Betulinic Acid-Nitrogen Heterocyclic Derivatives: Design, Synthesis, and Antitumor Evaluation in Vitro.

Yuqin Yang,Yuhao Gu,Penglong Wang,Wen Li,Feng Gao,Jinchai Qi,Hongshan Chen,Nana Han,Su Huo,Xiaojing Liu,Ziqi Dai,Haimin Lei,Qianwen Wu,Xuehao Tian,Tianxin Xie

doi:10.3390/molecules25040948

Yuqin Yang, Yuhao Gu + Show 13 more

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https://doi.org/10.3390/molecules25040948

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Abstract

Betulinic acid (BA) is a star member of the pentacyclic triterpenoid family, which exhibits great prospects for antitumor drug development. In an attempt to develop novel antitumor candidates, 21 BA-nitrogen heterocyclic derivatives were synthetized, in addition to four intermediates, 23 of which were first reported. Moreover, they were screened for in-vitro cytotoxicity against four tumor cell lines (Hela, HepG-2, BGC-823 and SK-SY5Y) by a standard methylthiazol tetrazolium (MTT) assay. The majority of these derivatives showed much stronger cytotoxic activity than BA. Remarkably, the most potent compound 7e (the half maximal inhibitory concentration (IC50) of which was 2.05 ± 0.66 μM) was 12-fold more toxic in vitro than BA-treated Hela. Furthermore, multiple fluorescent staining techniques and flow cytometry collectively revealed that compound 7e could induce the early apoptosis of Hela cells. Structure–activity relationships were also briefly discussed. The present study highlighted the importance of introducing nitrogen heterocyclic rings into betulinic acid in the discovery and development of novel antitumor agents.

Highlights

Natural products play a major role in the antitumor drug discovery
The syntheses of 21 betulinic acid (BA)-nitrogen heterocyclic derivatives were shown in Scheme 1
We found that the structure modification site on BA showed showed a certain degree of regularity in their effect upon activity, the structural modification at a certain degree of regularity in their effect upon activity, the structural modification at positions C-3 positions C-3 and C-28 could improve antitumor biological activity in vitro, while the structural and C-28 could improve antitumor biological activity in vitro, while the structural transformation of transformation of C-28 might have more potential to enhance cytotoxicity on the same series of tumor

Summary

Introduction

Natural products play a major role in the antitumor drug discovery. Over 60% of antitumor drugs are developed from natural products [1]. Pentacyclic triterpenoids are a class of pharmacologically active and structurally rich natural products with privileged motifs for further modifications and structure–activity relationship analyses [2–5]. As a lupane-type pentacyclic triterpenoid, betulinic acid (3β-hydroxy-lup-20(29)-en-28-oic acid, BA, Figure 1) is widespread in many plants. BA’s continuous structural modification had been an extremely attractive hot topic worldwide. It consisted of a 30-carbon skeleton which could be modified at three positions, the secondary hydroxyl group (C-3), the hydroxyl group (C-28) and at the alkene moiety (C-20), respectively. 20, 29-dihydro betulinic acid derivatives were synthesized with IC50 less than 0.4 μg/mL [14]

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