Synthesis and in vitro antitumor evaluation of dihydroartemisinin-cinnamic acid ester derivatives

Xu, Cangcang; Deng, Ting; Fan, Menglin; Lv, Wen-Bo; Liu, Jihua; Yu, Boyang

doi:10.1016/j.ejmech.2015.11.003

Cited by 64 publications

(60 citation statements)

References 39 publications

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“…Compared to 1a (IC 50 < 25 μM), it was found that the methoxy substituent might enhance cytotoxicity selectivity of GA–CA hybrids towards tumor cell lines, such as 4a , 6a , 7a , 8a . This was in accordance with the previous study that dihydroartemisinin-cinnamic acid ester hybrids with methoxy moiety displayed highly selective cytotoxicity against the human lung carcinoma A549 cells, although it showed low cytotoxicity on non-tumor hepatic L-02 cells [21]. However, there might be less relationship between cytotoxicity and the quantity, position of methoxy moiety.…”

Section: Resultssupporting

confidence: 92%

“…The previous researches showed the introduction of ester-joined groups at 3-OH of GA could enhance the antitumor effect [16, 17]. Meanwhile, CA and its phenolic analogues were also employed as the active scaffold in the design of anti-tumor drugs for their potent cytotoxicity [13, 18–21]. Moreover, CA moiety could induce selective cytotoxicity in developing anti-tumor agents [21].…”

Section: Introductionmentioning

confidence: 99%

“…Meanwhile, CA and its phenolic analogues were also employed as the active scaffold in the design of anti-tumor drugs for their potent cytotoxicity [13, 18–21]. Moreover, CA moiety could induce selective cytotoxicity in developing anti-tumor agents [21]. To further improve the anti-tumor effect of GA and CA derivatives and find a series of efficient, low toxicity, multi-target GA–CA hybrids, we integrated the GA and CA derivatives fragments into one molecule via an ester bond based on structural combination principle.…”

Section: Introductionmentioning

confidence: 99%

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Design, synthesis, and biological evaluation of the novel glycyrrhetinic acid-cinnamoyl hybrids as anti-tumor agents

Guo

Yan

et al. 2016

Chemistry Central Journal

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BackgroundGlycyrrhetinic acid (GA) derivatives had shown not only cytotoxicity but also could trigger apoptosis in various human cancer cell lines. Moreover, cinnamic acid (CA) and its phenolic analogues as potent antitumor agents were employed in the design of anti-tumor drugs. To further improve the anti-tumor activity of GA and CA derivatives, a series of novel compounds were designed and synthesized using GA and CA derivatives fragments.ResultsThe result showed that all the novel glycyrrhetinic acid-cinnamoyl (GA–CA) hybrids presented higher antitumor activity on the tumor cell lines of HepG2, HT-29, Hela and lower cytotoxicity on three non-tumor cells lines MDCK, HY926, H9C2 than the parent compounds (IC50 > 50 μM). It was worth noting that 8a had a superior cytotoxicity effect on Hela cells (IC50 = 8.54 μM) than on other cancer cell lines (IC50 > 15 μM). And it also indicated that 8a showed lower cytotoxicity (IC50 > 27 μM) towards MDCK, HY926 and H9C2 cells than cisplatin (DDP, IC50 < 10 μM). Moreover, according to the acute toxicity, it could be indicated that the LD50 of 8a exceeded 3.0 g/kg by oral administration in mice. The further research using Giemsa, H33342 staining, flow cytometric analysis and caspase-3 assay showed that 8a could cause Hela cell damage, nuclei lysis and apoptosis. In addition, the structure–activity relationships of these hybrids were briefly discussed.ConclusionsCompared with GA, target compounds demonstrated better anti-tumor activity, among which 8a was the most active one. What’s more, structure–activity relationship analysis also revealed that hybrids with trans olefinic bond group show higher antitumor activity than those without olefinic bond, such as 1a > 1b, 6a > 2b, 8a > 3b, 9a > 4b. In addition, it was found that the methoxy substituent might enhance selectivity of GA–CA hybrids towards regular non-cancerous cells MDCK, HY926 and H9C2, such as 4a, 6a, 7a, 8a. However, there might be less relationship between the cytotoxicity and the quantity, position of methoxy moiety. Hence, it is urgent need to synthesize efficient, low toxicity and multi-target anti-tumor compounds based on the structure combination principle.

