Synthesis of heterocycle-modified betulinic acid derivatives as antitumor agents

Cui, Hai-Wei; He, Yonghong; Wang, Jinhua; Gao, Wei; Liu, Ting; Qin, Min; Wang, Xue; Gao, Cheng; Wang, Yan; Liu, Mingyao; Yi, Zhengfang; Qiu, Wen‐Wei

doi:10.1016/j.ejmech.2015.03.048

Cited by 38 publications

(14 citation statements)

References 28 publications

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“…They attracted the attention of scholars due to their enormous chemopreventive and antineoplastic potential [ 7 , 8 ]. In view of this, the structural modification of pentacyclic triterpenoids is always a focus in drug research [ 9 , 10 , 11 ]. Hederagenin ( He , 3b,23-dihydroxyurs-12-ene-28-oic acid; Figure 1 ) is a member of the pentacyclic triterpenoid family, which is extracted mainly from the medicinal plant ivy ( Hedera helix L.) and Dipsacus asper [ 12 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

“…Therefore, there is a great interest in the synthesis and evaluation of novel He derivatives in order to develop more potential antitumor drugs. Pyrazine is an N -heteroaromatic ring, and the incorporation of N -heteroaromatic rings into organic molecules could improve their antitumor activity and aqueous solubility [ 10 , 22 , 23 ]. Our research group proved that the introduction of ligustrazine to betulinic acid, ursolic acid, glycyrrhetinic acid, and oleanolic acid could significantly improve their antitumor effects in vitro [ 24 , 25 ].…”

Section: Introductionmentioning

confidence: 99%

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Design, Synthesis, and Cytotoxic Analysis of Novel Hederagenin–Pyrazine Derivatives Based on Partial Least Squares Discriminant Analysis

Fang

Zhang

Han

et al. 2018

IJMS

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Hederagenin (He) is a novel triterpene template for the development of new antitumor compounds. In this study, 26 new He–pyrazine derivatives were synthetized in an attempt to develop potent antitumor agents; they were screened for in vitro cytotoxicity against tumor and non-tumor cell lines. The majority of these derivatives showed much stronger cytotoxic activity than He. Remarkably, the most potent was compound 9 (half maximal inhibitory concentration (IC50) was 3.45 ± 0.59 μM), which exhibited similar antitumor activities against A549 (human non-small-cell lung cancer) as the positive drug cisplatin (DDP; IC50 was 3.85 ± 0.63 μM), while it showed lower cytotoxicity on H9c2 (murine heart myoblast; IC50 was 16.69 ± 0.12 μM) cell lines. Compound 9 could induce the early apoptosis and evoke cell-cycle arrest at the synthesis (S) phase of A549 cells. Impressively, we innovatively introduced the method of cluster analysis modeled as partial least squares discriminant analysis (PLS-DA) into the structure–activity relationship (SAR) evaluation, and SAR confirmed that pyrazine had a profound effect on the antitumor activity of He. The present studies highlight the importance of pyrazine derivatives of He in the discovery and development of novel antitumor agents.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and Cytotoxic Analysis of Novel Hederagenin–Pyrazine Derivatives Based on Partial Least Squares Discriminant Analysis

Fang

Zhang

Han

et al. 2018

IJMS

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“…A different methodology was employed to prepare BA-based amide derivatives at C-3 [31]. The key intermediate 32 , a BA-based primary amine, was obtained in very good yield (82%) by Borch reduction of BoA 3 with sodium cyanoborohydride and ammonium acetate in methanol (Scheme 8).…”

Section: Simple Transformationsmentioning

confidence: 99%

Recent Developments in the Functionalization of Betulinic Acid and Its Natural Analogues: A Route to New Bioactive Compounds

et al. 2019

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Betulinic acid (BA) and its natural analogues betulin (BN), betulonic (BoA), and 23-hydroxybetulinic (HBA) acids are lupane-type pentacyclic triterpenoids. They are present in many plants and display important biological activities. This review focuses on the chemical transformations used to functionalize BA/BN/BoA/HBA in order to obtain new derivatives with improved biological activity, covering the period since 2013 to 2018. It is divided by the main chemical transformations reported in the literature, including amination, esterification, alkylation, sulfonation, copper(I)-catalyzed alkyne-azide cycloaddition, palladium-catalyzed cross-coupling, hydroxylation, and aldol condensation reactions. In addition, the synthesis of heterocycle-fused BA/HBA derivatives and polymer‒BA conjugates are also addressed. The new derivatives are mainly used as antitumor agents, but there are other biological applications such as antimalarial activity, drug delivery, bioimaging, among others.

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“…CPT has been used clinically for treating ovarian and small lung cancers [ 5 ] and has also exhibited potential anti-viral (HIV and herpes), anti-psoriatic, and anti-fungal activities [ 6 ]. Betulinic acid (3β-hydroxy-lup-20(29)-en-28-oic acid, BA, Figure 1 ), a natural pentacyclic triterpene also widely distributed in Camptotheca acuminata Decne., has antitumor, anti-HIV, anti-inflammatory, and antibacterial activities [ 7 , 8 , 9 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

Ultrasonic Assisted-Reflux Synergistic Extraction of Camptothecin and Betulinic Acid from Camptotheca acuminata Decne. Fruits

Zhang

Zhao

et al. 2017

Molecules

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A novel and efficient ultrasonic assisted-reflux synergistic extraction (UARSE) method for extracting camptothecin (CPT) and betulinic acid (BA) from Camptotheca acuminata Decne. fruits has been developed in this study. The advantages of the ultrasonic and reflux extraction methods have been combined in the UARSE method and used to extract CPT and BA for the first time. The parameters influencing the efficiency of UARSE were optimized using the Box-Behnken design (BBD) to obtain the maximum extraction yield of CPT and BA. The optimal extraction conditions were as follows: 225 W for the ultrasonic power; 24 min for the extraction time; and 32 mL/g for the liquid–solid ratio. The extraction yields obtained by UARSE were 2.386 ± 0.112 mg/g for CPT and 17.192 ± 0.808 mg/g for BA, which were 1.43-fold and 1.33-fold, respectively, higher than by using heating reflux extraction (HRE) and ultrasonic-assisted extraction (UAE). In addition, the 24-min extraction time using UARSE was 80% and 60% less than those provided by HRE and UAE, respectively. Therefore, UARSE can be considered a rapid and efficient method for extracting CPT and BA from the fruits of C. acuminata Decne.

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Synthesis of heterocycle-modified betulinic acid derivatives as antitumor agents

Cited by 38 publications

References 28 publications

Design, Synthesis, and Cytotoxic Analysis of Novel Hederagenin–Pyrazine Derivatives Based on Partial Least Squares Discriminant Analysis

Design, Synthesis, and Cytotoxic Analysis of Novel Hederagenin–Pyrazine Derivatives Based on Partial Least Squares Discriminant Analysis

Recent Developments in the Functionalization of Betulinic Acid and Its Natural Analogues: A Route to New Bioactive Compounds

Ultrasonic Assisted-Reflux Synergistic Extraction of Camptothecin and Betulinic Acid from Camptotheca acuminata Decne. Fruits

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