Novel spirobicyclic artemisinin analogues (artemalogues): Synthesis and antitumor activities

Liu, Gang; Song, Shanshan; Shu, Shiqi; Zhang, Ao; Ding, Chunyong

doi:10.1016/j.ejmech.2015.08.035

Cited by 26 publications

(13 citation statements)

References 22 publications

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“…Since the α-methylene-γ-lactone moiety in the STLs skeleton is one of major active sites, modifications of this moiety were being conducted 18 , 30 , 36 . It was reported that natural products bearing spirobicyclic moiety usually exhibited high biological activity 17 , 37 – 40 , such as inducing autophagy activity by clionamine D 40 . In order to discover interesting spiro compounds of STLs, a spirobislactone skeleton was conducted through a radical [3 + 2] cycloaddition reaction.…”

Section: Resultsmentioning

confidence: 99%

Diversity Modification and Structure-Activity Relationships of Two Natural Products 1β-hydroxy Alantolactone and Ivangustin as Potent Cytotoxic Agents

Tang

Dong

et al. 2018

Sci Rep

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Sesquiterpene lactones (STLs) are a class of plant secondary metabolites widely found in nature with potent antitumor activities. In this work, two isolated STLs 1β-hydroxy alantolactone (1) and ivangustin (2) were derivatized through diversity-oriented strategy, and in vitro cytotoxic activity assessments were conducted against six cell lines including HeLa, PC-3, HEp-2, HepG2, CHO and HUVEC. The cytotoxic structure-activity relationship showed that the double bond between C5 and C6 was beneficial to improve activity; C1-OH oxidized derivatives showed a slight stronger activity, comparable to the positive drug etoposide (VP-16). Yet, C1-OH esterified derivatives decreased the potency which were different from those of 1-O-acetylbritannilactone (ABL) reported previously by us, and C13-methylene reductive and spiro derivatives resulted in almost complete ablation of cytotoxic activity. Mechanistic basis of cytotoxicity of the representative compound 1i was assayed to relate with apoptosis and cell cycle arrest. Furthermore, 1i inhibited TNF-α-induced canonical NF-κB signaling in PC-3 cells. Molecular modeling studies exhibited additional hydrogen bond interaction between 1i and the residue Lys37 of p65, indicating that 1i could form covalent protein adducts with Cys38 on p65.

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Section: Resultsmentioning

confidence: 99%

Diversity Modification and Structure-Activity Relationships of Two Natural Products 1β-hydroxy Alantolactone and Ivangustin as Potent Cytotoxic Agents

Tang

Dong

et al. 2018

Sci Rep

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“…Organic peroxides have wide-ranging biological activities, especially as antimalarial candidates (O'Neill et al, 2010), drugs with antitumour activity (Liu et al, 2015) and anticancer agents (Bu et al, 2017). They are also used as explosives (Klapö tke et al, 2015;Landenberger et al, 2015) and additives for diesel fuel to increase the cetane number (Rode et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Twist-chair conformation of the tetraoxepane ring remains unchanged in tetraoxaspirododecane diamines

et al. 2020

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A detailed structural analysis has been performed for N,N′‐bis(4‐chlorophenyl)‐7,8,11,12‐tetraoxaspiro[5.6]dodecane‐9,10‐diamine, C20H22Cl2N2O4, (I), N,N′‐bis(2‐fluorophenyl)‐7,8,11,12‐tetraoxaspiro[5.6]dodecane‐9,10‐diamine, C20H22F2N2O4, (II), and N,N′‐bis(4‐fluorophenyl)‐7,8,11,12‐tetraoxaspiro[5.6]dodecane‐9,10‐diamine, C20H22F2N2O4, (III). The seven‐membered ring with two peroxide groups adopts a twist‐chair conformation in all three compounds. The lengths of the C—N and O—O bonds are slightly shorter than the average statistical values found in the literature for azepanes and 1,2,4,5‐tetraoxepanes. The geometry analysis of compounds (I)–(III), the topological analysis of the electron density at the (3, −1) bond critical points within Bader's quantum theory of `Atoms in molecules' (QTAIM) and NBO (natural bond orbital) analysis at the B3LYP/6‐31G(d,2p) level of theory showed that there are nO→σ*(C—O), nN→σ*(C—O) and nO→σ*(C—N) stereoelectronic effects. The molecules of compounds (I) and (III) are packed in the crystals as zigzag chains due to strong N—H…O and C—H…O hydrogen‐bond interactions, whereas the molecules of compound (II) form chains in the crystals bound by N—H…O, C—H…π and C—H…O contacts. All these data show that halogen atoms and their positions have a minimal effect on the geometric parameters, stereoelectronic effects and crystal packing of compounds (I)–(III), so that the twist‐chair conformation of the tetraoxepane ring remains unchanged.

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“…In our ongoing efforts in exploring SARs in anti-inflammatory potency, we herein semisynthesized five derivatives ( 2 – 6 , Figure 2 ) including oxidized 2 and esterified 3 (with increased lipophilicity) and 4 (with increased hydrophilicity) at the C1-OH position, which reduced 5 and spiral 6 at the C13-methylene motif. Therein, specific spiro-cycle natural products have been reported as having potent biological activities [ 18 , 19 , 20 , 21 , 22 ], for example antitumor activities (artemalogues) [ 20 ] and induction of autophagy activity (clionamine D) [ 22 ]. Furthermore, their anti-inflammatory activities, including the inhibitory against lipopolysaccharide (LPS)-induced NO production and TNF-α-induced NF-κB signaling in RAW 264.7 macrophages were evaluated.…”

Section: Introductionmentioning

confidence: 99%

Semisynthesis, an Anti-Inflammatory Effect of Derivatives of 1β-Hydroxy Alantolactone from Inula britannica

et al. 2017

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1β-hydroxy alantolactone, a sesquiterpene lactone mainly isolated from Inula genus plants, exhibits potent anti-inflammatory and anticancer activities. In this work, 1β-hydroxy alantolactone was isolated and five derivatives were prepared through different reactions at the C1-OH and C13-methylene motifs. The structure–activity relationships (SAR) of anti-inflammatory effects against NO production in RAW264.7 cells showed that the α-methylene-γ-butyrolactone motif was essential for NO production suppression and that retaining the C1-OH group can remarkably improve this effect. The NF-κB signaling pathway plays a pivotal role in the regulation of NO expression. Moreover, the levels of p65 and p50 phosphorylation were investigated and active compound 1 inhibited phosphorylation of p65 and p50 in TNF-α-induced NF-κB signaling. Further molecular docking suggested that 1 may target the p65 of NF-κB.

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Novel spirobicyclic artemisinin analogues (artemalogues): Synthesis and antitumor activities

Cited by 26 publications

References 22 publications

Diversity Modification and Structure-Activity Relationships of Two Natural Products 1β-hydroxy Alantolactone and Ivangustin as Potent Cytotoxic Agents

Diversity Modification and Structure-Activity Relationships of Two Natural Products 1β-hydroxy Alantolactone and Ivangustin as Potent Cytotoxic Agents

Twist-chair conformation of the tetraoxepane ring remains unchanged in tetraoxaspirododecane diamines

Semisynthesis, an Anti-Inflammatory Effect of Derivatives of 1β-Hydroxy Alantolactone from Inula britannica

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