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Section: Resultssupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Design, synthesis, and biological evaluation of the novel glycyrrhetinic acid-cinnamoyl hybrids as anti-tumor agents

Guo

Yan

et al. 2016

Chemistry Central Journal

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“…Ester S5, which was the structure of dihydroartemisinin esterified with TMCA, exhibited significant antitumor activity ( Fig. 6) [40], with The IC 50 values of ester S5 against cell lines: PC-3, SGC-7901, A549 and MDA-MB-435s were 17.22, 11.82, 0.50 and 5.33 mM, respectively. The cytotoxicities of ester S5 on normal hepatic L-02 cells was weak (IC 50 : 58.65 mM).…”

Section: Synthetic Tmca Esters As Antitumor Agentsmentioning

confidence: 99%

Research progress in the biological activities of 3,4,5-trimethoxycinnamic acid (TMCA) derivatives

Zhao

Song

Xie

et al. 2019

European Journal of Medicinal Chemistry

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a b s t r a c t TMCA (3,4,5-trimethoxycinnamic acid) ester and amide are privileged structural scaffolds in drug discovery which are widely distributed in natural products and consequently produced diverse therapeutically relevant pharmacological functions. Owing to the potential of TMCA ester and amide analogues as therapeutic agents, researches on chemical syntheses and modifications have been carried out to druglike candidates with broad range of medicinal properties such as antitumor, antiviral, CNS (central nervous system) agents, antimicrobial, anti-inflammatory and hematologic agents for a long time. At the same time, SAR (structure-activity relationship) studies have draw greater attention among medicinal chemists, and many of the lead compounds were derived for various disease targets. However, there is an urgent need for the medicinal chemists to further exploit the precursor in developing chemical entities with promising bioactivity and druggability. This review concisely summarizes the synthesis and biological activity for TMCA ester and amide analogues. It also comprehensively reveals the relationship of significant biological activities along with SAR studies.

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“…In recent years, a great many of attempts were made to exploit natural products as starting points for pharmaceutical industry's drug discovery [1,2]. Tetrandrine (Tet), a bisbenzylisoquinoline alkaloid isolated from the Chinese herb Stephania Tetrandra S. Moore, has been reported to comprise many pharmacological effects, including antihypertensive, heart-protective, anti-inflammation, and anti-silicosis [3].…”

Section: Introductionmentioning

confidence: 99%

Design and synthesis of new tetrandrine derivatives and their antitumor activities

Xiao

Yang

et al. 2016

Journal of Asian Natural Products Research

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A series of tetrandrine derivatives were designed and synthesized using Suzuki coupling reaction. Eleven targeted compounds with over 50% inhibition against HL60 and A549 human cancer cell lines at 10 μM were further evaluated for the in vitro antitumor activities by MTT or SRB assay. The biological results revealed that some compounds exhibited potent antitumor activities. Thiophene derivative 6 and acetylphenyl derivative 5 were the most active ones against HL60 and A549 cell lines, with IC50 values less than 5 μM, which thus could be considered as useful candidate for further development of new antitumor agents.

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Synthesis and in vitro antitumor evaluation of dihydroartemisinin-cinnamic acid ester derivatives

Cited by 64 publications

References 39 publications

Design, synthesis, and biological evaluation of the novel glycyrrhetinic acid-cinnamoyl hybrids as anti-tumor agents

Design, synthesis, and biological evaluation of the novel glycyrrhetinic acid-cinnamoyl hybrids as anti-tumor agents

Research progress in the biological activities of 3,4,5-trimethoxycinnamic acid (TMCA) derivatives

Design and synthesis of new tetrandrine derivatives and their antitumor activities

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