and further modifications were carried out by substitution of C-28 carboxyl group by ester and amide linkage to enhance the antitumor activity. The biological screening results showed that all of the derivatives exhibited more significant antiproliferative activity than the parent compound. In particular compound 12a exhibited the most potent activity with IC50 values of 3.53 μM, 4.42 μM and 5.13 μM against cell lines SF-763, B16 and Hela, respectively. In the preliminary mechanism study, 12a caused cell arrest in G1 phase and significantly induced apoptosis of B16 cells in a dose-dependent manner. Furthermore, the in vivo antitumor activity of 12a was validated (tumor inhibitory ratio of 55.6% and 62.7%, respectively) in mice with H22 liver cancer and B16 melanoma.

KW - 23-Hydroxybetulinic acid

KW - Antitumor activity

KW - Apoptosis

KW - Pyrazine

KW - Triterpenoid

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SN - 0223-5234

VL - 97

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EP - 244

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

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ER -

Design, synthesis and antitumor activity of triterpenoid pyrazine derivatives from 23-hydroxybetulinic acid

Abstract

Bibliographical note

Funding

UN SDGs

Keywords

ASJC Scopus subject areas

Access to Document

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